O.J. Watson et al.

Global impact of the first year of COVID-19 vaccinationa mathematically modelling study

The Lancet Infectious Diseases, June 2022; doi.org/10.1016/S1473-3099(22)00320-6

Abstract

Background

The first COVID-19 vaccine outside a clinical trial setting was administered on Dec 8, 2020. To ensure global vaccine equity, vaccine targets were set by the COVID-19 Vaccines Global Access (COVAX) Facility and WHO. However, due to vaccine shortfalls, these targets were not achieved by the end of 2021. We aimed to quantify the global impact of the first year of COVID-19 vaccination programmes.

Methods

A mathematical model of COVID-19 transmission and vaccination was separately fit to reported COVID-19 mortality and all-cause excess mortality in 185 countries and territories. The impact of COVID-19 vaccination programmes was determined by estimating the additional lives lost if no vaccines had been distributed. We also estimated the additional deaths that would have been averted had the vaccination coverage targets of 20% set by COVAX and 40% set by WHO been achieved by the end of 2021.

Findings

Based on official reported COVID-19 deaths, we estimated that vaccinations prevented 14·4 million (95% credible interval [Crl] 13·7–15·9) deaths from COVID-19 in 185 countries and territories between Dec 8, 2020, and Dec 8, 2021. This estimate rose to 19·8 million (95% Crl 19·1–20·4) deaths from COVID-19 averted when we used excess deaths as an estimate of the true extent of the pandemic, representing a global reduction of 63% in total deaths (19·8 million of 31·4 million) during the first year of COVID-19 vaccination. In COVAX Advance Market Commitment countries, we estimated that 41% of excess mortality (7·4 million [95% Crl 6·8–7·7] of 17·9 million deaths) was averted. In low-income countries, we estimated that an additional 45% (95% CrI 42–49) of deaths could have been averted had the 20% vaccination coverage target set by COVAX been met by each country, and that an additional 111% (105–118) of deaths could have been averted had the 40% target set by WHO been met by each country by the end of 2021.

Interpretation

COVID-19 vaccination has substantially altered the course of the pandemic, saving tens of millions of lives globally. However, inadequate access to vaccines in low-income countries has limited the impact in these settings, reinforcing the need for global vaccine equity and coverage.

U. Storz

The COVID-19 vaccine patent race

Nature Biotechnology, July 2022; doi.org/10.1038/s41587-022-01376-1

Abstract

COVID-19 has kept the world in its grip for two years and counting. The unfolding of the pandemic came with some remarkable — and in part concerning — developments, including the speed with which the SARS-CoV-2 virus spread across the globe, the rapid development and approval of vaccines, the unexpected vaccine skepticism, and finally the inequitable distribution of the vaccines in different regions of the world.

COVID-19 is also historic in terms of its patent background. Several aspects regarding the patent protection of COVID-19 vaccines have been discussed, including disputes over patent ownership and the role of patents in limiting vaccine access to developing countries1,2. Here, we discuss the development of mRNA vaccine technology, the race to the vaccine and the issues surrounding securing patent rights.

C.J. Reynolds et al .

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

Science, June 2022; doi: 10.1126/science.abq1841

Abstract

The Omicron, or Pango lineage B.1.1.529, variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection against severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple BioNTech BNT162b2 messenger RNA–vaccinated health care workers (HCWs) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple-vaccinated individuals, but the magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCWs who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.

M. Dennis

Pfizer, BioNTech's Omicron-adapted COVID-19 candidate vaccines show promise

First Word Pharma, June 2022; https://firstwordpharma.com/story/5602941

Abstract

Pfizer and BioNTech announced that booster doses of two different Omicron-adapted COVID-19 vaccine candidates elicited a substantially higher immune response against Omicron BA.1 than the companies' current mRNA-based shot Comirnaty. Pfizer CEO Albert Bourla said "based on these data, we believe we have two very strong Omicron-adapted candidates."

The vaccine candidates tested in the Phase II/III trial include an Omicron-adapted monovalent immunisation and a bivalent shot, which combines Comirnaty with a vaccine candidate targeting the spike protein of the Omicron BA.1 variant of concern. The study included 1234 participants aged 56 years and older who received a fourth booster dose with either the monovalent or bivalent vaccine candidate at a dose of 30µg or 60µg.

Adams et al.

Vaccine Effectiveness of Primary Series and Booster Doses against Omicron Variant COVID-19-Associated Hospitalization in the United States

medRxiv, June 2022; doi.org/10.1101/2022.06.09.22276228

Abstract

Objectives: To compare the effectiveness of a primary COVID-19 vaccine series plus a booster dose with a primary series alone for the prevention of Omicron variant COVID-19 hospitalization.

Design: Multicenter observational case-control study using the test-negative design to evaluate vaccine effectiveness (VE).

Setting: Twenty-one hospitals in the United States (US).

Participants: 3,181 adults hospitalized with an acute respiratory illness between December 26, 2021 and April 30, 2022, a period of SARS-CoV-2 Omicron variant (BA.1, BA.2) predominance. Participants included 1,572 (49%) case-patients with laboratory confirmed COVID-19 and 1,609 (51%) control patients who tested negative for SARS-CoV-2. Median age was 64 years, 48% were female, and 21% were immunocompromised; 798 (25%) were vaccinated with a primary series plus booster, 1,326 (42%) were vaccinated with a primary series alone, and 1,057 (33%) were unvaccinated.

Main Outcome Measures: VE against COVID-19 hospitalization was calculated for a primary series plus a booster and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. VE analyses were stratified by immune status (immunocompetent; immunocompromised) because the recommended vaccine schedules are different for these groups. The primary analysis evaluated all COVID-19 vaccine types combined and secondary analyses evaluated specific vaccine products.

Results: Among immunocompetent patients, VE against Omicron COVID-19 hospitalization for a primary series plus one booster of any vaccine product dose was 77% (95% CI: 71–82%), and for a primary series alone was 44% (95% CI: 31–54%) (p<0.001). VE was higher for a boosted regimen than a primary series alone for both mRNA vaccines used in the US (BNT162b2: primary series plus booster VE 80% (95% CI: 73-85%), primary series alone VE 46% (95% CI: 30-58%) [p<0.001]; mRNA-1273: primary series plus booster VE 77% (95% CI: 67-83%), primary series alone VE 47% (95% CI: 30-60%) [p<0.001]). Among immunocompromised patients, VE for a primary series of any vaccine product against Omicron COVID-19 hospitalization was 60% (95% CI: 41-73%). Insufficient sample size has accumulated to calculate effectiveness of boosted regimens for immunocompromised patients.

Conclusions: Among immunocompetent people, a booster dose of COVID-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing COVID-19 hospitalization due to the Omicron variant.

Comunicato stampa, 17 Giugno 2022

Coronavirus (COVID-19) Update: FDA Authorizes Moderna and Pfizer-BioNTech COVID-19 Vaccines for Children Down to 6 Months of Age

https://www.fda.gov/news-events/press-announcements/coronaviruscovid-19-update-fda-authorizes-moderna-and-pfizer-biontech-covid-19-vaccines-children 11.

Abstract

Today, the U.S. Food and Drug Administration authorized emergency use of the Moderna COVID-19 Vaccine and the Pfizer-BioNTech COVID-19 Vaccine for the prevention of COVID-19 to include use in children down to 6 months of age. 

  • For the Moderna COVID-19 Vaccine, the FDA amended the emergency use authorization (EUA) to include use of the vaccine in individuals 6 months through 17 years of age. The vaccine had been authorized for use in adults 18 years of age and older.
  • For the Pfizer-BioNTech COVID-19 Vaccine, the FDA amended the EUA to include use of the vaccine in individuals 6 months through 4 years of age. The vaccine had been authorized for use in individuals 5 years of age and older. 

K. Mohan Vadrevu et al.

Immunogenicity and reactogenicity of an inactivated SARS-CoV-2 vaccine (BBV152) in children aged 2–18 years: interim data from an open-label, non-randomised, age deescalation phase 2/3 study

Lancet; June 2022; doi.org/10.1016/ S1473-3099(22)00307-3

Abstract

Background Despite having milder symptoms than adults, children are still susceptible to and can transmit SARSCoV-2. Vaccination across all age groups is therefore necessary to curtail the pandemic. Among the available COVID-19 vaccine platforms, an inactivated vaccine platform has the advantage of excellent safety profile across all age groups; hence, we conducted an age de-escalation study to assess the safety, reactogenicity, and immunogenicity of an inactivated COVID-19 vaccine, BBV152 (COVAXIN; Bharat Biotech International, Hyderabad, India), in children aged 2–18 years.

Methods In this phase 2/3 open-label, non-randomised, multicentre study done in six hospitals in India, healthy children (male or female) aged 2–18 years were eligible for inclusion into the study. Children who had positive SARSCoV-2 nucleic acid and serology tests at baseline, or any history of previous SARS-CoV-2 infection, or with known immunosuppressive condition were excluded. Children were sequentially enrolled into one of three groups (>12 to ≤18 years [group 1], >6 to 12 years [group 2], or ≥2 to 6 years [group 3]) and administered with adult formulation of BBV152 as two 0·5 mL intramuscular doses on days 0 and 28. Co-primary endpoints were solicited adverse events for 7 days post-vaccination and neutralising antibody titres on day 56, 28 days after the second dose. Immunogenicity endpoints were compared with Biodefense and Emerging Infections, Research Resources Repository (BEI) reference serum samples and from adults who received two doses of BBV152 in the same schedule in a previously reported phase 2 study. The trial is registered with the Clinical Trials Registry, India (CTRI/2021/05/033752) and ClinicalTrials. gov (NCT04918797).

Findings From May 27, 2021, to July 10, 2021, we enrolled 526 children sequentially into groups 1 (n=176), 2 (n=175), and 3 (n=175). Vaccination was well tolerated, with no differences in reactogenicity between the three age groups, and no serious adverse events, deaths, or withdrawals due to an adverse event. Local reactions mainly consisted of mild injection site pain in 46 (26%) of 176 participants in group 1, 61 (35%) of 175 in group 2, and 39 (22%) of 175 in group 3 after dose 1; and 39 (22%) of 176 in group 1, 43 of 175 (25%) in group 2, and 14 of 175 (8%) in group 3 after dose 2; there were no cases of severe pain and few reports of other local reactions. After dose 1, the most frequent solicited systemic adverse event was mild-to-moderate fever, reported in eight (5%) of 176 participants in group 1, 17 (10%) of 175 in group 2, and 22 (13%) of 175 in group 3. No case of severe fever was reported, and rates of all fever were all 4% or less after dose 2. Geometric mean titres (GMTs) of microneutralisation antibodies at day 56 in groups 1 (138·8 [95% CI 111·0–173·6]), 2 (137·4 [99·1–167·5]), and 3 (197·6 [176·4–221·4]) were similar to titres in vaccinated adults (160·1 [135·8–188·8]) and with BEI reference serum samples (103·3 [50·3–202·1]). Similar results were obtained using the plaque reduction neutralisation test (PRNT), in which 166 (95%) of 175 participants in group 1, 165 (98%) of 168 in group 2, and 169 (98%) of 172 in group 3 seroconverted at day 56. The GMT ratio of PRNT titres in children and adults was 1·76 (95% CI 1·32–2·33), indicating a superior response in children compared with adults.

Interpretation BBV152 was well tolerated in children aged 2–18 years, and induced higher neutralising antibody responses than those observed in adults, in whom the efficacy (ie, the prevention or decrease in the severity of COVID-19 infection) has been demonstrated.

R. Ochoa-Azze et al.

Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial

Lancet Respir. Med., June 2022; doi.org/10.1016/ S2213-2600(22)00100-X

Abstract

Background A phase 1, clinical trial to evaluate FINLAY-FR-1A vaccine in COVID-19 convalescent individuals was completed. Here, we report results of the phase 2, clinical trial.

Methods We studied 450 convalescent participants with a history of asymptomatic, mild, or moderate COVID-19 at the National Institute of Hematology and Immunology and the National Centre for Sexual Education in Havana, Cuba. The study included adults aged 19–78 years who had recovered from COVID-19 and had had a negative PCR test at least 2 months before the initiation of the study. Phase 2 was done sequentially in two stages. The first stage to assess safety comprised an open, non-controlled phase 2a study in participants aged 60–78 years who received a single dose of the FINLAY-FR-1A vaccine (50 µg of recombinant dimeric receptor binding domain [RBD]). The second stage comprised the placebo-controlled, double-blind, phase 2b trial in participants aged 19–78 years, where participants were randomly assigned (4:1) into two groups: an experimental group vaccinated with a single dose of the FINLAY-FR-1A vaccine, and a control (placebo) group injected with vaccine excipient. The primary outcomes were safety, evaluated 28 days after vaccination by the occurrence of serious adverse events in all participants, and successful immune response, assessed by neutralising antibody ELISA, and defined as half-maximal surrogate virus neutralisation titres of 250 or more. Secondary endpoints included vaccine immunogenicity assessed by ELISA anti-RBD and live-virus neutralisation test.All randomly assigned participants were included in the safety analysis (safety population), and immunogenicity was evaluated in participants without study interruptions (per-protocol population). The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000366-En and WHO-ICTRP and is complete.

Findings From April 9, 2021, to April 17, 2021, 663 COVID-19 convalescent participants were enrolled in the study; 213 participants did not meet the selection criteria and 450 volunteers were recruited. 20 participants aged 60–78 years were included in the open, single-group, phase 2a study and 430 participants were randomly assigned to the experimental (n=344) or control groups (n=86) in the phase 2b study of participants aged 19–78 years. 19 (95%) of 20 phase 2a volunteers achieved a successful immune response after vaccination. No vaccine-associated serious adverse events were reported in the whole study population. Minor adverse events were found, the most common being pain at the injection site (105 [29%] of 364 in the intervention group; 13 [15%] of 86 in the placebo group). A successful immune response was found in 289 (81%) of 358 participants 28 days after vaccination. The vaccine elicited a greater than 31-times increase in anti-RBD-IgG antibodies compared with prevaccination rates, and the seroconversion rate was 302 (84%) of 358 on day 28 after vaccination; the geometric mean titres of live-virus neutralisation test increased from 15·4 (95% CI 10·3–23·2) to 400·3 (272·4–588·1) and high response was found against alpha, beta, and delta variants of concern.

Interpretation A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 strengthened the pre-existing natural immunity, with excellent safety profile.

R. Vikkurthi et al.

Inactivated whole-virion vaccine BBV152/Covaxin elicits robust cellular immune memory to SARS-CoV-2 and variants of concern

Nature Microbiology, June 2022; doi.org/10.1038/s41564-022-01161-5

Abstract

BBV152 is a whole-virion inactivated vaccine based on the Asp614Gly variant. BBV152 is the first alum-imidazoquinolin-adjuvanted vaccine authorized for use in large populations. Here we characterized the magnitude, quality and persistence of cellular and humoral memory responses up to 6 months post vaccination. We report that the magnitude of vaccine-induced spike and nucleoprotein antibodies was comparable with that produced after infection. Receptor binding domain-specific antibodies declined against variants in the order of Alpha (B.1.1.7; 3-fold), Delta (B.1.617.2; 7-fold) and Beta (B.1.351; 10-fold). However, pseudovirus neutralizing antibodies declined up to 2-fold against the Delta followed by the Beta variant (1.7-fold). Vaccine-induced memory B cells were also affected by the Delta and Beta variants. The SARS-CoV-2-specific multicytokine-expressing CD4+ T cells were found in ~85% of vaccinated individuals. Only a ~1.3-fold reduction in efficacy was observed in CD4+ T cells against the Beta variant. We found that antigen-specific CD4+ T cells were present in the central memory compartment and persisted for at least up to 6 months post vaccination. Vaccine-induced CD8+ T cells were detected in ~50% of individuals. Importantly, the vaccine was capable of inducing follicular T helper cells that exhibited B-cell help potential. These findings show that inactivated vaccine BBV152 induces robust immune memory to SARS-CoV-2 and variants of concern that persists for at least 6 months after vaccination.

S. Monge et al.

Effectiveness of mRNA vaccine boosters against infection with the SARS-CoV-2 omicron (B.1.1.529) variant in Spain: a nationwide cohort study

The Lancet, June 2022; doi.org/10.1016/ S1473-3099(22)00292-4

Abstract

Background     The omicron (B.1.1.529) variant of SARS-CoV-2 has increased capacity to elude immunity and cause breakthrough infections. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters (third dose) against infection with the omicron variant by age, sex, time since complete vaccination, type of primary vaccine, and type of booster.

Methods     In this nationwide cohort study, we linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) to select community-dwelling individuals aged 40 years or older, who completed their primary vaccine schedule at least 3 months before the start of follow-up, and had not tested positive for SARS-CoV-2 since the start of the pandemic. On each day between Jan 3, and Feb 6, 2022, we matched individuals who received a booster mRNA vaccine and controls of the same sex, age group, postal code, type of vaccine, time since primary vaccination, and number of previous tests. We estimated risk of laboratory-confirmed SARS-CoV-2 infection using the Kaplan-Meier method and compared groups using risk ratios (RR) and risk differences. Vaccine effectiveness was calculated as one minus RR. Findings Between Jan 3, and Feb 6, 2022, 3 111 159 matched pairs were included in our study. Overall, the estimated effectiveness from day 7 to 34 after a booster was 51·3% (95% CI 50·2–52·4). Estimated effectiveness was 52·5% (51·3–53·7) for an mRNA-1273 booster and 46·2% (43·5–48·7) for a BNT162b2 booster. Effectiveness was 58·6% (55·5–61·6) if primary vaccination had been with ChAdOx1 nCoV-19 (Oxford–AstraZeneca), 55·3% (52·3–58·2) with mRNA-1273 (Moderna), 49·7% (48·3–51·1) with BNT162b2 (Pfizer–BioNTech), and 48·0% (42·5–53·7) with Ad26.COV2.S (Janssen). Estimated effectiveness was 43·6% (40·0–47·1) when the booster was administered between 151 days and 180 days after complete vaccination and 52·2% (51·0–53·3) if administered more than 180 days after primary scheduled completion.

Interpretation     Booster mRNA vaccine-doses were moderately effective in preventing infection with the omicron variant of SARS-CoV-2 for over a month after administration, which indicates their suitability as a strategy to limit the health effects of COVID-19 in periods of omicron variant domination. Estimated effectiveness was higher for mRNA-1273 compared with BNT162b2 and increased with time between completed primary vaccination and booster.

Moderna

Moderna announces Omicron-containing bivalent booster candidate mRNA-1273.214 demonstrates superior antibody response against Omicron

June 2022; https://investors.modernatx.com/news/news-details/2022/Moderna-Announces-Omicron-Containing-Bivalent-Booster-Candidate-mRNA-1273.214-Demonstrates-Superior-Antibody-Response-Against-Omicron/default.aspx

Moderna, Inc., (NASDAQ:MRNA) a biotechnology company pioneering messenger RNA (mRNA)therapeutics and vaccines, announced new clinical data on its Omicron-containing bivalent COVID boostercandidate, mRNA-1273.214, containing mRNA-1273 (Spikevax) and a vaccine candidate targeting theOmicron variant of concern. A 50 µg booster dose of mRNA-1273.214 met all pre-specified endpoints including superior neutralizing antibody response (geometric mean ratio) against the Omicron variant one month after administration when compared to the original mRNA-1273 vaccine.The booster dose of mRNA-1273.214 was generally well-tolerated, with side effects comparable to a booster dose of mRNA-1273 at the 50 µg dose level.

M. Patel

Increasing children's global access to COVID-19 vaccines

The Lancet, June 2022; Vol 399, pp 2171-2173

Abstract

Expanding COVID-19 vaccination to children is an issue for parents and decision makers worldwide. Among nine vaccines with WHO Emergency Use Listing (EUL), only two are authorised for children: Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273. The WHO EUL is required for vaccines purchased through the COVAX mechanism, but other vaccines without EUL for paediatric use, such as BBIBP-CorV (SinoPharm), CoronaVac (SinoVac), and Covaxin (Bharat Biotech), are used in children with local approvals. Because of lower rates of severe COVID-19 in children than in older adults, and inequities in vaccine supply, the WHO SAGE Roadmap for prioritising the use of COVID-19 vaccines classifies children as a lower priority group. However, a COVID-19 risk in children does exist. Complications in children with COVID-19 have included respiratory failure, neurological involvement, cardiovascular dysfunction, multisystem inflammatory syndrome, and long COVID.

C. Buddy Creech et al.

Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age

New England Journal of Medicine, May 2022; doi: 10.1056/NEJMoa2203315

Abstract

BACKGROUND

Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown.

METHODS

Part 1 of this ongoing phase 2–3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported.

RESULTS

In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant.

CONCLUSIONS

Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults.

Grace Li et al

Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in children aged 12-17 years: a preliminary report of a phase 2, single-blind, randomised controlled trial (COV006)

The Lancet, June 2022;  doi: 10.1016/S0140-6736(22)00770-X.

Abstract

Background: Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults.

Methods: COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6-17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12-17 years were enrolled before those aged 6-11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12-17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344).

Findings: Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12-17 years and 112 [43%] aged 6-11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6-11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12-17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685-91 733] and 299 half-maximal inhibitory concentration [IC50; 95% CI 230-390]) compared with those aged 12-17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852-52 246] and 150 IC50 [95% CI 116-194]). Humoral responses were higher in those aged 6-11 years than in those aged 12-17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07-2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89-4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination.

Interpretation: ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6-17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial.

J. Weitzer et al.

Willingness to receive an annual COVID-19 booster vaccine in the German-speaking D-A-CH region in Europe: A cross-sectional study

The Lancet Regional Health – Europe, June 2022;  doi.org/10.1016/j.lanepe.2022.100414

Abstract

Background Emergence of new coronavirus variants and waning immunity may necessitate regular COVID-19 vaccine boosters, but empirical data on population willingness for regular vaccination are limited.

Methods In August 2021, we surveyed 3,067 quota-sampled German-speaking adults residing in the D-A-CH region (Germany, Austria, Switzerland). Using multivariable adjusted ordered logistic regression models we calculated odds ratios (OR) and 95% confidence intervals (95% CIs) to assess factors associated with willingness to vaccinate annually against COVID-19.

Findings Among 2,480 participants vaccinated or planning to get vaccinated, 82·4% indicated willingness to receive annual COVID-19 boosters. This willingness was higher in Austria (OR=1·47, 95% CI, 1·19–1·82; p < 0·001) and Germany (OR=1·98, 95% CI, 1·60–2·45; p < 0·001) versus Switzerland and increased with age. Having voted in the last national election (ORopposition party voters=1·51, 95% CI=1·18–1·92; p = 0·001 and ORgoverning party voters=1·57, 95% CI=1·28–1·93; p < 0·001, versus non-voters) and not regularly participating in religious meetings (OR=1·37, 95% CI=1·08–1·73; p = 0·009, versus participation at least monthly) were significantly associated with willingness to vaccinate, as was partial (OR=1·97, 95% CI=1·43–2·72; p < 0·001) or total (OR=5·20, 95% CI=3·76–7·19; p < 0·001) approval of COVID-19 mitigation measures (versus non-approval). By country, Austrians showed the strongest association of voting behavior and mitigation measure approval with willingness to vaccinate.

Interpretation Targeted promotion programs informed by political and religious engagement and mitigation measure approval are needed to increase willingness to receive regular COVID-19 boosters.

G. Lorenzoni et al.

COVID-19 Vaccination Status Among Adults Admitted to Intensive Care Units in Veneto, Italy

Jama, May 2022; doi:10.1001/jamanetworkopen.2022.13553

Abstract

Effectiveness of vaccination to prevent severe COVID-19 requiring admission to the intensive care unit (ICU) has been reported to be approximately 90%. However, few data are available regarding duration of vaccination coverage to prevent ICU admission for severe COVID-19 and outcomes in patients who require ICU admission despite prior vaccination. This study aimed to provide a descriptive analysis of ICU admissions for severe COVID-19 after a vaccination campaign in the Veneto region of Italy that started at the end of December 2020 and prioritized health care workers, older individuals, nursing home residents, and patients with severe comorbidities.

Methods

This cohort study included all consecutive patients aged 18 years or older admitted to the Veneto ICU Network from May to December 2021 for COVID-19–associated acute respiratory distress syndrome. The Institutional Ethical Committee of Padova University Hospital approved the study; informed consent was waived because of the observational design and retrospective analysis of data from an anonymous database. The study followed the STROBE guideline.

Vaccination status (vaccinated [≥2 doses], partially vaccinated [1 dose], or not vaccinated), date of vaccine administration, age, hospital and ICU admission date, and ICU outcome (death or discharge) were collected for each patient. Data were analyzed using R, version 4.1.0, and 2-sided P < .05 was significant. A full description of statistical methods is available in the eMethods in Supplement 1.

Results

A total of 748 patients were admitted to ICUs of the Veneto ICU Network during the study period (mean [SD] age, 62 [14] years); 138 (18%) were vaccinated, 58 (8%) were partially vaccinated, and 552 (74%) were not vaccinated. Vaccinated patients were more often older than 80 years (29 [21%]) compared with partially vaccinated patients (3 [5%]) and nonvaccinated patients (19 [3%]) (P < .001) (Table). Median time from vaccine administration to ICU admission for partially vaccinated patients was 22.5 days (IQR, 16.0-49.8 days) and for vaccinated patients, 159.0 days (IQR, 112.0-192.0 days).

The Figure shows ICU admissions per million inhabitants during the study period. A statistically significant increasing trend was detected for ICU admissions among nonvaccinated patients. Conversely, the trend remained stable for vaccinated patients. Overall, 145 patients died in the ICU: 93 nonvaccinated (17%; 95% CI, 14%-20%), 19 partially vaccinated (33%; 95% CI, 21%-46%), and 33 vaccinated (24%; 95% CI, 17%-32%) patients.

Discussion

The study data revealed that vaccinated patients received the second dose of vaccine a median of 5 months before admission to the ICU, whereas for partially vaccinated patients, the median ICU admission time occurred while they awaited the second dose. A statistically significant increase in ICU admissions was observed only for nonvaccinated patients. The data suggest that mortality was higher among vaccinated patients than among nonvaccinated patients, and the proportion of patients older than 80 years was greater among vaccinated patients than among partially vaccinated and nonvaccinated patients. The data are consistent with recent work showing that among 1585 ICU patients, only 7% were vaccinated and hospital mortality was higher among vaccinated individuals than among nonvaccinated individuals.4

This study has limitations. Patients could not be characterized according to clinical characteristics and type of vaccine administered because this information was not available. Furthermore, confounding by indication may be problematic given that the priority schemes used in vaccination programs were often determined by health outcomes among nonvaccinated patients. The study’s findings suggest that vaccination was associated with fewer ICU admissions and that a COVID-19 booster campaign5 and a fourth dose of mRNA vaccine may be warranted, especially for older patients and individuals with comorbidities.

J.X. Li et al.

Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, openlab

The Lancet , May 2022;  doi.org/10.1016/ S2213-2600(22)00087-X

Abstract

Background Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine.

Methods We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine—Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0×10¹¹ viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0×10¹¹ viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259.

Findings Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (78·5 [60·5–101·7]; p<0·0001).

Interpretation We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination.

Lustig et al.

Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose

Nature immunology, May 2022; doi.org/10.1038/s41590-022-01212-3

Abstract

As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen decreases with time, a third dose has been recommended. Here, we assessed immunogenicity, vaccine effectiveness and safety of the third BNT162b2 vaccine dose in a prospective cohort study of 12,413 healthcare workers (HCWs). Anti-RBD immunoglobulin G (IgG) levels were increased 1.7-fold after a third dose compared with following the second dose. Increased avidity from 61.1% (95% confidence interval (CI), 56.1–66.7) to 96.3% (95% CI, 94.2–98.5) resulted in a 6.1-fold increase in neutralization titer. Peri-infection humoral markers of 13 third-dose Delta variant of concern (VOC) breakthrough cases were lower compared with 52 matched controls. Vaccine effectiveness of the third dose relative to two doses was 85.6% (95% CI, 79.2–90.1). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG antibodies and safely boosts protection from infection.

Islam et al.

Comparative effectiveness over time of themRNA-1273 (Moderna) vaccine and the BNT162b2 (Pfizer-BioNTech) vaccine

Nature communications, May 2022; doi.org/10.1038/s41467-022-30059-3

Abstract

Real-world analysis of the incidence of SARS-CoV-2 infection post vaccination is important in determining the comparative effectiveness of the available vaccines. In this retrospective cohort study using deidentified administrative claims for Medicare Advantage and commercially insured individuals in a research database we examine over 3.5 million fully vaccinated individuals, including 8,848 individuals with SARS-CoV-2 infection, with a follow-up period between 14 and 151 days after their second dose. Our primary outcome was the rate of Covid-19 infection occurring at 30, 60, and 90 days at least 14 days after the second dose of either the mRNA-1273 vaccine or the BNT162b2 vaccine. Sub-analyses included the incidence of hospitalization, ICU admission, and death/hospice transfer. Separate analysis was conducted for individuals above and below age 65 and those without a prior diagnosis of Covid-19. We show that immunization with mRNA-1273, compared to BNT162b2, provides slightly more protection against SARS-CoV-2 infection that reaches statistical significance at 90 days with a number needed to vaccinate of >290. There are no differences in vaccine effectiveness for protection against hospitalization, ICU admission, or death/hospice transfer (aOR 1.23, 95% CI (0.67, 2.25).

A.C. Garfinkel et al.

From Resentment to Reconnection — Reflections on Caring for the Unvaccinated

New England J Medicine, April 2022; doi: 10.1056/NEJMp2119720

Abstract

As cautious, fully vaccinated, but immunocompromised people die of Covid, a physician finds herself resenting the patients filling up the hospital after declining vaccination. Then an encounter with one very ill and frightened patient changes her perspective.

H.C. Meissner

Understanding Vaccine Safety and the Roles of the FDA and the CDC

New England J Medicine, April 2022;doi: 10.1056/NEJMra2200583

Abstract

Throughout human history, epidemics and pandemics have resulted in untold suffering, localized reductions in population size, and damaged economies. Often, economic harm has caused greater loss of wellbeing than the infection itself. Increasing population density and economic and social changes, such as population shifts and the requirement for increased food production, have resulted in human encroachment into less populated areas of the globe. These factors bring people into closer contact with wildlife and arthropod vectors, as well as livestock and poultry, which increases the risk that zoonotic pathogens will spill over to humans. In the past two decades, bats have been reservoirs of three betacoronaviruses that have crossed the species barrier, causing severe acute respiratory syndrome (SARS)–like disease in humans. Recent outbreaks caused by noncoronaviruses such as pandemic influenza A (H1N1), Ebola, and Zika viruses underscore the threat of future outbreaks (Table 1). In the decades ahead, diseases caused by currently unknown viruses are likely to emerge as changes in human behavior continue to increase exposure to infectious organisms in the environment. The development and widespread acceptance of vaccines will be crucial for controlling disease caused by pathogenic organisms, especially those that acquire the capability of efficient human-to-human transmission. As existing microbes evolve and new microbes emerge, nonpharmacologic interventions, including containment, isolation, and quarantine, will play a role in outbreak control, but vaccines will form the foundation for converting a viral pandemic into manageable endemic disease. Containment of past viral pandemics has been accomplished without vaccines, but minimizing the morbidity and mortality associated with future pandemics is likely to be difficult to achieve without high rates of vaccine acceptance, especially for viruses that use the respiratory tract as a portal of entry. A widespread understanding and acceptance of vaccines will be an integral aspect of public health strategies for limiting the consequences of future pandemics. This review discusses how vaccine safety and efficacy are evaluated, the pathways by which vaccines become authorized or licensed, and considerations addressed by advisory bodies in establishing vaccine recommendations.

O. Magen et al.

Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

New England J Medicine, 2022; doi: 10.1056/NEJMoa2201688

Abstract

Background

With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.

Methods

To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19–related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.

Results

The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction–confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19–related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19–related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19–related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.

Conclusions

A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19–related outcomes among persons who had received a third dose at least 4 months earlier.

J. Lang-meli et al.

SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA-vaccinated individual

Nature Microbiology, April 2022; doi.org/10.1038/s41564-022-01106-y

Abstract

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.

H.M. El Sahly et al.

Is a fourth dose of covid-19 mRNA vaccine needed?

N Engl J Med, Journal Watch, April 2022;

Abstract

Two retrospective Israeli cohort studies suggest that, after a fourth dose of BNT162b2, participants aged ≥60 had reduced risk for infection and severe disease in the short term.

In the wake of the surging SARS-CoV-2 Omicron variant, a fourth dose of the Pfizer-BioNTech (BNT162b2) vaccine in those aged ≥60 was approved in Israel. Now, two retrospective cohort studies have evaluated its effectiveness at preventing COVID-19 outcomes. Using public health data from 1.2 million eligible adults, Bar-On et al. evaluated the incidence of severe COVID-19 (respiratory rate >30 breaths per minute, oxygen saturation <94%, or ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <300) in 623,000 persons who received a fourth dose (8–14 days previously) compared with three doses (629,000 recipients) and an internal control (days 3–7 after a fourth dose). From week 4 through week 6, adjusted rates of severe disease ranged from 3.5–4.3-fold lower in the four-dose group than in the three-dose group, and from 2.3–2.8-fold lower than in the internal control group. From week 4 through week 8, adjusted rates of confirmed SARS-CoV-2 infection were 2.0–1.1-fold lower in the four-dose group than in the three-dose group and 1.8–1.0-fold lower than in the internal control.

In a second study, Magen et al. used data from an Israeli healthcare organization to match a cohort of 182,000 members aged ≥60 who received a fourth dose with those who received three doses. Between days 7 and 30 postvaccination, the relative effectiveness of a fourth versus third dose was 45% against SARS-CoV-2 infection, 55% against symptomatic COVID-19, 68% against COVID-19–related hospitalization, 62% against severe COVID-19, and 74% against COVID-19–related death.

A.S. Brett et al.

Second Booster for COVID-19 Vaccination: Early Results

N Engl J Med, Journal Watch, April 2022

Abstract

Studies provide data on short-term effectiveness of a second booster (i.e., the fourth dose of an mRNA vaccine).

The U.S. CDC recently authorized a second mRNA COVID-19 vaccine booster (i.e., a fourth dose overall) for middle-aged and older adults (age, ≥50). In part, the CDC's decision was informed by two observational studies from Israel, where a fourth dose of the BNT162b2 vaccine (Pfizer-BioNTech) was approved on January 2, 2022, for older adults and others at high risk.

Taken together, the two studies involved more than 1 million older people (age, ≥60); short-term outcomes for those receiving a fourth dose between January and March 2022 were compared with outcomes among those who had received only 3 doses. The B.1.1.529 (Omicron) variant was dominant during this period. Findings were as follows:

  • The fourth dose began to show protection against confirmed SARS-CoV-2 infection during the second week after vaccination; the peak effect occurred at roughly 4 weeks (a roughly 50% reduction in infection, compared with infections in 3-dose recipients), but the effect had disappeared by 8 weeks.
  • Protection against a global category of severe COVID-19 also was noted by the second week after the fourth dose; protection was still peaking at 6 weeks (the last time-point for this observation), when the rate of severe infection was lower by roughly two thirds among four-dose recipients, compared with three-dose recipients.
  • Between days 7 and 30 after the fourth dose, relative reductions in COVID-19–related hospitalization and death were both roughly 70%; absolute reductions were 180 fewer hospitalizations and 23 fewer deaths per 100,000 people.

COMMENT

Although general protection against testing positive for SARS-CoV-2 had waned by 8 weeks after a fourth dose of mRNA vaccine, it afforded substantial protection against severe COVID-19 for 1 or 2 months during the B.1.1.529 Omicron-variant wave; however, that variant is no longer dominant in the U.S., new variants likely will emerge, and longer-term effects remain unclear. An editorialist discusses the potential tradeoffs and even detriments of too-frequent boosting; clinicians whose patients are seeking advice about additional boosting might find it worthwhile to read his discussion.

J. D. Altman

T cells in COVID-19 — the kids are all right

Nature Immunology, April 2022; doi.org/10.1038/s41590-022-01190-6

Thomas and colleagues describe how multiple mRNA vaccine boosters, with or without natural SARS-CoV-2 infection, shape T cell immunity.

A. Minervina et al.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memoryCD8+ T cells

MedRxiv, January 2022: doi: 10.1101/2021.07.12.21260227

Abstract

Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence and breakthrough infections have changed vaccine policy to include booster immunizations. However, the effect of diverse and repeated antigen exposures on SARS-CoV-2 memory T cells is poorly understood. Here, we utilize DNA-barcoded MHC-multimers combined with scRNAseq and scTCRseq to capture the ex vivo profile of SARS-CoV-2-responsive T cells within a cohort of individuals with one, two, or three antigen exposures, including vaccination, primary infection, and breakthrough infection. We found that the order of exposure determined the relative distribution between spike- and non-spike-specific responses, with vaccination after infection leading to further expansion of spike-specific T cells and differentiation to a CCR7-CD45RA+ effector phenotype. In contrast, individuals experiencing a breakthrough infection mount vigorous non-spike-specific responses. In-depth analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all types of exposures elicit diverse repertoires characterized by shared, dominant TCR motifs, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and that current vaccination protocols continue to expand and differentiate spike-specific memory responses.

N. Andrews et al.

Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

N Engl J Med 2022; doi: 10.1056/NEJMoa2119451

Abstract

BACKGROUND

A rapid increase in coronavirus disease 2019 (Covid-19) cases due to the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 in highly vaccinated populations has aroused concerns about the effectiveness of current vaccines.

METHODS

We used a test-negative case–control design to estimate vaccine effectiveness against symptomatic disease caused by the omicron and delta (B.1.617.2) variants in England. Vaccine effectiveness was calculated after primary immunization with two doses of BNT162b2 (Pfizer–BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccine and after a booster dose of BNT162b2, ChAdOx1 nCoV-19, or mRNA-1273.

RESULTS

Between November 27, 2021, and January 12, 2022, a total of 886,774 eligible persons infected with the omicron variant, 204,154 eligible persons infected with the delta variant, and 1,572,621 eligible test-negative controls were identified. At all time points investigated and for all combinations of primary course and booster vaccines, vaccine effectiveness against symptomatic disease was higher for the delta variant than for the omicron variant. No effect against the omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% confidence interval [CI], 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks. Among ChAdOx1 nCoV-19 primary course recipients, vaccine effectiveness increased to 62.4% (95% CI, 61.8 to 63.0) at 2 to 4 weeks after a BNT162b2 booster before decreasing to 39.6% (95% CI, 38.0 to 41.1) at 10 or more weeks. Among BNT162b2 primary course recipients, vaccine effectiveness increased to 67.2% (95% CI, 66.5 to 67.8) at 2 to 4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI, 44.7 to 46.7) at 10 or more weeks. Vaccine effectiveness after a ChAdOx1 nCoV-19 primary course increased to 70.1% (95% CI, 69.5 to 70.7) at 2 to 4 weeks after an mRNA-1273 booster and decreased to 60.9% (95% CI, 59.7 to 62.1) at 5 to 9 weeks. After a BNT162b2 primary course, the mRNA-1273 booster increased vaccine effectiveness to 73.9% (95% CI, 73.1 to 74.6) at 2 to 4 weeks; vaccine effectiveness fell to 64.4% (95% CI, 62.6 to 66.1) at 5 to 9 weeks.

CONCLUSIONS

Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time.

D. Abbass et al.

BNT162b2 vaccine induces antibody release in saliva: a possible role for mucosal viral protection?

Embo Molecular Medicine, April 2022; doi.org/10.15252/emmm.202115326

Abstract

Vaccination against an airborne pathogen is very effective if it induces also the development of mucosal antibodies that can protect against infection. The mRNA-based vaccine-encoding SARS-CoV-2 full-length spike protein (BNT162b2, Pfizer/BioNTech) protects also against infection despite being administered systemically. Here, we show that upon vaccination, cognate IgG molecules are also found in the saliva and are more abundant in SARS-CoV-2 previously exposed subjects, paralleling the development of plasma IgG. The antibodies titer declines at 3 months from vaccination. We identified a concentration of specific IgG in the plasma above which the relevant IgG can be detected in the saliva. Regarding IgA antibodies, we found only protease-susceptible IgA1 antibodies in plasma while they were present at very low levels in the saliva over the course of vaccination of SARS-CoV-2-naïve subjects. Thus, in response to BNT162b2 vaccine, plasma IgG can permeate into mucosal sites and participate in viral protection. It is not clear why IgA1 are detected in low amount, they may be proteolytically cleaved.

S. May Sidik et al.

COVID vaccine plus infection can lead to months of immunity

Nature, News 06 April 2022; doi: https://doi.org/10.1038/d41586-022-00961-3

Findings from Brazil, Sweden and the United Kingdom show that before the advent of Omicron, vaccination benefited even those who had had a bout of COVID-19.

K. Kobiyama et al.

Making innate sense of mRNA vaccine adjuvanticity

Nat Immunol., 2022; doi.org/10.1038/s41590-022-01168-4

Abstract

mRNA vaccines such as those used to prevent COVID-19 owe part of their success to methylation that masks immunostimulatory properties of the mRNA, but the immunological mechanisms of adjuvanticity are unclear. Two new studies reveal distinct mechanisms for innate sensing of this hidden adjuvant.

Tangye SG et al.

Getting to the (germinal) center of humoral immune responses to SARS-CoV-2   

Cell, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8928419/pdf/main.pdf

CONTENUTO E COMMENTO: La protezione a lungo termine contro SARS-CoV-2 richiede una risposta immunitaria efficace e duratura. In questo numero di Cell due articoli esaminano i centri germinativi linfonodali (luogo di nascita e sviluppo dell’immunità adattativa) per quantificare la specificità, l’intensità e la persistenza delle risposte immunitarie umorali locali e sistemiche indotte dall’infezione o dalla vaccinazione contro SARS-CoV-2. Entrambi gli studi ipotizzano che la vaccinazione, rispetto all’infezione naturale, produca una risposta umorale superiore, dovuta alla formazione di centri germinativi spike-specifici.

Regev-Yochay G. et al.

Efficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMc2202542

CONTENUTO E COMMENTO: Studio clinico non randomizzato open-label condotto con lo scopo di valutare l’immunogenicità e la sicurezza di una quarta dose di vaccino per Sars-CoV2 a mRNA (BNT162b2 e mRNA-1273) somministrata a 4 mesi dalla terza dose di vaccino (nell’ambito di un protocollo a tre dosi di BNT162b2). Dei 1050 operatori sanitari arruolati nel protocollo Sheba, 155 hanno ricevuto la quarta dose di vaccino Pfizer e, una settimana dopo, 120 persone hanno ricevuto invece mRNA-1273. Dopo la quarta dose in entrambi i gruppi è stato riscontrato un aumento degli anticorpi IgG contro il RBD di Sars-Cov2 e del titolo di anticorpi neutralizzanti. Tale crescita è risultata essere maggiore rispetto al valore di partenza di un fattore 9-10, maggiore anche a quella riscontrata dopo la terza dose, in assenza di particolari differenze tra i due composti utilizzati. In entrambi i gruppi inoltre è stata riscontrata una maggiore risposta in vivo alla variante omicron, attualmente predominante. Non sono stati riscontrati particolari eventi avversi nel corso del follow-up, se non reazioni sistemiche moderate o lievi del sito di iniezione. Nel gruppo di controllo il 25% dei partecipanti si è infettato con la variante omicron vs. il 18.3% del gruppo ricevente la quarta dose. Questi ultimi in ogni caso hanno presentato sintomi trascurabili anche se tutti in corso di infezione sono stati probabilmente infettivi, con una carica virale relativamente alta riscontrata. Le limitazioni dello studio riguardano in particolare la non randomizzazione, la differenza di una settimana nell’arruolamento dei due gruppi di intervento e il campione ridotto.

Peng Q. et al.

Waning immune responses against SARS-CoV-2 variants of concern among vaccinees in Hong Kong

EBioMedicine, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893246/pdf/main.pdf

CONTENUTO E COMMENTO: In questo studio longitudinale prospettico condotto ad Hong Kong viene comparata l’immunogenicità e la « durability » della risposta immunitaria di due vaccini, BNT162b2, (a mRNA) e CoronaVac (inattivato). Sono state valutate in soggetti pienamente vaccinati la capacità di produrre anticorpi neutralizzanti e la risposta CD4 T spike-specifica. In particolare, nei pazienti sottoposti a vaccinazione con BNT162b2 è stata riscontrata una produzione di anticorpi neutralizzanti nel 100% dei casi, mentre in quelli sottoposti a vaccinazione con CoronaVac nell’85.7% dei casi. In media la produzione di anticorpi neutralizzanti e la frequenza media di subset di CD4 reattivi è stata significativamente più bassa nei soggetti vaccinati con CoronaVac. Inoltre CoronaVac non ha indotto livelli misurabili di IFN-γ al test di stimolazione con la proteina nucleocapsidica specifica. Per quanto riguarda le varianti Delta e Omicron, la produzione di anticorpi neutralizzanti nei loro confronti è stata significativamente più bassa nei vaccinati con CoronaVac rispetto a quelli con BNT162b2 e dopo 3 mesi dalla vaccinazione nel gruppo CoronaVac i livelli di anticorpi neutralizzanti e la risposta delle cellule T della memoria tendono a diminuire fino a raggiungere il limite di detettabilità.

Gli autori dello studio mettono in luce evidenti differenze per quanto riguarda la stimolazione della risposta immunitaria conseguente al completamento della vaccinazione con i due vaccini in esame : CoronaVac sembra stimolare una risposta cellulare e umorale complessivamente inferiore rispetto a  BNT162b2, specialmente nei confronti delle variant of concern Delta e Omicron.

Abu-Rabbad L.J. et al.

Effect of mRNA Vaccine Boosters against  SARS-CoV-2 Omicron Infection in Qatar

The NEJM , https://www.nejm.org/doi/pdf/10.1056/NEJMoa2200797?articleTools=true

CONTENUTO E COMMENTO : Due studi retrospettivi di coorte con matching condotti in Qatar nel dicembre 2021 fino al gennaio 2022, per valutare l’efficacia della dose booster dei vaccini per Sars-CoV2 a mRNA, comparata con l’efficacia delle sole due prime dosi, nei confronti dell’infezione sintomatica, dell’ ospedalizzazione COVID-relata e dell’exitus dovuti alla variante Omicron. Sono state appaiate nel corso dello studio due coorti (1 :1 ratio a seconda del sesso, intervalli di età di 10 anni e nazionalità), una di persone boosterate da almeno sette giorni con BNT162b2 o mRNA-1273 e una coorte di persone vaccinate con due dosi. Un totale di 1.299.010 tra il gennaio 2021 e il gennaio 2022 hanno ricevuto almeno due dosi di vaccino. Pfizer, e di queste 281.093 anche la dose booster. Nella coorte di persone con booster sono state registrate nel periodo di studio 17.745 infezioni, di cui 12 progredite verso una malattia severa ma nessuna ha portato al decesso. Nel gruppo dei non boosterati invece sono state riscontrate 25.266 infezioni, di cui 45 progredite a COVID severo, 4 a malattia critica da COVID e nessuna al decesso. A 35 giorni dalla somministrazione della terza dose l’incidenza cumulativa di infezioni sintomatiche stimata è stata del 2.4% contro il 4.5% del gruppo dei non-booster. La riduzione stimata dell’incidenza di infezione sintomatica dovuta alla variante Omicron dopo la dose booster di BNT162b2, rispetto alle sole due dosi, è stata del 49.4%, mentre nei confronti della malattia severa e dell’exitus del 76.5%.

Stesso tipo di studio è stato effettuato per il vaccino mRNA-1273, con il riscontro di una efficacia nei confronti dell’infezione sintomatica, rispetto alle prime due dosi, del 47.3%, mentre non sono stati riscontrati casi di malattia severa o exitus. Sicuramente lo studio dimostra in entrambi i gruppi una protezione nei confronti della malattia severa e dell’ospedalizzazione, anche dopo due sole dosi, con una minore efficacia anche del booster nei confronti dell’Omicron rispetto alle precedenti varianti, aprendo iil dibattito su un possibile cambio di strategia vaccinale nel futuro, con composti differenti rispetto ad ulteriori dosi booster. Lo studio ha delle limitazioni legate all’età media giovane della popolazione del Qatar, alla minore severità della variante Omicron rispetto alle precedenti, all’efficacia duratura anche del ciclo vaccinale primario nei confronti dell’ospedalizzazione e dell’exitus, tutte variabili influenti sui dati ottenuti.

Bar-On Y. M. et al.

Preprint not peer reviewed

Protection by 4th dose of BNT162b2 against Omicron in Israel  

https://www.medrxiv.org/content/10.1101/2022.02.01.22270232v1

CONTENUTO E COMMENTO : analisi condotta in Israele su partecipanti dai 60 anni in su che abbiano ricevuto 3 dosi di vaccino BNT162b2 da almeno 4 prima dell’inizio dello studio nel periodo tra il 15 e il 27 gennaio 2022 (periodo a prevalenza omicron) per indagare infezione da SARS-CoV2 e patologia severa, studiando stato vaccinale, variabili demografiche e area di residenza. Sui 1 138 681 soggetti studiati, si e’ effettuata una regressione di Poisson per calcolare i tassi di infezione e patologia severa per 100 000 persone-giorni di rischio in ogni gruppo (3 gruppi : individui eleggibili per non abbiano ricevuto la quarta dose, individui a 3-7 giorni dalla quarta dose, individui a 12 giorni o piu’ dalla quarta dose).

Il tasso di infezione confermata nel gruppo vaccinato da 12 giorni o piu’ era piu’ basso di 2 volte (95% confidence interval [CI], 2.0 a 2.1) rispetto al gruppo eleggibile non vaccinato e di 1,9 (95% CI, 1.8 a 1.9) rispetto a coloro che avevano ricevuto la quarta dose 3-7 giorni prima. Le differenze aggiustate dei tassi erano 279 (95% CI, 271 a 287) e 234 (95% CI, 219 a 247) casi per 100,000 persone-giorni a rischio tra il gruppo di trattamento e gli altri due gruppi.  Il tasso di patologia severa nel gruppo di persone che avevano ricevuto la quarta dose 12 o piu’ giorni prima era piu’ basso di 4.3 (95% CI 2.4 a 7.6) rispetto al gruppo vaccinato con 3 dosi e di 4.0 volte (95% CI 2.2 a 7.5) rispetto a coloro che avevano ricevuto la quarta dose 3-7 giorni prima. Le differenze aggiustate dei tassi erano di 3.8 (95% CI, 2.8 a 4.8) e 3.5 (95% CI, 2.1 a 5.1) casi per 100,000 persone-giorni di rischio rispetto ai due gruppi di controllo, rispettivamente. Il rapporto di incidenza durante I primi 3-7 giorni dopo la vaccinazione e’ circa 1, aumentando di 2-3 volte 2 settimane dopo la vaccinazione.

I dati dimostrano che una quarta dose ad almeno 4 mesi dalla terza puo’ aumentare la protezione verso la patologia severa, specialmente in popolazioni a rischio.

LIMITAZIONI : differenze di comorbidita’ nei gruppi non analizzate in quanto dati non disponibili ; non analizzate differenze comportamentali (richiesta di supporto medico ecc) ; modifica delle linee guida nazionali per il testing nello stesso periodo che puo’ sovra o sottostimare l’effetto osservato nello studio.

Andrews N. et al.

Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2119451?articleTools=true

CONTENUTO E COMMENTO : :  studio caso controllo, a design test-negativo per valutare l’efficacia del vaccino contro la malattia sintomatica dovuta alle varianti delta ed omicron nel Regno Unito (novembre 2021-gennaio2022). Tale efficacia è stata valutata dopo due dosi di BNT162b2 (Pfizer–BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), o mRNA-1273 (Moderna) e dopo una dose booster di BNT162b2, ChAdOx1 nCoV-19, o mRNA-1273. La popolazione di studio contava 886.774 persone con variante omicron, 204.154 con variante delta e 1.572.621 controlli test-negativi. I risultati hanno mostrato, in ogni momento dello studio, una superiorità della protezione vaccinale nei confronti della malattia sintomatica contro la variante delta rispetto alla omicron. A 20 settimane dalle due dosi di ChAdOx1 nCoV-19 non sono stati evidenziati effetti contro Omicron, mentre per BNT162b2 la protezione risultava del 65.5% fino a 4 settimane dalla seconda dose vs. 8.8% oltre le 25 settimane. Nei pazienti vaccinati con ChAdOx1 nCoV19 e riceventi il booster BNT162b2 si oscillava tra il 62.4% dopo 2-4 settimane fino al 39.6% oltre le 10 settimane. In pazienti con ciclo vaccinale omologo con BNT162b2 si riscontrava il 67.2% di protezione nel primo periodo per poi decrescere fino al 45.7% oltre le 10 settimane. Quando la dose booster considerata era mRNA-1273 nei pazienti con ciclo primario con Astrazeneca la protezione risultava maggiore, del 70.1% dopo 2-4 settimane per poi ridursi al 60.9% fino alla nona settimana dalla somministrazione booster. La combinazione con i migliori dati di protezione risulta essere quella con ciclo iniziale Pfizer e booster Moderna (73.9% nelle prime 4 settima e 64.4% fino a 9 settimane dal booster). Lo studio evidenzia come il ciclo vaccinale con due dosi, indipendentemente dal composto ricevuto, non garantisce una immunizzazione efficace nei confronti della variante omicron ed inoltre che anche la protezione garantita da una dose booster decresce significativamente con il passare del tempo.

Hongjie X. et al.

Neutralization and durability of 2 or 3 doses of the BNT162b2 vaccine against Omicron SARS-CoV-2 (journal pre-proof)

Cell Host and Microbe, https://doi.org/10.1016/j.chom.2022.02.015     

CONTENUTO E COMMENTO: studio che indaga l’attivita’ neutralizzante anticorpale dei sieri di pazienti vaccinati, testandola contro la variante wild-type USA-WA1/2020 e una variante USA-WA1/2020 ingegnerizzata per esprimere la glicoproteina spike di Omicron. Tramite test in vitro, come ad esempio l’analisi su cellule Vero E6, entrambi i virus hanno mostrato rapporti di genoma virale RNA/PFU equivalenti, suggerendo infettivita’ specifiche comparabili. I sieri sono stati testati a 2 o 4 settimane dopo la seconda dose, somministrata a 3 settimane dalla prima, e per quanto riguarda la terza dose, testati il giorno prima della stessa, 1 e 4 mesi dopo. A 2 o 4 settimane post seconda dose, i titoli medi geometrici di neutralizzazione (GMTs) contro il virus wild-type e il virus Omicron-spike erano rispettivamente 511 e 20; a 1 mese post terza dose, la neutralizzazione GMTs e’ incrementata a 1342 e 336; a 4 mesi dalla terza dose, i GMTs sono calati a 820 e 171.

A 2 o 4 settimane dopo la seconda dose, i GMT contro il virus Omicron-spike erano 25,6 volte piu’ bassi che contro la variante wild-type, come gia’ dimostrato in studi in letteratura.

A 1 mese dopo la terza dose, i GMTs sia contro variante wild-type che contro Omicron-spike sono aumentati di 2,6 e 16,8 volte rispetto ai corrispettivi dalle 2 alle 4 settimane post seconda dose, supportando dati preliminari che una terza dose di BNT162b2 aumenti la magnitudine e l’ampiezza della neutralizzazione gia’ mostrata contro le varianti Delta e Beta. Da 1 a 4 mesi dopo la terza dose, i GMTs contro il virus wild-type e Omicron e’ diminuito di 1,6 e 2 volte, suggerendo una dinamica di decadimento articorpale simile per entrambe le varianti, seppur sia necessario un campione piu’ grande e osservazioni piu’ lunghe per confermare il dato. Da cio’ deriva il fatto che la terza dose di vaccino BNT162b2 possa ridurre l’impatto sulla salute della variante Omicron, specialmente sull’ospedalizzazione, come gia’ dimostrato in altri studi.

L’utilizzo di varianti USA-WA1/2020 ingegnerizzate per esprimere la glicoproteina spike di Omicron rispetto alla variante Omicron naturale e’ giustificata dagli autori per la rapidita’ di analisi rispetto agli isolati clinici e perche’ il vaccino BNT162b2 colpisce solo la proteina spike (unica differenza tra le due varianti in studio), eliminando tramite questa metodica le variazioni legate a mutazioni virali su altri bersagli non spike.

LIMITAZIONI: non utilizzo di isolati clinici, non dati real-word, corto periodo di osservazione, piccolo campione, analisi solo umorale e non indagata immunita’ cellulo-mediata.

Shinde V. et al.

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

NEJM,

https://www.nejm.org/doi/10.1056/NEJMoa2103055?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

CONTENUTO E COMMENTO: studio clinico randomizzato controllato di fase 1-2 mirato a testare efficacia e sicurezza del vaccino NVX-CoV2373 vaccine (5 μg di proteina spike ricombinante e 50 μg di adiuvante Matrix-M1) verso placebo (rapporto 1 :1), studiato su partecipanti sani tra i 18 e gli 84 anni, seronegativi o HIV positivi con infezione controllata, in Sud Africa, arruolati tra agosto 2020 e novembre 2020. Dei 6324 partecipanti sottoposti a screening, 4387 hanno ricevuto almeno una iniezione di NVXCoV2373 o placebo (rispettivamente 2199 e 2188); 4332 partecipanti hanno ricevuto entrambe le iniezioni previste.

Caratteristiche demografiche: l’eta’ media di tutti i partecipanti era di 32.0 anni, 20% era obeso, 5.6% iperteso, 1.6% era affetto da diabete mellito. 30% circa era sieropositivo albaseline tramite valutazione degli anticorpi IgG antiSpike.

Sicurezza: dopo la prima dose, l’evento avverso locale piu’ frequente era dolore nel sito di iniezione, descritto nel 37% dei partecipanti sieronegativi e 39% dei sieropositivi nel gruppo dei vaccinati e 15% e 16% nel gruppo placebo, rispettivamente. Dopo la seconda dose, il tasso di eventi avversi locali era simile, con una durata lievemente maggiore, comunque sotto ai 3 giorni. Nel gruppo vaccinato, l’evento avverso sistemico piu’ comune dopo la prima dose e’ stato cefalea (20-25%), mialgie (17-20%), astenia (12-16%), con una durante lievemente maggiore dopo la seconda dose, comunque sotto i 3 giorni. Eventi avversi di grado 3 sono stati infrequenti, con tassi simili nel gruppo placebo (13 vs. 6 eventi avversi con necessita’ di intervento medico nel gruppo vaccinato vs placebo e 2 vs. 1 eventi avversi gravi rispettivamente).

Efficacia: dei 2684 partecipanti sieronegativi per SARS-CoV2 al baseline (94% HIV-negativi e 6% HIV-positivi) e che potessero essere valutati nell’analisi di efficacia dopo 28 giorni, si sono osservati 15 casi sintomatici COVID19 nel gruppo vaccino e 29 nel gruppo placebo, corrispondendo a una efficacia vaccinale di 49.4% (95% confidence interval [CI], 6.1 a 72.8), che incontra il criterio primario di efficacia nella valutazione di fase 2b. Tutti i casi di COVID nell’analisi per-protocol erano lievi-moderati, eccetto per un caso grave nel gruppo placebo. Tra i partecipanti HIV negativi, si sono osservati 11 casi COVID sintomatici nel gruppo vaccino e 27 nel placebo nei seronegativi per SARS-CoV2 al baseline, corrispondendo a un’efficacia vaccinale di 60,1%. Nei partecipanti HIV+, si sono osservati 4 casi sintomatici nel gruppo vaccino (sui 76 partecipanti) e 2 su 72 nel gruppo placebo. Tra i partecipanti seronegativi per SARS-CoV2 al baseline, si sono osservati 44 casi sintomatici nei due gruppi tra il 23 novembre 2020 e il 30 dicembre 2020. Dei 41 campioni testati tramite whole-genome sequencing, 38 sono stati indentificati come attribuibili alla variante B.1.351, ampiamente diffusa nel territorio sudafricano in quel momento. L’efficacia vaccinale contro la variante B.1.351 era 51.0% (95% CI, −0.6 a 76.2) tra i partecipanti HIV negativi (11 nei vaccinati e 22 nei placebo) e 43.0% (95% CI, −9.8 a 70.4) nella popolazione combinata HIV negativa e positiva (14 e 24 rispettivamente). Pur se necessario la conferma con ulteriori studi, il vaccino NVX-CoV2373 sembra conferire un grado di cross-protezione contro varianti ad escape immune.

LIMITAZIONI: risultati di efficacia preliminary (follow-up di 66 giorni dopo la prima dose e 45 dopo la seconda), piccolo campione per le analisi in sottogruppi, popolazione giovane e poco comorbida.

Yunkai Yu et al.

mRNA vaccine‑induced antibodies more efective than natural immunity in neutralizing SARS‑CoV‑2 and its high afnity variants

Nature, https://www.nature.com/articles/s41598-022-06629-2.pdf

CONTENUTO E COMMENTO : Studio in vitro volto a quantificare il titoloanticorpale e la capacitàneutralizzante di due popolazioni : vaccinati con due dosi di composto a m-RNA e pazienticonvalescenti COVID-19, in un contestoepidemiologicocaratterizzato da numerosevarianti del virus, alcune delle quali con mutazioni del RBD-ACE2, particolamente virulente. Un totale di 41 campioni di siero sono statiacquisiti da pazienti con COVID-19 accertato e ulterioricampioni sono statiprelevati ad unapopolazione di 28 personevaccinate con due dosi di Pfizer o Moderna. Neicampioni di siero di questiultimi sono statiriscontrati valori di anticorpi anti-RBD con unamediana 17 volte superiore rispetto a quelli di pazienti con infezionenaturale, con unasovrapponibilecapacitàneutralizzantecontro RBD-ACE2. Inoltre è stata valutata la capacità di neutralizzazioneneiconfrontidella variante N501Y dei convalescenti e dei pazientivaccinati. I risultatihannomostratounaridottacapacità di neutralizzazionecontro il RBD di N501Y in tutti i campioni di sangue dei pazienticonvalescenti, controunaelevatacapacità di neutralizzazioneneipazientivaccinati. Le limitazionidello studio riguardano l’impossibilità di rappresentarenelmodelloutilizzato la strutturatridimensionaledellaproteinaspike virale e dell’ACE2, la densitàsuperficiale di entrambe le molecole e il processo di ingressonellacellula del virus. Inoltre i profiili di mutazione del virus sono estremamentesemplificati in tale modello.

Matusali G. et al

Differential Dynamics of SARS-CoV-2 Binding and Functional Antibodies upon BNT162b2 Vaccine: A 6-Month Follow-Up

MDPI Viruses, https://doi.org/10.3390/v14020312

CONTENUTO E COMMENTO : : Studio in vitro finalizzato a valutare la associazione dinamica tra i binding e functional antibodies per Sars-Cov2 in operatori sanitari vaccinati con due dosi di BNT162b2 a sei mesi dalla seconda dose di vaccino. Un totale di 152 campioni di siero sono stati prelevati da 52 operatori sanitari tra gennaio e giugno 2021. Tali campioni sono stati testati per la ricerca di IgG anti-RBD, IgG anti-Trimeric Spike e anticorpi neutralizzanti per Sars-Cov2 a due settimane, tre mesi e sei mesi dalla seconda somministrazione di Comirnaty. Il livello maggiore di IgG anti-spike è stato registrato a due settimane dal vaccino. Una significativa riduzione di tali livelli è stata osservata già a tre mesi (anti-RBD IgG: median 479.7, IQR 283.7–920.8; anti-Trimeric S IgG: median 970.5, IQR 551.3–1598) e ulteriormente a sei mesi (anti-RBD IgG: median 171.8, IQR 84.6–281.9; anti-Trimeric S IgG, median 578.5, IQR 288.5–991.0). Il dato interessante riguarda il decadimento più rapido delle IgG anti-RBD rispetto alle anti-Trimeric S nel corso del follow-up ( riduzione IgG anti RBD pari a 4.5 volte a 3 mesi e a 13 volte dopo 6 mesi vs. riduzione anti-Trimeric S a 3 mesi pari a 2.8 a 3 mesi e 4.7 volte a 6 mesi). Una differente. dinamica è stata riscontrata per la riduzione degli anticopri neutralizzanti, con valori comprarabili tra loro  a tre e sei mesi. La mutevole relazione tra le IgG anti-RBD e anti-Trimeric S ed anticorpi neutralizzanti sta ad indicare che l’affinità degli stessi per la proteina virale Spike si evolve nel tempo in pazienti vaccinati con Comirnaty, così come è stato osservato nell’infezione da Sars-CoV2. Sicuramente una limitazione dello studio è legata al ridotto numero di campioni analizzati e alla prevalenza di soggetti di sesso femminile nella popolazione di studio.

Sadoff J. et al.

Final Analysis of Efficacy and Safety of Single-Dose Ad26.COV2.S

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2117608

CONTENUTO E COMMENTO : studio di fase 3 randomizzato, doppio cieco, controllato con placebo, multicentrico in cui e’ stata effettuata vaccinazione crossover nel gruppo di controllo (una volta autorizzato il vaccino negli stati dei partecipanti) con il fine di valutare l’efficacia di una singola dose di  Ad26.COV2.S  nel prevenire la comparsa di infezioni da SARS-CoV2 moderato-severe confermate tramite test molecolare RT-PCR con esordio ad almeno 14 giorni dalla somministrazione e 28, con una sottopopolazione di studio di sicurezza con 6000 partecipanti circa con valutazione degli effetti avversi a 7 e 28 giorni dalla somministrazione. I partecipanti sono stati assegnati in maniera random in gruppi 1 :1 con l’uso di gruppi random permutati per ricevere o una dose di Ad26.COV2.S (5x1010 viral particles) o un placebo salino intramuscolo (0.5 ml). Nella popolazione di partecipanti trattati per-protocol (39185), l’efficacia vaccinale nella protezione contro la COVID19 moderata-severa ad almeno 14 giorni dalla somministrazione e’ stata 56,3% (95% confidence interval [CI], 51.3 a 60.8; 484 casi nel gruppo vaccinato vs. 1067 nel gruppo placebo). Una singola dose di vaccino Ad26.COV2.S ad almeno 28 giorni dalla somministrazione e’ rimasta efficace nella prevenzione della COVID19 moderata-severa (52,9%, 95% CI, 47.1 a 58.1)  e di tutte le forme COVID sintomatiche (52,4%, 95% CI, 46.6 a 57.6), nonostante l’emergenza di nuove varianti (dati pre emergenza di Omicron). L’efficacia contro le forme severe e critiche e’ rimasta alta (74,6%), in minor misura per le nuove varianti (93.1% efficacia contro il ceppo di riferimento e 71.8% verso le varianti non di riferimento). La riduzione dell’efficacia nei dati finali rispetto all’analisi primaria (efficacia vaccinale per l’endpoint primario ad almeno 28 giorni dall’amministrazione, 66,1% nell’analisi primaria e 52,9% nell’analisi finale) e’ verosimilmente attribuibile a una minore efficacia vaccinale verso le varianti (ad esempio, 10.1% contro la variante lambda e 36.5% contro la gamma, dati non disponibili per omicron). L’efficacia vaccinale contro l’infezione sintomatica nelle persone che vivono con HIV in questo trial e’ stata bassa, con ampi intervalli di confidenza (23,5%, 95% CI, −78.3 a 68.2).

Nei partecipanti con pregressa infezione asintomatica (serologia positiva per proteina N SARS-CoV2 all’arruolamento), la pregressa infezione da sola provvedeva a una protezione del 90.4% contro l’infezione sintomatica e dopo la somministrazione di Ad26.COV2.S, 97.7% di protezione rispetto ai partecipanti placebo seronegativi.

Le infezioni da SARS-CoV2 nei partecipanti che hanno ricevuto una dose di Ad26.COV2.S si sono mostrate piu’ brevi, meno severe e con piu’ basse cariche virali con una minore necessita’ di intervento medico (90% di protezione iniziale, fino ad arrivare al 70% a 6 settimane, rimanendo a tale livello per I successive 5-6 mesi).

Gli eventi avversi sono stati rari, con eventi avversi gravi in circa l’1% e si e’ osservato nel periodo di post autorizzazine il tinnito, classificato come evento molto raro. Non ci sono stati casi di anafilassi o capillary leak syndrome e si e’ osservato un solo caso di VITT.

Barin B. et Al.

Comparison of SARS-CoV-2 anti-spike receptor binding domain IgG antibody responses after CoronaVac, BNT162b2, ChAdOx1 COVID-19 vaccines, and a single booster dose: a prospective, longitudinal population-based study

The Lancet,

 https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00305-0/fulltext

CONTENUTO E COMMENTO : studio longitudinale prospettico per esaminare le concentrazioni di IgG SARS-CoV-2 anti-spike RBD dopo vaccinazione con BNT162b2, ChAdOx1, e CoronaVac o dopo dose booster, svoltosi nel nord di Cipro. Le valutazioni sono state effettuate a 1 mese e 3 mesi dalla seconda dose di ciascun vaccino nella coorte principale con gli intervalli temporali tra le dosi di 4 settimane per CoronaVac, 3 per BNT162b2, 12 per ChAdOx1.

Sono state inoltre valutati sottocoorti di partecipanti che hanno ricevuto inizialmente due dosi di CoronaVac e 6 mesi dopo una dose di BNT162b2 o di CoronaVac e un gruppo indipendente di riferimento che ha avuto il covid nei 3 mesi precedenti e non abbia ricevuto vaccino.

Si e’ osservato un alto tasso di seropositivita’ e di titoli anticorpali in tutti i timepoint testati per i vaccini BNT162b2 e ChAdOx1 rispetto a CoronaVac per tutti i gruppi di eta’ (gruppo BNT162b2 : 100% di tasso di sieroposivita’ in pazienti sopra e sotto i 60 anni e si e’ mantenuto stabile a 3 mesi; gruppo ChAdOx1 : tasso di sieropositivita’ ad un mese dalla seconda dose di 100% nei piu’ giovani e 96% nei piu’ anziani con una riduzione a 3 mesi  dalla seconda dose a 97% nei piu’ giovani e  90% nei piu’ anziani; gruppo CoronaVac, tasso di sieropositivita’ a un mese di 97% nei piu’ giovani e 88% nei piu’ anziali, con un calo a 76% nei giovani e 60% nei piu’ anziani a 3 mesi) e i titoli IgG indotti da BNT162b2 erano maggiori quando comparati con ChAdOx1.

Per gli soggetti piu’ anziani ad alto rischio, il tasso di seropositivita’ a 3 mesi dalla seconda dose era del 100% per BNT162b2, 90% per ChAdOx1 e 60% per CoronaVac.

Nonostante l’eta’, il tasso di declino degli anticorpi da 1 a 3 mesi dalla vaccinazione completa e’ stato piu’ veloce nel gruppo CoronaVac, seguito da ChAdOx1, e poi da BNT162b2.

Negli individui piu’ anziani (eta’ maggiore di 60 anni) vaccinati con ciclo primario di CoronaVac, una singola dose booster di BNT162b2 ha comportato un significativo incremento dei titoli di IgG (gruppo BNT162b2: la mediana dei titoli anticorpali era di 5·0 (1·8–13·9) a un mese e 1·2 (0·5–3·1) a 3 mesi, con tassi di seropositivita’ a 86·5% a 1 mese e  59·6% a 3 mesi) rispetto a una singola dose booster di CoronaVac  (gruppo CoronaVac: la mediana dei titoli anticorpali era di 3·2 (0·9–8·6) ad un mese e 0·9 (0·4–1·3) a 3 mesi con un tasso di sieropositivita’ del 75% a un mese e 50% a 3 mesi): nonostante i titoli anticorpali ad uno e 3 mesi dopo la seconda dose di CoronaVac fossero simili tra i due gruppi maggiormente anziani (Wilcoxon two-sample test; p=0·25 a un mese e p=0·41 a 3 mesi), una singola dose booster di of BNT162b2 ha indotto un maggior titolo di anticorpi IgG anti-spike RBD rispetto al booster CoronaVac (p<0·0001; figure 2A).

I risultati dello studio sono consistenti con precedenti studi: il sesso maschile e la eta’ avanzata sono associati a un piu’ basso livello generale di anticorpi.

Si e’ osservata una forte relazione tra gli alti titoli di anticorpi IgG anti-spike e un ridotto stato di malattia come anche una piu’ bassa incidenza di infezioni breakthrough, dove un piu’ alto livello di IgG leganti l’antigene ha comportato una maggiore protezione: da qui l’assunto che i titoli anticorpali possano servire da correlato di protezione contro l’infezione e come surrogato della risposta generale immune allo specifico vaccino.

Una dose booster di CoronaVac somministrato a 6 mesi dal ciclo primario di CoronaVac ha indotto un piu’ modesto incremento dei titoli IgG rispetto a booster con BNT162b2 (l’aumento della media geometrica e’ stato di circa 3 volte per

CoronaVac vs 8x per BNT162b2).

Limitazioni: singola nazionalita’, campione piccolo (384 di cui 222 CoronaVac, 106 BNT162b2, 56 ChAdOx1), metodo di campionamento “convenience” rispetto ad un vero arruolamento, studio effettuato in periodo non Omicron (1 marzo 2021-settembre 2021).

Corrao G. et al.

Persistence of protection against SARS-CoV-2 clinical outcomes up to 9 months since vaccine completion: a retrospective observational analysis in Lombardy, Italy

The Lancet, https://doi.org/10.1016/ S1473-3099(21)00813-6

CONTENUTO E COMMENTO : : Studio osservazionel retrospettivo, finalizzato a valutare la persistenza della protezione nei confronti degli otucomes clinici (infezione e malattia severa) del Sars-Cov2, a nove mesi dal completamento del ciclo vaccinale. In questo studio, 5.351.085 individui sono stati seguiti a 14 giorni dal completamento del ciclo vaccinale tra il gennaio ed il giugno 2021 e poi fino all’ ottobre dello stesso anno. In tale lasso di tempo sono stati valutati i cambiamenti nel tempo degli outcomes considerati, come l’infezione e la gravità della stessa nella popolazione vaccinata ed il trend dell’efficacia dei vaccini. In totale sono state osservate 14.140 infezioni e 2450 malattie severe (1.2 casi/10000 persone). Dal primo mese di follow-up fino al mese di ottobre si è osservato un aumento di questo tasso fino al 6.7/10000. Le infezioni più severe sono state riscontrate nella popolazione over60, senza una particolare variazione nella popolazione ricevente un vaccino a mRNA o con vettore virale. Ovviamente tale dato è direttamente proporzionale alla riduzione dell’efficacia della protezione vaccinale nel tempo, ponendo l’attenzione sull’importanza della necessità di una dose booster, con tempistiche non eccessivamente prolungate.

Shuo Feng et al.

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

Nature, https://doi.org/10.1038/s41591-021-01540-1

CONTENUTO E COMMENTO : Trial randomizzato di efficacia, condotto nel Regno Unito, per determinare i livelli anticorpali in pazienti vaccinati con ChAdOx1 nCoV19 (vettore virale), a 28 giorni dalla seconda dose in pazienti infetti (171 pazienti) e non infetti (1404) da Sars-Cov2. Il proposito di tale studio era appunto valutare la correlazione della protezione anticorpale in pazienti vaccinati, infetti, con infezione sintomatica e non. Elevati livelli anticorpali sono stati correlati ad una riduzione del rischio di infezioni sintomatiche, con una protezione dell’89% nei confronti della stessa a 28 giorni dalla seconda dose. La limitazione principale dello studio riguarda la popolazione presa in considerazione e l’intervallo di tempo considerato, predominante la variante Beta nei pazienti considerati. 

Atmar R.L. et al.

Homologous and Heterologous Covid-19 Booster Vaccinations

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2116414?articleTools=true

CONTENTUO E COMMENTO : : Trial clinico open-label di fase 1-2, condotto in 10 siti degli Stati Uniti, finalizzato a valutare la sicurezza, la immunogenicità e la reattogenicità al giorno 15 e 29 del trial di una dose booster omologa o eterologa (9 possibili combinazioni tra prima vaccinazione e booster) di mRNA-1273, Ad26.COV2.S o BNT162b2 in pazienti con ciclo vaccinale completo da almeno 12 settimane, senza precedenti infezioni da Sars-Cov2. 458 pazienti hanno partecipato al trial, di questi 154 hanno ricevuto mRNA-1273, 150 Ad26.COV2.s e 153 BNT162b2. Non vi sono state differenze nella reattogenicità rispetto al ciclo vaccinale iniziale con due reazioni avverse severe dopo la dose booster con Ad.26.COV2.S. Tutte le combinazioni vaccinali hanno dimostrato un netto aumento del titolo di anticorpi neutralizzanti (booster omologhi hanno portato ad un amento del titolo di un fattore da 4 a 20, gli eterologhi da 6 a 73). Un livello maggiore e persistente di T-cell CD8+ è stato riscontrato nei riceventi il vaccino Janssen sia come booster etereologo che omologo. In conclusione, tutte le combinazioni di vaccini booster hanno dimostrato un profilo di sicurezza accettabile e di efficacia. Sicuramente la mancanza di un gruppo di controllo costituisce un limite importante per lo studio.

Cheng S.M.S. et al.

Neutralizing  antibodies against the SARS-CoV-2 Omicron variant following homologous  and heterologous CoronaVac or BNT162b2 vaccination

Nature, https://www.nature.com/articles/s41591-022-01704-7_reference.pdf

CONTENUTO E COMMENTO : Studio in vitro condotto per valutare  e confrontare il plaque reduction neutralization (PRNT50) e PRNT90 GMT antibody titre contro la variante Omicron in pazienti vaccinati con due dosi di CoronaVac (n=30) o con BNT162b2 (n=31) mai affetti da Sars-CoV2, in pazienti vaccinati con dose booster CoronaVac o con booster eterologo BNT162b2 ed infine pazienti con dose booster BNT162b2 omologa. Inoltre è stato valutato il siero di pazienti guariti dal COVID-19 non vaccinati e pazienti convalescenti vaccinati con una solo dose dei sopracitati composti. I dati hanno mostrato una  riduzione  marcata del titolo anticorpale contro la variante  Omicron (comparta con il virus wild-type)  dopo due dosi di BNT162b2 ( GMT 218.8) o CoronaVac (GMT 32.5). Una dose booster di BNT162b2 ha elicitato un titolo PRNT50 >25.6 contro Omicron nell’88% dei riceventi il ciclo vaccinale omologo e nell’80% nei riceventi CoronaVac nelle prime due somministrazioni. Nei cicli vaccinali omologhi con CoronaVac solo un paziente su trenta ha raggiunto tali livelli. Tali risultati suggeriscono di procedere alla somministrazione della dose booster con vaccini a mRNA nei paesi ad alta prevalenza di vaccinati con CoronaVac, al fine di garantire una maggiore protezione contro la variante Omicron.

Franco-Paredes C. Knol M.J. et al. Ko H.H.T.

Transmissibility of SARS-CoV-2 among fully vaccinated individuals

The Lancet,

https://www.thelancet.com/journals/laninf/article/PIIS14733099(21)007684/fulltext?fbclid=IwAR2DVUiGh16mPpNFRJk5ngugpsGcg7u1FhR008aEAq3RgTnvLfOYOa68m5M

CONTENUTO E COMMENTO: 3 correspondences in risposta allo studio prospettico di coorte condotto nel Regno Unito da Anika Singanayagam et al sulla trasmissione comunitaria di SARS-CoV2 tra individui vaccinati e non.

Franco-Paredes evidenzia come i dati presentati indeboliscano il razionale scientifico sottostante l’obbligo vaccinale in quanto non si e’ mostrato un impatto significativamente differente della vaccinazione sulla circolazione del virus. Questi dati sono stati inoltre confermati in altri studi, come, ad esempio, gli studi attestanti rispettivamente la presenza di breakthrough infection in personale sanitario vaccinato in israele, titoli virali delle alte vie respiratorie e colture virali al picco dell’infezione sovrapponibili tra vaccinati e non, nonche’ la sovrapponibile carica virale di SARS-CoV2 a livello nasofaringeo in vaccinati e non, persino nei soggetti con infezione asintomatica provata.

Knol MJ et al affrontano invece l’importanza dell’aggiustamento per eta’ nel confronto tra soggetti vaccinati e non vaccinati, in quanto fattore confondente associato sia allo stato vaccinale che al rischio di trasmissione di SARS-CoV2 (incremento del picco di carica virale medio con l’aumentare dell’eta’ e dunque una minore contagiosita’ dei bambini o la maggiore propensione a vaccinare i soggetti anziani). Per questa ragione, l’efficacia del vaccino contro la trasmissione dello studio di Singanayagam et al e’ verosimilmente sottostimata.

HHT Ko esplora invece l’eventualita’ che i vaccini possano favorire l’accumulo di grandi cariche virali e dunque comportare un aumentato rischio di escape immune, in quando non conferiscono un’immunita’ totalmente neutralizzante. Tracciando con tecniche di whole-genome sequencing, si potrebbero confrontare nel tempo per evidenziare possibili mutazioni i dati dei partecipanti vaccinati e non dello studio Singanayagam et al. Se queste mutazioni sono occorse principalmente nei contatti vaccinati rispetto ai non vaccinati, questo suggerirebbe una mutazione indotta da vaccino.

Andrews N. et al.

Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2115481?articleTools=true

CONTENUTO E COMMENTO :  Studio caso-controllo (dicembre 2020-ottobre 2021, Regno Unito) finalizzato a stimare l’efficacia di due dosi dei vaccini per Sars-CoV-2 ChAdOx1-S, BNT162b2 e mRNA-1273 contro l’infezione sintomatica, l’ospedalizzazione entro 14 giorni da un test molecolare positivo e control’exitus a28 giorni dal tampone nasofaringeo positivo. Per tutti glioutcomes sono stati confrontati i dati di pazienti vaccinati, sintomatici e con molecolare positivo per Sars-Cov-2 e di pazienti vaccinati con sintomi da COVID-19 ma con test molecolare negativi(n. tot=6,056,673). L’efficacia dei vaccini nei confronti della variante delta ha mostrato la massima efficacia nei confronti dell’infezione sintomatica nelle prime settimane dopo la seconda dose con una riduzione a 5 mesi fino al 44.3% con ChAdOx-1-S ed al66.3% con BNT162b2. A 5 mesi dalla seconda dose vaccinale si è invece osservato un tasso minore di riduzione di efficacia nei confronti dell’ospedalizzazione (80%. ChAdOx-1-se. 91.7% BNT162b2) e dei decessi da Sars-CoV-2 (84.8% vs 91.9%). Lo studio fornisce dati importanti sul timing della terza dose di vaccino, alla luce dell’elevata protezione nei confronti dell’ospedalizzazione e del decesso a 5 mesi dalla seconda somministrazione. Le limitazioni dello studio sono in primis legate allo stesso disegno test-negative case-control, uno studio osservazionale soggetto a bias potenziali.

Roos S.G. Sablerolles et al

Immunogenicity and Reactogenicityof Vaccine Boosters afterAd26.COV2.S Priming

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116747

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato multicentrico in singolo cieco in operatori sanitari (HCW) nei Paesi Bassi : sono stati selezionati HCW tra i 18 e 65, senza fattori coesistenti/comorbidita’ gravi, nessuna storia di infezione da SARS CoV-2, vaccinati con Ad26.COV2.S 3 mesi prima dell’arruolamento e assegnati in maniera casuale (ratio 1:1:1:1) a booster con Ad26.COV2.S, mRNA-1273, BNT162b2 o nessun booster (n=434 partecipanti).

L’endpoint primario, ossia il livello di anticorpi IgG contro la subunita’ S1 della proteina spike dopo booster, e’ stato significamente superiore nei pazienti che hanno ricevuto booster rispetto a chi non lo ha ricevuto e questo maggiormente dopo booster con mRNA 1273 (beta coefficient, 0.21; 98.3% CI, 0.13 to 0.37). La vaccinazione eterologa con booster a mRNA hanno avuto livelli di anticorpi leganti superiori alla vaccinazione omologa, con una maggiore quota di anticorpi neutralizzanti.

Per quanto riguarda le risposte cellulari T-mediate, queste sono state maggiori nel gruppo che ha ricevuto il booster a mRNA:  risposta al 91.7% con il booster mRNA-1273 e 91.5%con il booster BNT162b2; entrambi con migliori performance del booster omologo (risposta 72.7%).

Sul versante reattogenicita’, il booster mRNA1273 e’ stato associato a una piu’ grande percezione di severita’ e durata delle reazioni locali e sistemiche (comunque lievi-moderate senza necessita’ di ospedalizzazione, risoltesi nelle 48 ore).

Nawal Al Kaabi et al.

The incidence of COVID19 infection following emergency use authorization of BBIBPCORV inactivated vaccine in frontline workers in the United Arab Emirates

Nature, https://www.nature.com/articles/s41598-021-04244-1.pdf

CONTENUTO E COMMENTO : Studio di coorte prospettico condotto tra i lavoratori degli Emirati Arabi, esposti in prima linea al rischio di contagio da Sars-CoV2 e sottoposti ad un ciclo vaccinale con due dosi di BBIBP-CORV (settembre-dicembre 2020). Si tratta di un vaccino inattivato, approvato dalla WHO nella Emergency Use Listing. 11.322 individui sono stati sottoposti alla vaccinazione con due dosi di tale composto, con un’incidenza di infezioni sintomatiche pari allo 0.08 per 1000 persone al giorno, con un rischio assoluto di sviluppare un’infezione sintomatica dello 0.97%. Il tasso di sierconversione è risultato essere del 92.8%. Non sono stati riportati eventi avversi severi dopo la somministrazione, e nessuno dei vaccinati ha sviluppato una patologia severa da Sars-CoV2. In conclusione i dati dello studio risultano promettenti, con la forte limitante di un’assenza di un gruppo di controllo di non vaccinati e considerando che in assoluto molte altre variabili possono ridurre il tasso di infezioni osservato nel periodo dello studio.

Eyre D.W. et al.

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116597?query=featured_coronavirus

CONTENUTO E COMMENTO:  Studio osservazionale retrospettivo di coorte, svolto nel Regno Unito (1 gennaio-31 luglio 2021) nel quale sono stati studiati adulti di età maggiore di 18 anni, contatti di casi e casi indice(146243 contatti testati, 108498 indici testati) al fine di investigare associazioni tra trasmissione e stato vaccinale tra casi indice e contatti e studiare come queste cambino con le diverse varianti virali (alpha e delta) e la distanza temporale dal termine della vaccinazione.

Dei 146,243 contatti testa, 52,667 (37%) sono risultati positivi al test PCR per SARS-CoV2. I vaccini BNT e ChAd si sono dimostrati associati a una minore trasmissione di SARS-CoV2 dai casi che si sono infettati nonostante la vaccinazione (adjusted rate ratio BNT162b2, 0.32; 95% confidence interval [CI], 0.21 to 0.48; and with ChAdOx1 nCoV-19, 0.48; 95% CI, 0.30 to 0.78), seppur nei casi vaccinati con BNT e in maggiormente con ChAd, questa riduzione e’ stata minore sulla trasmissione della variante delta che sulla variante alfa (adjusted rate ratio BNT, 0.50; 95% CI, 0.39 to 0.65; adjusted rate ratio ChAdOx1, 0.76; 95% CI, 0.70 to 0.82).).

La vaccinazione e’ stata associata a piu’ basse cariche virali (alte Ct) nella variante alfa (non vaccinati median Ct value, 18.4; interquartile range, 15.7 to 22.5; BNT nei pazienti sintomatici,Valore mediano Ct, 27.4; interquartile range, 19.7 to 32.1 : ChAdOx, Ct mediano, 23.9; interquartile range, 18.1 to 32.5) e minor misura nella variante delta (BNT Ct mediano 18.0 (interquartile range, 15.8 to 21.8), ChAd Ct mediano 17.3 (interquartile range, 15.3 to 20.6), Non vaccinato Ct mediano 17.0 (interquartile range, 15.1 to 20.3): lo studio ha pero’ mostrato che la differenza nei valori Ct alla diagnosi dei casi era attribuibile solo per il 7/23% all’effetto della vaccinazione.

L’incidenza delle infezioni con la variante alfa e quelle con la delta erano minori nei contatti vaccinati con 2 dosi di BNT che in coloro vaccinati con 2 dosi di ChAd.

La protezione verso la trasmissione ai contatti e’ andata scemando nel periodo di 3 mesi dopo la seconda vaccinazione, in misura maggiore verso la variante delta, specialmente nei vaccinati con ChAd. I contatti erano piu’ soggetti a infettarsi maggiore il tempo trascorso della seconda vaccinazione.

Limitazioni : bias comportamentale (non investigati i soggetti che non avessero eseguito un test PCR), possibili altre fonti di contagio per i contatti altri che il caso, dati insufficienti su precedenti infezioni, utilizzati come proxy il periodo (10 maggio come spartiacque) e il S-gene target failure, non aggiustamenti su comorbidita’ e condizioni coesistenti.

Eyre, D. W., et al.

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2116597?articleTools=true

 CONTENUTO E COMMENTO: Studio osservazionale su contatti di casi accertati di COVID che valuta gli effetti dei vaccini Pfizer ed AstraZeneca sulla trasmissione della variante alpha e Delta di SARS-CoV-2. I contatti stretti di casi di COVID-19 che avevano ricevuto il vaccino BNT162b2 avevano un rischio  inferiore di risultare positivi durante le 14 settimane dopo la seconda vaccinazione rispetto a coloro che avevano ricevuto ChAdOx1 nCoV-19, anche se l'effetto protettivo di BNT162b2 svaniva più rapidamente.

Bar-On Y.M. et al.

The NEJM

Protection against Covid-19 by BNT162b2 Booster across Age Groups

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2115926?articleTools=true

CONTENUTO E COMMENTO : Studio analitico retrospettivo, condotto in Israele, utilizzando i dati del Ministero della Salute nel periodo di tempo tra il 30 luglio ed il 10 ottobre 2021, di 4.696.865 persone di età >16aa che avevano ricevuto almeno due dosi di vaccino BNT162b2 per Sars-CoV2 nei 5 mesi precedenti.  Tali dati sono stati poi utilizzati in una analisi primaria per comparare il tasso di casi di COVID-19, di malattia severa e di morte nel gruppo denominato booster, in persone sottoposte alla terza dose almeno 12 giorni prima dell’infezione vs un gruppo nonbooster. In una analisi secondaria sono state comparate le medesime variabili nel booster group vs. un early postbooster group, ovvero pazienti vaccinati con la terza dose dai 3 ai 7 giorni prima, il tutto stratificato per 5 diverse fasce di età. I risultati hanno mostrato che il tasso di infezioni da Sars-CoV2 confermate era inferiore di circa 10 volte nel booster group rispetto al nonbooster, e altresì minore nel booster rispetto all’early postbooster (da 4.9 fino 10.8 volte a seconda delle fasce di età considerate). Il tasso di malattie severe nel booster group era inferiore rispetto al nonbooster ed all’early postbooster rispettivamente di 17.9 e 6.5 volte nelle persone di età superiore ai 60 aa e di 21.7 e 3.7 rispettivamente nella popolazione tra i 40 e i 59 aa. Nella popolazione >60 aa la mortalità nel booster group era inferiore di 14.7 nell’analisi primaria e di 4.9 volte nella secondaria. Risulta quindi che il tasso di infezioni, di malattia severa e mortalità, risultano inferiori nella popolazione vaccinata con tre dosi, a distanza di 12 giorni dal booster.

Stuart A. S. V. et al.

Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902718-5

CONTENUTO : Trial di non inferiotità, randomizzato, in singolo cieco di fase 2, svolto nel Regno Unito (19 aprile-14 maggio 2021) nel quale adulti di età maggiore di 50 anni (1072 partecipanti), precedentemente vaccinati con una singola dose di BNT o ChAd sono stati randomizzati in tre gruppi con un rapporto di 1 :1 :1 al fine di ricevere una seconda dose I.M. dello stesso vaccino, di m1273 o di NVX (8-12 settimane dopo la prima dose). L’end point primario era una non inferiorità del GMR (superiore 0.63 per il one-sided 98·75% CI, criterio di non inferiorità) delle IgG anti spike nei riceventi il vaccino eterologo vs omologo a 28 giorni dalla seconda dose. Nel gruppo vaccinato con ChAd (prima dose) la GMC a 28 giorni dalla seconda dose con m 1273 o NVX risultava non inferiore a quello dei riceventi la dose omologa (GMR 10.2, one-sided 98·75% CI 8·4 to ∞ per m1273 e 2.8 per NVX). Nella popolazione vaccinata con BNT veniva dimostrata allo stesso modo una non inferiorità nei riceventi m1273 vs. 2 dosi di BNT ma non nel gruppo vaccinato con NVX come seconda dose, nonostante una buona risposta anticorpale elicitata da quest’ultimo a 28 giorni. In totale sono stati segnalati 15 eventi avversi severi, con un profilo di sicurezza buono per entrambi i gruppi eterologhi. I risultati mostrano che un ciclo vaccinale eterologo, in particolare con m1273 come seconda dose in vaccinati con BNT e ChAd risulta essere una strategia percorribile ed efficace al fine di rendere più rapida una immunizzazione a livello globale.

COMMENTO :  Studio molto interessante che dimostra la possibilità di immunizzazione primaria eterologa, cioè una seconda dose con vaccino diverso dalla prima. L’end point è la non inferiorità in termini di risposte immuni fra recipienti vaccinazione eterologa rispetto all’omologa. Come seconda dose viene usato il vaccino Novavax, od il vaccino Moderna mentre come prima dose sono usat i vaccini Asta-Zeneca (ChadOx) e Pfizer Biontechancora non approvato in Europa o negli States.  In termini immunologici, l’eterologa Astra-Zeneca-Novavx  è non inferiore all’omologa ma la non inferiorità non è raggiunta da Novavax come seconda dose quando la prima è Pfizer. Comunque sempre, la secinda di Novavax è meno reattogenica. I dati suggeriscono che Novavax può anche potenziare immunologicamente l’immunizzazione con Chadox e la rende più sicura, delineando per questo vaccino proteico sopratutto l’uso come richiamo.

Elie Dolgin

Omicron is supercharging the COVID vaccine booster debate

Nature, https://www.nature.com/articles/d41586-021-03592-2

CONTENUTO : Articolo pubblicato su Nature finalizzato ad analizzare le attuali strategie vaccinali, la disparità tra l’allocazione delle dosi vaccinali nei vari paesi del mondo ed il possibile approccio diversificato e specifico, con l’introduzione di nuovi composti vaccinali, per le VOC in circolazione, in particolare l’Omicron.

COMMENTO : dovrebbe essere letto integralmente da tutti gli stake-holders  di politica sanitaria.

Clinical Infectious Diseases

Rate and Risk Factors for Severe/Critical Disease Among Fully Vaccinated Persons with Breakthrough SARS-CoV-2 Infection in a High-risk National Population

Butt AA et al, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab1023/6459161

CONTENUTO : Studio retrospettivo caso-controllo con l’obiettivo di valutare la gravità clinica dell’infezione da SARS-CoV-2 in persone precedentemente vaccinate, in termini di ricovero in terapia intensiva, necessità di ventilazione meccanica e morte entro 28 giorni o durante l’ospedalizzazione.Nello studio sono state incluse 1728 persone vaccinate con infezione da SARS-CoV-2, messe a confronto con 1728 persone non vaccinate matchate secondo propensity-score.I risultati mostrano un tasso di incidenza di malattia severa/critica per 1000 giorni-paziente di 0.55 nei soggetti vaccinati e di 1.22 nei soggetti non vaccinati (p<0.0001). Il rischio di malattia severa/critica aumenta con l’età ed è maggiore nei pazienti con ≥4 comorbidità, mentre è significativamente minore nei soggetti vaccinati.

COMMENTO: Si tratta di un interessante studio caso-controllo anche se condotto in maniera retrospettiva. Vengono comparati gravità clinica e spressa come ricovero in terapia intensiva, necessità di ventilazione meccanica e morte entro 28 giorni o nel caso dell’ospedalizzazione nel gruppo dei vaccinati nei confronti dei non vaccinati. Lo studio piuttosto numeroso (ha incluso oltre 1200 soggetti) ha mostrato l’efficacia della vaccinazione nel prevenire le forme gravi di malattia. Anche se il rischio aumentava con l’età e con la presenza di un certo numero di co-morbidità, le persone vacciante avevano un livello di protezione più alto rispetto a chi non era vaccinato.

Gillot C et al.

Dynamics of Neutralizing Antibody Responses Following Natural SARS-CoV-2 Infection and Correlation with Commercial Serologic Tests. A Reappraisal and Indirect Comparison with Vaccinated Subjects

Viruses, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621742/pdf/viruses-13-02329.pdf

COMMENTO: Studio che mira a valutare la dinamica degli anticorpi neutralizzanti in paziente con infezione da SARS-CoV-2. In particolare, la maggior parte dei pazienti con infezione da SARS-CoV-2 tenderebbero a mantenere la positività degli anticorpi neutralizzanti a sei mesi dall’esordio dei sintomi. Tale coorte di pazienti viene poi indirettamente confrontata con una coorte di operatori sanitari vaccinati con doppia dose di Pfizer-BioNTech: meno della metà dei vaccinati sembrerebbe mantenere a sei mesi la positività degli anticorpi neutralizzanti.

Rosemberg E.S. et al.

Covid-19 Vaccine Effectiveness in New York State

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2116063?articleTools=true

CONTENUTO :Studio di coorte retrospettivo svolto nello stato di New York (maggio-agosto 2021), unendo quattro database contenenti le informazioni sanitarie e dei cicli vaccinali per Sars-CoV2 con i tre vaccini approvati dall’FDA (BNT162b2, mRNA-1273 e Ad26.COV2.S), di 8.690.825persone (età>18 aa), e finalizzato a valutarne l’efficacia nei confronti dell’infezione da Sars-Cov-2 e l’ospedalizzazione ad esso legata e la variazione nel tempo di queste ultime due variabili. La coorte includeva 5.638.142 persone che avevano completato entrambe le dosi di vaccino, delle quali il 45% con BNT162b2, il 41.5% con mRNA-1273 ed il 10% con Ad26.COV.S. Durante il follow-up si sono osservati 38.419 casi di COVID-19 e 2534 ricoveri in tale gruppo, contro i 122.446 casi di COVID-19 e 12.123 ospedalizzazioni nel gruppo dei non vaccinati (2.074.191 persone). Nella prima settimana di Maggio 2021 la mediana del numero di casi di COVID-19 nel gruppo dei vaccinati era di 2.4 ogni 100.000 persone vs. 34.6 casi ogni 100.000 persone nei non vaccinati. Una riduzione dell’efficacia dei vaccini si è riscontrata con l’aumento della prevalenza della variante Delta; infatti nelle persone riceventi la seconda dose entro aprile si riscontrava a maggio un efficacia del 91.3% per BNT162b2, del 96.9% per mRNA-1237 e dell’86.8% per Ad26.COV2.S. Nell’ultima settimana di  agosto dello stesso anno l’efficacia per BNT162b2 risultava del 72.3%, per mRNA-1273 del 77.8% e per Ad26.COV2.S del 69.4%. In particolare la percentuale maggiore di riduzione di efficacia tra i periodi analizzati si è osservata per tutti e tre i composti nella fascia di età tra i 50 ed i 64 aa. La protezione dei vaccini analizzati nei confronti dell’ospedalizzazione risultava essere > del 90% tra i 18 ed i 64 aa. In conclusione la riduzione dell’efficacia dei vaccini è risultata essere correlata all’aumento della diffusione della variante delta, con un declino della protezione, in proporzione, più evidente nel gruppo ricevente BNT162b2. In ogni caso la protezione nei confronti dell’ospedalizzazione si è mantenuta alta nel tempo, con una minore efficacia nel gruppo>65 aa e nei riceventi Ad26.CoV2.S.

COMMENTO :  In questo corposissimo studio, eseguito su pazienti dello  Stato di New York  viene chiaramente dimostrato che l’effettività vaccinale contro l’infezione da SARS-CoV-2 cala sensibilmente , gradualmente entro 6 mesi con tutt’e tre i vaccini in correlazione inversa con la prevalenza della variante delta, ma non cala significativamente la protezione contro l’ospedalizzazione per COVID-19. Un pò di waningimmunity c’è ma la ragione profonda per il decadimento anti-infettivo è l’emergenza di delta. Interessante notare i dati della Tabella ospedalizzazione : nei giovani e negli anziani. Nei primi , vaccinati con BNT o Moderna, di fatto non c’è alcun decadimento di effettività vaccinale. Nei secondi un pochino ce n’è , specialmente nei vaccinati con BNT(da 95% ad 87%, significativa perchè i numeri sono altissimi, più di due milioni di soggetti). Questi dati fanno pensare che la dose booster andrebbe usata solo dopo 6 mesi e comunque solo nei soggetti anziani (noi la stiamo usando dai 5 mesi ed anche nei quarantenni).

Munro A.P.S. et al.

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902717-3

CONTENUTO :Trial multicentrico, controllato, randomizzato, in doppio cieco, di fase 2, condotto in 18 centri del Regno Unito, al fine di valutare l’immunogenicità e la reattogenicità di 7 differenti vaccini utilizzati come dose booster (terza somministrazione, dopo due dosi di ChAdOx1 nCov-19 o BNT162b2). Un totale di 2557 partecipanti (tra i 30 e i 70 aa), ad almeno 84 giorni dalla seconda dose di vaccino, sono stati randomizzati in tre gruppi A, B e C. I partecipanti di tutti i gruppi sono stati inoltre assegnati al gruppo ricevente il vaccino sperimentale come booster o nel gruppo di controllo. Il gruppo A è stato a sua volta diviso in sottogruppi che hanno ricevuto una dose booster di NVX-CoV2373, metà dose di quest’ultimo, ChAd, o il vaccino coniugato quadrivalente meningococcio (controllo) in un rapporto di 1 :1 :1 :1. I partecipanti del gruppo B hanno ricevuto con lo stesso rapporto (1 :1 :1 :1 :1) una dose di BNT, di VLA2001, metà dose di quest’ultimo, Ad26.COV2.S o MenACWY. Il gruppo C ha ricevuto mRNA1273, CVnCoV, metà dose di BNT o MenACWY. Tre composti vaccinali hanno dimostrato una reattogenicitàmaggiore : m1273 (dopo Chad/Chad e BNT/BNT) e Chad e Ad26 (dopo BNT/BNT). L’astenia e il dolore nella sede di iniezione sono stati gli eventi avversi più frequentemente registrati. In totale si sono registrati 24 eventi evversi severi : 5 nel gruppo di controllo, 2 nel gruppo Ad26, 5 nel gruppo VLA, 1 nel gruppo con dose dimezzata di VLA, 1 nel gruppo BNT, 2 nel gruppo con dose dimezzata di BNT, 2 nel ChAd, 1 in CVn, 2 in NVX, 2 nella dose dimezzata di NVXw ed 1 in m1273.Nei partecipanti vaccinati con Chad/Chad gli spike IgG geometricmeanratios (GMRs) tra i vaccini dello studio e i controlli variavano dall’ 1.8 nei riceventi la dose dimezzata di VLA al 32.3 nel gruppo ricevente m1273. Nei partecipanti vaccinati con BNT/BNT variavano dall’1.3 del gruppo con dose dimezzata di VLA all’11.5 del gruppo m1273. Non sono state denotate particolari variazioni nella risposta tra differenti fasce di età. In conclusione tutti i vaccini presi in considerazione (ad eccezione di VLA dopo BNT/BNT) hanno dimostrato che l’immunogenicità elicitata da essi utilizzati come booster è risultata essere superiore rispetto ai controlli, indipendentemente da quale ciclo vaccinale avessero completato in precedenza, con un sostanziale buon profilo di sicurezza.

COMMENTO : Uno studio complesso, controllato e randomizzato a blocchi, in cui si dimostra che parecchi vaccini, anche a dosaggi diversi, sono in grado di ben funzionare come booster eterologo, alzando marcatamente il livello anticorpale, sia dopo una immunizzazione primaria (due dosi) del vaccino Chadox  (AtraZeneca) che dopo quella con BNT (Pfizer BionTech). Un booster con Moderna (50 microgrammi) eleva di parecchio la reattogenicità dopo la vaccinazione primaria sia ChaDOX che BNT (entro 15% soprattutto fatigue, spossatezza). Tener conto della disponibilità vaccinale, categorie di soggetti, prevalenza dell’infezione e della malattia  ed ovviamente autorizzazione all’uso  per la scelta (alcuni dei vaccini usati non sono ancora disponibili).

Tenforde MW et al.

Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2786039

CONTENUTO : Studio caso-controllo condotto su 4.513 pazienti ricoverati in 21 centri statunitensi tra l’11 marzo e il 14 luglio 2021, dove 1983 pazienti ricoverati per COVID-19 sono stati confrontati con 2530 pazienti ricoverati per cause non COVID-relate. In questa popolazione, i non vaccinati rappresentavano l’84% dei pazienti COVID, ed essere ricoverati per COVID-19 è risultato significativamente associato con l’essere non vaccinati, e tale dato è stato confermato sia per infezioni determinate dalla variante Alpha che dalla variante Delta. L’associazione, tuttavia, si è dimostrata meno significativa a partire da 120 giorni dopo la vaccinazione con BNT162b2 (Pfitzer). Inoltre, nei pazienti COVID, morte e necessità di ventilazione meccanica sono risultati significativamente associati con l’essere non vaccinati.

COMMENTO: Lo studio è stato condotto su 4.513 pazienti ospedalizzati di sesso bilanciato (49% femminile), di etnia variata (33% di etnia nera e 16% di ispanica) e includente un 20% di soggetti immunocompromessi. Il gruppo dei casi comprendeva 1.983 pazienti ricoverati per COVID-19 confrontati con un gruppo controllo di 2.530 pazienti. In particolare i risultati dello stdio evidenziano per il gruppo dei pazienti ricoverati per COVID-19: 1) l’efficacia della vaccinazione, più robusta nei soggetti immunocompetenti, per quanto riguarda l’ospedalizzazione, le probabilità di essere sottoposti a ventilazione meccanica e la morte, entro 28 giorni; 2) il declino dell’efficacia vaccinale dopo 120 giorni, specie per il vaccino Pfizer più che per il vaccino Moderna. In sostanza questi dati rappresentano ulteriore conferma di quanto segnalato in altri studi.

Mizrai B et al.

Correlation of SARS-CoV-2-breakthrough infections to time-from-vaccine

Nature Communications, https://www.nature.com/articles/s41467-021-26672-3                              

CONTENUTO : Studio analizzante l’incidenza di infezioni breakthrough in una popolazione di 1,395,134 individui che hanno completato il ciclo vaccinale con BNT162b2 (Pfitzer/BioNTech) in Israele. Analizzando, nel periodo tra il 1° giugno e il 27 luglio 2021, l’incidenza delle infezioni in questa popolazione, lo studio rileva una significativa correlazione con l’intervallo di tempo trascorso dal completamento del ciclo vaccinale. In particolare, il tasso di incidenza standardizzato per 10,000 individui è risultato del 36.5, 33.6, 23.1, 16,9 per i soggetti che hanno completato la vaccinazione, rispettivamente, nei mesi di gennaio, febbraio, marzo e aprile 2021.

COMMENTO: Il rilievo di un declino dell’efficienza vaccinale di 1,5 volte globalmente nel periodo considerato dallo studio, ma di 2,25 volte a distanza di 5 mesi dal completamento del ciclo di vaccinazione con vaccino Pfizer, ha avuto un forte impatto sulla comunità scientifica e sulle istituzioni preposte alla regolamentazione delle campagne vaccinali. Il dato ha potuto essere riscontrato in Israele dove la vaccinazione di massa è stata avviata più precocemente. Questo, congiuntamente all’irruzione sulla scena della variante Delta più trasmissibile, ha indotto all’adozione di una “terza dose di rinforzo” in tutti i paesi dell’Occidente industrializzato. Ma indubbiamente complica terribilmente la policy vaccinale preconizzata per i paesi in via di sviluppo, dove si prevede la somministrazione delle “prime dosi” nel 70% della popolazione entro il 2022.

Toledo-Romani M.E. et al.

Efficacy and safety of SOBERANA 02, a COVID-19 conjugate vaccine in heterologous three-dose combination

MedRxiv, https://www.medrxiv.org/content/10.1101/2021.10.31.21265703v2.full.pdf

CONTENUTO :Trial clinico randomizzato, in doppio cieco, placebo-controllo di fase 3 svolto a Cuba (marzo 2021), finalizzato a valutare l’efficacia nel prevenire l’infezione da Sars-CoV2 sintomatica e la sicurezza di un vaccino glico-coniugato (RBD ricombinante e tossina del tetano, SOBERANA 02) anche nell’ambito di una combinazione di tre somministrazioni vaccinali eterologhe. In particolare sono stati randomizzati 44.031 partecipanti, tra i 19-80 aa, in tre gruppi differenti : un primo gruppo ricevente due dosi di SOBERANA 02 a distanza di 28 gg (14.697 persone), un secondo gruppo ricevente due dosi di SOBERANA 02, con la terza dose di SOBERANA plus, booster avente come antigene un dimero RBD (14.677 persone) e un terzo gruppo ricevente placebo (14.675 persone). I risultati dello studio hanno dimostrato un buon profilo di sicurezza del vaccino, con il dolore nella sede di iniezione come disturbo più frequentemente evidenziato (7.7% dei casi dopo la prima dose di vaccino vs. 2.6% nel placebo), con reazioni sistemiche avverse severe nello 0.6% dei casi dopo la prima dose di vaccino, in particolare in una popolazione tra i 19-64 aa. Dal punto di vista dell’efficacia nel prevenire un’infezione da Sars-CoV2 sintomatica i risultati hanno mostrato il riscontro di 43 casi di COVID-19 nel gruppo dei vaccinati con due dosi vs. 155 casi nel gruppo placebo, con un efficacia vaccinale del 71%. Nel gruppo ricevente tre dosi eterologhe l’efficacia del vaccino nel prevenire l’infezione sintomatica è risultata del 92.4% (15 casi vs.155 casi). La prevenzione del COVID-19 severo delle due dosi è risultata essere del 63% mentre per lo schema a tre dosi del 100%. La prevenzione dell’exitus nel primo gruppo è risultata del 59%, mentre nel secondo del 100%.

COMMENTO : Questa pubblicazione ( ancora da sottoporre a peer review) è un esempio di un vaccino fatto in casa (Cuba) causa anche l’embargo di reagenti verso Cuba da parte degli US. E’ una classica formulazione di una o due molecole di RBD dello Spike coniugato alla tossina tetanica, e con l’alluminio come adiuvante, insomma un classico dei coniugati ma fatto con peptide al posto dei polisaccaridi come antigene. Nonostante manchino dettagli nè su come è stato ftto il trial nè sulla sicurezza ( definita molto buona comunque) si riporta una buona efficacia (attorno al 70%) con due dosi del vaccino con una molecola di RBD  ed una decisamnete più alta se alle due dosi del primo fa seguito una terza dose conil vaccino RBD duplex. Il vaccino è stato autorizzato dall’Ente regolatorio cubano e viene correntemente usato. Un buon esempio di chi fa per sè ma una parola definitiva sul rapporto rischio benefico potrà venire dalla pubblicazione dei dettagli della sperimentazione e dell’uso reale nella popolazione.

Tenforde M.W. et al.

Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2786039

CONTENUTO : Studio caso-controllo svolto negli Stati Uniti dall’ Influenza and OtherViruses in the Acutely Ill (IVY) Network, una rete di collaborazione tra 21 strutture ospedaliere ed i Centers for Disease Control and Prevention, al fine di valutare l’associazione tra la precedente vaccinazione a m-RNA con due dosi per Sars-Cov2 e l’ospedalizzazione per COVID-19 ( casi : pazienti ospedalizzati per COVID-19 ; controlli : pazienti ospedalizzati per altre cause). Inoltre è stata valutata la progressione della patologia da Sars-CoV2 nei pazienti ospedalizzati ( casi e controlli : pazienti con e senza progressione verso il decesso o la ventilazione meccanica). In particolare su una popolazione di 4513 pazienti ospedalizzati tra il marzo e l’agosto 2021 (mediana di età di 59aa), 1983 sono stati i pazienti con COVID-19 (casi, 82% non vaccinati) vs 2530 non affetti da Sars-Cov2 (controlli). I risultati dello studio hanno dimostrato che l’ospedalizzazione è risultata essere molto più frequentemente osservata in una popolazione non vaccinata (casi : 15.8% ; controlli : 54.8%). Tale associazione è risultata essere più forte nei pazienti immunocompetenti, meno in una popolazione immunocompromessa. Inoltre la probabilità di ospedalizzazione era maggiore a 120 giorni di distanza dalla seconda dose di vaccino BNT162b2 rispetto al vaccino mRNA.1273 (rispettivamente 5.8% vs. 11.5% per il primo ; 1.9% vs. 8.3% per il secondo). Una probabilità crescente di progressione di malattia verso il decesso o la ventilazione meccanica a 28 giorni dal ricovero risulta essere maggiormente rappresentata nella popolazione non vaccinata (12% vs 24.7%). Tali dati dimostrano il ruolo protettivo della vaccinazione a m-RNA per Sars-CoV2 nei confronti dell’ospedalizzazione e del COVID-19 severo o il decesso.

COMMENTO : C’è una chiara associazione fra vaccinazione(due dosi di uno dei due vaccini ad mRNA) e protezione da COVID-19, nelle sue varie forme cliniche, soprattutto nei soggetti immunocmpetenti ed anche in infetti dalla variante delta, almeno fino  a 4 mesi dopo la seconda dose ( sappiamo che negli immunocompetenti, l’intervallo di protezione delle due dosi è parecchio più lungo, almeno verso la malattia che richiede ventilazione meccanica invasiva). Un dato interessante, che anche collima con risultati di altre riceche, è un’associazione fra vaccinazione e minore ospedalizzazione più forte con l’uso del vaccino di Moderna rispetto a quello della Pfizer BT.  I numeri sono buoni ma non tanto da consentire importanti stratificazioni per età e sesso od altri fattori. Infine , ha i soliti limiti degli studi osservazionali (fattori confondenti non misurabili).

Burckhardt RM, et al.

Are COVID-19 Vaccine Boosters Needed? The Science behind Boosters

J Virol, https://journals.asm.org/doi/epdf/10.1128/JVI.01973-21

CONTENUTO E COMMENTO: Interessante review che passa in rassegna gli aspetti che influenzano la riduzione dell’immunità nel tempo, il rischio di reinfezione e gli ostacoli al raggiungimento dell’immunità di gregge per SARS-CoV-2.

Bosch W et al.

COVID-19 Vaccine-Breakthrough Infections Requiring Hospitalization in Mayo Clinic Florida through August 2021

Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab932/6415962

CONTENUTO : Studio retrospettivo analizzante i dati dei pazienti vaccinati ricoverati alla Mayo Clinic, Florida, entro il 28 agosto 2021. Su 6161 pazienti con COVID-19, le infezioni “breaktrough” sono state 1120 (18%), quasi tutte (97%) diagnosticate dopo l’avvento della variante Delta. La popolazione con infezione “breaktrough” è risultata essere significativamente più anziana e immunocompromessa. Questo studio mette in risalto come, assieme ai vaccini, non debbano essere trascurate altri interventi non-farmacologici come mascherine, distanziamento sociale e ventilazione degli spazi chiusi.

COMMENTO: Lo studio evidenzia come, con l’avvento della variante Delta, il vaccino non metta completamente al riparo anche dall’evenienza di casi di malattia grave ospedalizzata. La variante Delta infatti in una piccola percentuale “buca” la protezione vaccinale specie nei pazienti immunocompromessi e anziani. Anche per i vaccinati pertanto devono essere mantenuti i sistemi di contenimento di sanità pubblica. Aggiungiamo che l’avvento della variante Delta ha evidenziato l’utilità della terza dose, almeno per le popolazioni fragili e maggiormente esposte al rischio di contagio.

Naam Barda et al.

Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902249-2

CONTENUTO : Studio osservazionale, condotto in Israele, al fine di valutare l’efficacia della terza dose di vaccino per Sars-CoV2 BNT162b2 nel prevenire gli outecomes del COVID-19 severo. A tale scopo sono stati utilizzati i dati raccolti dalla più vasta organizzazione sanitaria di Israele (Clalit Health Services), prendendo in considerazione la popolazione ricevente la terza dose dal 30 luglio 2020 al 23 settembre 2021. La popolazione eleggibile doveva aver ricevuto la seconda dose di vaccino almeno 5 mesi prima del reclutamento, non doveva aver avuto infezioni pregresse da Sars-CoV2 documentate e nessun accesso in strutture sanitarie nei tre giorni precedenti il reclutamento. Outcome primari : ricoveri ospedalieri COVID-19-relati, la malattia severa e l’exitus dovuto al COVID-19. La popolazione ricevente la terza dose ed eleggibile è stata comparata ad una popolazione di controllo, demograficamente e clinicamente simile, che non ha ricevuto la terza dose (728.321 persone per gruppo, 51% di sesso femminile, mediana di 52 aa). I risultati ottenuti, dopo un follow-up medio di 13 giorni per entrambi i gruppi, hanno mostrato una efficacia della terza dose di vaccino, comparata con le due dosi, del 93% contro il ricovero ospedaliero (231 nel gruppo delle due dosi vs. 29 nel gruppo con tre dosi), del 92% contro lo sviluppo di una malattia severa (157 vs. 17 casi) e dell’81% contro il decesso COVID-19 relato (44 vs. 7 casi). Tali evidenze suggeriscono una protezione efficace e maggiore delle tre somministrazioni del vaccino BNT162b2 nei confronti degli outecomes presi in considerazione nello studio.

COMMENTO :Questo importantissimo studio  mostra che  La terza dose del vaccino Pfizer-BT rialza il livello di protezione  sia dall’ospedalizzazione che dalla malattia grave in una popolazione, quella israeliana, che aveva ricevuto le due dosi entro i primi mesi del 2021 e con una documentata perdita di livello anticorplale, in una situazione epidemica con la variante delta dominante .  Il dato sembra chiaro, ma è interessante guadare le Tabelle in cui si notano differenze non piccole nella protezione per sesso e fasce di età. In particolare, nella fascia di età giovane, 16-39 anni, in cui il rischio di ospedalizzazione e malattia grave è molto piccolo, non ci sono apprezzabili differenze di rischio  di ospedalizzazione/malattia grave fra chi ha ricevuto solo due dosi e chi ha fatto anche la terza dose.  Sono dati importanti per stabilire a chi somministrare la terza dose oltre ai soggetti immunodepressi, fragili per anzianità ed esposizione ripetute ad infezione, tenendo anche conto che in quella fascia di età i soggetti di sesso maschile, in particolare quellifra 12 e 24 anni, hanno un rischio non trascurabile (1 :10000-1 :20000) di  un evento avverso grave quale pericardite/miocardite. E’ molto interessante come i colleghi israeliani hanno organizzato questo studio, in particolare le modalità del confronto fra casi (tre dosi) e controlli (due dosi) : per ogni dato giorno di reclutamento per la terza dose il soggetto veniva comparato, per ogni evento studiato, ad una altro soggetto con pari caratteristiche (età (entro due anni di differenza), sesso, fattore di rischio, etc) che aveva fatto solo  le due dosi, quindi un controllo, ma quando quest’ultimo soggetto faceva la terza dose, era arruolato nei casi e veniva a sua volta paragonato ad un nuovo controllo di due dosi e così via : questo sistema ha richiesto una perfetta programmazione a monte   perchè tutti i soggetti alla fine sono diventati dei casi e le differenze di protezione sono evidentemente limitate al breve periodo di follow-up dello studio.

Lucas C. et al.

Nature, Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity

https://www.nature.com/articles/s41586-021-04085-y_reference.pdf

CONTENUTO : : Studio in vitro, condotto presso la Yale University, al fine di valutare la produzione anticorpale e la risposta  cellulo-mediata in due gruppi di pazienti (con pregressa infezione da Sars-CoV2 o naive) successivamente vaccinati con due dosi di vaccini a mRNA e l’impatto delle varianti del virus circolanti nel periodo di studio, sull’immunità vaccino-indotta. 40 lavoratori dello Yale-New Heaven Hospital sono stati arruolati tra il novembre 2020 al gennaio 2021, per un totale di 198 campioni di plasma. I campioni sono stati ottenuti al tempo 0, 7 e 28 giorni dopo la prima dose di vaccino e 7-28 e 70 giorni dopo la seconda dose. Così come già documentato in altri studi è stato riscontrato un titolo anticorpale di IgG virus-specifiche più elevato nei pazienti con pregressa infezione e vaccinati. Non sono state rilevate differenze sostanziali tra i due gruppi nell’attività neutralizzante nei confronti della variante SARS-CoV-2 USA-WA1/2020 (lineage A). E’ stata inoltre valutata la capacità neutralizzante dei campioni di plasma nei confronti di 18 differenti tipi di Sars-CoV2, geneticamente distinti tra loro. Il panel considerato includeva varianti attualmente classificate come variants of concern e variants of interest. Inoltre sono state considerate varianti con mutazioni del gene S come B.1.517 con N501T, e B.1 ed R.1 con E484K. 8 delle 11 mutazioni del gene S hanno mostrato effetti negativi sulla neutralizzazione da parte degli anticorpi indotti dal  vaccino-, in particolare con un impatto maggiore tra tutti, dei ceppi sopracitati (E484K e N502Y/T) e della singola mutazione L452R. Dallo studio inoltre si evince che la presenza di anticorpi neutralizzanti nei pazienti con pregressa infezione e successivamente vaccinati, è risultata essere maggiore rispetto al gruppo dei non infetti, anche nei confronti delle varianti con mutazioni della regione del receptor binding domain.

COMMENTO: Sembra del tutto ovvio che i soggetti vaccinati dopo una precedente infezione abbiano risposte anticorpali e cellulari più alte dei soggetti vaccinati ma naive per l’infezione, visto  la dimostrata presenza nei convalescenti di cellule di memoria specifica assenti nei non infetti... Ciò detto, non si capisce perché , secondo gli Autori, questi dati dimostrano la necessità della terza dose su cui in realtà questo paper non dimostra né l’urgenza né l’ovvietà. Interessanti i dati sulla neutralizzazione delle varianti, ma sono pochi i soggetti studiati per una conclusione davvero significativa.

Shachor-Meyouhas Y. et al.

Single BNT162b2 vaccine dose produces seroconversionin under 60 s cohort

Vaccine,

https://reader.elsevier.com/reader/sd/pii/S0264410X2101327X?token=518D1B8C0FFA126D303B837155C367FC9F77D95D2C8F1787BF9E23EE14B7532C9BC2EB6901AEA987E6F94FEA3D750F80&originRegion=eu-west-1&originCreation=20211105152040

CONTENUTO : Studio retrospettivo, condotto in Israele presso l’RHHC, una struttura sanitaria con un bacino di utenza di 2.3 milioni di cittadini. Tale studio è finalizzato alla valutazione della sieroconversione dopo la prima dose di vaccino BNT162b2 e l’associazione tra tale sieroconversione ed età e sesso. 1898 membri del personale di tale struttura, dopo la prima dose di vaccino, sono stati sottoposti ad un test sierologico subito prima di ricevere la seconda dose, con il 68.7% della popolazione testata di sesso femminile ed una mediana di età di 47.4 aa. Il tasso di positività delle sierologie è stato del 92.7% a 21 giorni dalla prima somministrazione, con una mediana dei livelli anticorpali di 61 AU/mL. I risultati inoltre hanno dimostrato una più frequente positività delle sierologie nei soggetti testati di sesso femminile, a qualsiasi intervallo di tempo dalla prima dose preso in considerazione nello studio. Inoltre i pazienti di età> di 60 anni hanno mostrato un tasso di sieropositività inferiore rispetto alle fasce di età più giovani. Lo studio è finalizzato a dimostrare che l’importante tasso di sieroconversione dopo una singola dose di vaccino per Sars-CoV2 BNT162b2 può aprire nuovi scenari rispetto alla campagna vaccinale portata avanti a livello globale, giustificando un intervallo maggiore tra la somministrazione delle due dose (rispetto ai 21 giorni), riducendo comunque nel contempo i contagi legati al Sars-CoV2.

COMMENTO : E’ un ampio survey retrospettivo della cinetica di produzione degli anticorpi anti spike a vari tempi dalla somministrazione del vaccino Pfizer-Biontech, con molti dati, in essenza, già noti. Mette in rilievo la più alta risposta anticorpale distanziando fra prima e seconda dose più di quanto stabilito nel trial clinico, e questo fa dire agli Autori che la strategia di questo distanziamento di dosi è stata utile per immunizzare più persone. In realtà, un distanziamento ragionevole /fino a 6 settimane, è quello consigliato dai CDC, mentre uno più lungo è costato in Inghilterra un certo numero di soggetti infetti ed alcuni decessi nel lungo tempo intercorrente fra prima e seconda dose. Assolutamente non consigliabile in periodi di elevata circolazione del virus, meno che mai se questo virus si chiama delta.

Tenforde MW et al

Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2786039

CONTENUTO : Studio retrospettivo caso-controllo condotto su 4513 pazienti ospedalizzati per COVID-19 con l’obiettivo di valutare l’associazione tra aver ricevuto un vaccino anti-COVID-19 a mRNA (sia Pfizer-BioNTech che Moderna) e l’ospedalizzazione per COVID-19 o la progressione di malattia (morte o ventilazione meccanica).

L’ospedalizzazione per COVID-19, incluse le varianti Alfa e Delta, si è dimostrata associata in maniera significativa ad una ridotta probabilità di aver ricevuto la vaccinazione. Quest’associazione si è dimostrata più forte per i pazienti immunocompetenti che per gli immunocompromessi. Inoltre, anche la probabilità di morte o ventilazione meccanica al giorno 28 è risultata associata ad una ridotta probabilità di aver ricevuto il vaccino.

Questi risultati supportano una riduzione del rischio di infezioni gravi da SARS-CoV-2 e di outcome clinico sfavorevole nei pazienti vaccinati in confronto ai pazienti non vaccinati.

COMMENTO: Questo studio conferma, su un numero significativo di soggetti vaccinati con vaccino a mRNA (sia Moderna che Pfizer) che il rischio di ospedalizzazione per infezioni da varianti Alfa e Delta, è molto maggiore nei soggetti non vaccinati rispetto a quelli vaccinati  anche se questi ultimo possono essere non indenni dall’infezione.

North MC et al.

Determining the Incidence of Asymptomatic SARS-CoV-2 Among Early Recipients of COVID-19 Vaccines (DISCOVER-COVID-19): A Prospective Cohort Study of Healthcare Workers Before, During and After Vaccination

Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab643/6345339?searchresult=1

CONTENUTO : Studio di coorte prospettica coivolgente 2247 operatori sanitari residenti Boston, Massachissets, tra il 30 dicembre 2020 e il 2 aprile 2021, a cavallo dell’introduzione e dell’implementazione della vaccinazione anti-SARS-CoV2. In totale, 19 pazienti (0.8%) hanno sviluppato infezione da COVID-19 nel periodo di studio, nessuno dei quali necessitante di ricovero ospedaliero, con incidenza significativamente inferiore nel periodo post-vaccinazione. I 4 pazienti che hanno sviluppato infezione asintomatica sono risultati positivi con alti cicli di replicazione (indicanti bassa carica virale) e hanno presentato tampone negativo dopo soli 2 giorni, mettendo in dubbio l’effettiva validità della diagnosi di infezione.

COMMENTO: L’impatto favorevole della vaccinazione negli operatori sanitari è indirettamente dimostrata dall’incidenza significativamente inferiore di casi di infezione da SARS-CoV-2 nel periodo successivo all’esordio della pratica di vaccinazione. Nessuno ha dovuto ricorrere alla ospedalizzazione e, fra i casi asintomatici, è stata evidenziata la presenza di basse cariche virali e precoce negativizzazione del tampone molecolare. Oggi, peraltro, sappiamo che, assodata l’efficacia a breve, è particolarmente importante monitorare la durata dell’immunizzazione conferita dal vaccino.

Andreano E. et al.

Hybrid immunity improves B cells and. antibodies against SARS-CoV-2 variants

Nature, https://www.nature.com/articles/s41586-021-04117-7_reference.pdf

CONTENUTO : Studio in vitro in collaborazione con l’Azienda Ospedaliera Senese, riguardante l’analisi delle singole B cells della memoria su campioni di sangue di 5 pazienti naive e 5 pazienti convalescenti dal COVID-19, tutti vaccinati con BNT162b2mRNA, per analizzare la natura di tali cellule e la risposta anticorpale correlata. Più di 6000 cellule sono state  selezionate e oltre 3000 di esse hanno prodotto anticorpi monoclonali contro la proteina spike del Sars-CoV2. Più di 400 anticorpi hanno dimostrato di neutralizzare il ceppo originario di Sars-CoV2 di Wuhan, mentre più del 70% degli anticorpi oggetti di studio si sono dimostrati inefficaci nei confronti delle varianti beta e gamma. La differenza sostanziale nella produzione di anticorpi neutralizzanti tra il gruppo naive e quello dei convalescenti, è da ascrivere perlopiù alla presenza di una linea germinale (IGHV2-5;IGHJ4-1) presente solo nel secondo gruppo, responsabile di una produzione anticorplare robusta e ad ampio spettro. Il gruppo dei sieropositivi ha mostratro un aumento 2.46 volte superiore. Questa evidenza suggerisce una maggiore protezione della popolazione convalescente e successivamente vaccinata, nei confronti delle varianti di nuova insorgenza.

COMMENTO : Questo magnifico lavoro diretto da Rino Rappuoli, un ricercatore di altissimo calibro, dimostra che nei soggetti vaccinati con un vaccino mRNA e poi infettati e convalescenti da COVID-19 si attiva una linea germinale di linfociti B (IGHV2-5;IGHJ4-1) diversa dalle linee germinali  VH3-53 e VH3-66  che erano note produrre molti anticorpi  contro l’RBD della proteina spike. Questa linea, che non è presente nei soggetti vaccinati ma non infetti dal virus, che produce anticorpi con maggiore capacità neutralizzante e cui appare le varianti preoccupanti, compresa la delta, hanno maggiore difficoltà a sfuggire alla nautralizzazione. Si forma nei vaccinati convalescenti una sorta di immunità ibrida da vaccino e da infezione che nel complesso sarebbe la responsabile della maggiore e più lunga durata della protezione vaccinale comunenemte osservata in questi soggetti con doppia immunizzazione,vaccinale e naturale. Queste osservazioni suggeriscono di esaminare se un soggetto vaccinato ha avuto una infezione  dopo la vaccinazione perchè, ad esempio, questi soggetti probabilmente non hanno bisogno della terza dose.

Glockner S.

Robust Neutralizing Antibody Levels Detected after Either SARS-CoV-2 Vaccination or One Year after Infection

Viruses, https://www.mdpi.com/1999-4915/13/10/2003/htm

CONTENUTO : Studio longitudinale condotto nella prima metà del 2021 presso il Jena University Hospital in Germania, ottenendo campioni di siero di tre gruppi differenti di partecipanti, al fine di valutare in un anno di follow-up le modifiche nei livelli anticorpali e nella produzione di anticorpi neutralizzanti, in pazienti guariti dall’infezione da Sars-CoV2 ed in pazienti vaccinati. Un primo gruppo comprendeva 40 pazienti guariti dal Sars-Cov2 nel marzo 2020, in una delle prime ondate del virus. Ulteriori due gruppi erano composti da personale dello staff dell’ospedale universitario in questione, vaccinati tra il dicembre 2020 ed il febbraio 2021 con ciclo vaccinale omologo (22 persone, due dosi Pfizer) o eterologo (21 persone, Astrazeneca+Moderna o Pfizer). Nel. Gruppo dei pazienti guariti dall’infezione 39/40 avevano IgG positive a 7 settimane dall’infezione. Dopo questa prima determinazione con un livello anticorpale medio pari a 507.7 BAU/mL si è osservata una netta riduzione a 6 mesi con 147.6 BAU/mL fino al valore stabile di 102.5 BAU/mL a 12 mesi di follow-up. Dei 39 testati ad un anno un totale di 7 partecipanti è risultato negativo al test sierologico. Tutti i partecipanti del gruppo vaccinato hanno sviluppato una risposta anticorpale almeno dieci volte superiore al cut-off di positività del test sierologico utilizzato dopo la dose booster (vaccinazione omologa con un livello medio di IgG pari a 1755 BAU/mL, quella eterologa 2411 BAU/mL), con un andamento discendente del titolo nel tempo analogo e comprabile a quello dei pazienti guariti. Dato importante riguarda la sostanziale stabilità dei livelli anticorpali in pazienti guariti a più di un anno dall’infezione, in controtendenza rispetto alle evidenze acquisite nella prima fase della pandemia. Inoltre il risultato del neutralizing assay ha dimostrato nei convalescenti la persistenza di anticorpi neutralizzanti dopo 55 settimane dall’infezione. Allo stesso modo la risposta immunitaria stimolata dai vaccini si è dimostrata robusta e stabile nei mesi, con un ruolo importante degli stessi anche nei pazienti guariti, al fiine di neutralizzare le varianti predominanti al momento.

COMMENTO :  Tutto bene se non fosse che la capacità neutralizzante degli anticorpi (da convalescenti o vaccinati) è stata testata contro un isolate virale del marzo 2020, forse non era neanche quello con la prima mutazione 614G. Oggi, con delta sappiamo che il titolo neutralizzante degli anticorpi si abbassa decisamente a partire dal 5-6sto mese dalla vaccinazione ed a più luno intervallo anche nei convalescenti.

Siddle K. J. et al.

Evidence of transmission from fully vaccinated individuals in a large outbreak of the SARS-CoV-2 Delta variant in Provincetown, Massachusetts

MedRxiv, https://www.medrxiv.org/content/10.1101/2021.10.20.21265137v1.full.pdf

CONTENUTO : Studio preprint fiinalizzato ad esplorare gli aspetti epidemiologici, sfruttando anche il sequenziamento genomico (outbreak investigatiion) di SARS-CoV2 di 467 persone (ed il ruolo tra essi dei vaccinati), del cluster di più di 1000 casi a Provincetown, in Massachusetts, nel Luglio 2021. Dal 3 all’11 luglio in tale zona si è osservato un passaggio da 0 a 456casi/100.000 persone al giorno. In particolare il 74% dei casi riportati erano individui che avevano completato il ciclo vaccinale (di cui 79% con sintomi lievi e moderati), rappresentando il primo vero cluster di COVID-19 in una popolazione ad alto tasso di vaccinati. Sono stati analizzati i genomi di SARS-CoV2 dai campioni raccolti tra il 9 luglio ed il 2 agosto a Princetown dei suddetti 467 soggetti. Di questi 439 sono stati epidemiologicamente correlati all’outbreak, con il riscontro di un 99% di genomi appartenenti alla variante Delta del virus, con una carica virale ai tamponi nasali pressochè uguale tra individui vaccinati e non. Tra gli individui vaccinati il 48% aveva ricevuto il vaccino Pfizer-BioNTech, il 37% Moderna e il 14% Janseen. Ruolo rilevante nella trasmissione del virus è stato imputato a individui vaccinati, evidenza che ha attirato l’attenzione su tale cluster, portando i CDC a reintrodurre la raccomandazione dell’utilizzo della mascherina in ambienti chiusi anche per individui vaccinati. La velocità di insorgenza e il numero di casi di questo outbreak dimostrano che eventi ad alta densità di popolazione, in luoghi chiusi, possono scatenare una ampia trasmissione di infezione da SARS-CoV2 variante delta, anche in individui vaccinati.

COMMENTO : Combinando genomica e classica epidemiologia investigativa,  gli Autori di questo interessante studio mostrano quanto condizioni di alta trasmissibilità del virus delta possano comportare multipli distinti clusters epidemici con un ruolo attivo anche di soggetti perfettamente vaccinati (due dosi) i quali si infettano e diventano casi indice di altri secondari clusters.  Notare che si tratti comunque di casi COVID-19 lievi o moderati  e per capire il perchè leggete il commento al paper sottostante.

Collier A. Y. et al

Immune Responses in Fully Vaccinated Individuals Following Breakthrough Infection with the SARS-CoV-2 Delta Variant in Provincetown, Massachusetts

MedRxiv, https://www.medrxiv.org/content/10.1101/2021.10.18.21265113v1.full.pdf

CONTENUTO : Studio in vitro della risposta anticorpale di 35 individui vaccinati e testati (di cui 14 risultati positivi e 21 negativi) per lo screening associato al cluster di Provincetown, Massachusetts, descritto nello studio di cui sopra. Dei 14 risultati positivi il 100% ha manifestato sintomi, quali tosse, febbre, anosmia e ageusia, senza necessità di ospedalizzazione. Sono poi stati raccolti campioni ematici e tamponi nasofaringei (con una mediana di circa 34 giorni da quelli eseguiti per l’investigazione del cluster). Lo studio ha evidenziato nei soggetti vaccinati, con infezione da SARS-CoV2, una presenza marcatamente più elevata di anticorpi neutralizzanti rispetto ai vaccinati non infetti, suggerendo che l’evento infettivo abbia scatenato una robusta risposta immunnitaria. Inoltre una marcata risposta immunitaria cellulare e umorale cross-reattiva, anche nei confronti della variante delta, è stata evidenziata in tutti i soggetti infetti coinvolti, a circa sei mesi dalla prima dose di vaccino, evidenziando una possibile protezione anche dopo un periodo prolungato dalla somministrazione. Tali evidenze portano gli autori dello studio ad ipotizzare che l’elevato titolo anticorpale successivo all’infezione nei vaccinati possa poi portare ad una protezione long-term in questi individui nei confronti del SARS-CoV2.

COMMENTO : Le infezioni erano lievi e moderate perchè i vaccinati montavano una forte risposta immune di richiamo all’infezione, una risposta che si mantiene molto elevata ed ha tutte le caratteristiche di espansione della memoria immunitaria per mantenersi protettiva (almeno contro l’ospedalizzazione) per molti mesi. Questo paper, dopo peer review e pubblicazione conterà parecchio nella corrente discussione su chi, oltre gli immunodepressi, fragili e superesposti, e quando dovrà fare la terza dose.

Goel R. R. et al

mRNA vaccines induce durable immune memory to  SARS-CoV-2 and variants of concern

Science, https://www.science.org/doi/epdf/10.1126/science.abm0829

CONTENUTO : Studio longitudinale della durata di 6 mesi, condotto dalla University of Pennsylvania, su campioni di siero di 61 pazienti (45 SARS-CoV2 naive e 16 pazienti guariti dall’infezione, campioni raccolti in 6 momenti:baseline, ~2 settimane post-primary immunization, day of secondary immunization, ~1 settimana post-secondary immunization, ~3 mesi post-primary immunization, e ~6 mesi post-primary immunization) vaccinati con BNT162b2 o mRNA-1273, per valutare l’evoluzione nel corso dei mesi di studio della risposta immunitaria al vaccino. In particolare, la continua crescita di cellule B specifiche per SARS-CoV2 tra 3 e 6 mesi, nonostante una riduzione negli stessi individui dei livelli anticorpali, suggerisce che reazioni prolungate del centro germinativo sostengono la produzione di cellule B cicrcolanti per molti mesi dopo la somministrazione vaccinale. Una maggioranza di queste cellule, erano cross-reattivei con le principali variants of concern di SARS-CoV2 (Alpha, Beta e Delta). Come mostrato nello studio tali cellule sono in grado di riattivare una rapida risposta immunitaria con nuova produzione anticorpale in seguito all’infezione da SARS-CoV2 o dopo una dose booster di vaccino. L’immunità cellulo mediata legata alla vaccinazione, dai dati raccolti nello studio, appare duratura per almeno sei mesi dopo la somministrazione.

COMMENTO : Questo studio aggiunge un importante tassello sulla durata, attività e cross-reattività delle risposte immuni contro le principali varianti di SARS-CoV-2. Dimostra che pur in una situazione di caduta progressiva del titolo anticorpale, i soggetti vaccinati conservano una lunga e funzionale risposta cellulo-mediata, in grado di proteggere almeno dalle forme gravi di malattia. Anche questi risultati vanno considerati nella discussione sull’opportunità di uso della terza dose in tutti i soggetti.

Casadevall A.

The mRNA vaccine revolution is the dividend from decades of basic science research

The Journal of Clinical Investigation, https://www.jci.org/articles/view/153721/pdf

CONTENUTO: Articolo inerente la creazione dei vaccini a m-RNA e del ruolo fondamentale ricoperto dalla Dr.ssa Karikò e del Dr. Weissman nel loro sviluppo e perfezionamento. Tali due protagonisti di spicco sono stati insigniti del premio Lasker-DeBakey 2021 per la ricerca medica clinica, alla luce del ruolo chiave svolto dai vaccini a m-RNA nella lotta al Sars-CoV2. Inoltre le evidenze di efficacia di tale approccio vaccinale nella recente pandemia implicano che, in futuro, tale approccio possa essere utilizzato per qualsiasi patogeno per il quale una proteina, sfruttata come antigene, porti ad elicitare una risposta imunitaria protettiva.

COMMENTO : E’ un’ottima sintesi fatta da Arturo Casadevall, President dell’American Academy of Microbiology, sulla storia dei vaccini ad m-RNA e del fondamentale ruolo ricoperto da ricercatori in particolare dalla dott.ssa Karicò, cui per molti anni nessuno credeva.  Arturo Casedevall mette in risalto che, come sempre accade, l’importante progresso fatto da alcuni sia stato reso possibile dal concorso di parecchie altre ricerche ed avanzamenti tecnologici ( per esempio, la tecnologia delle nanoparticelle) fatti da parecchi altri validi e magari non premiati ricercatori. Un fenomeno che potremmo chiamare il  « sottostante del Nobel ».

Jeong Seri et al.

Comparing Results of Five SARS-CoV-2 Antibody Assays Beforeand After the First Dose of ChAdOx1 nCoV-19 Vaccine amongHealth Care Workers

ASM, https://journals.asm.org/doi/epdf/10. 1128/JCM.01105-21

CONTENUTO: Studio in vitro su campioni di siero di 228 operatori sanitari provenienti da due Università (Hallym University Dongtan Sacred Heart Hospital and Hallym University Kangnam SacredHeart Hospital), di età >18 aa, sottoposti a vaccinazione con Astrazeneca nel periodo tra il 4 ed il 12 Marzo 2021. I campioni di siero sono stati ottenuti al tempo 0 (basale) e tra 11 e 28 giorni dalla prima dose di vaccino. Tutti i partecipanti inoltre hanno compilato un questionario dopo la prima dose di vaccino riguardante gli effetti avversi. I campioni di siero sono stati testati utilizzando 5 diversi antibody-assays, 3 binding antibody e due surrogate virus neutralazing antibody assay : Elecsys Anti-SARS-CoV-2 S total-antibody assay on the Cobas e801 platform (RocheDiagnostics, Mannheim, Germany), the SARS-CoV-2 IgG II Quant assay on the Alinity i platform (AbbottLaboratories Abbott Park, IL, USA), the SARS-CoV-2 IgG assay on the Atellica platform (Siemens, Munich,Germany), the STANDARD E SARS-CoV-2 nAb ELISA kit (SD Biosensor, Suwon, Korea), and the cPassSARS-CoV-2 neutralization antibody detection kit (GenScript, NJ, USA). I tassi di positività dopo la prima dose di vaccino sono stati : 84.6% for the Roche assay, 92.5% for the Abbott assay, 75.4% for the Siemens assay,90.7% for the SD Biosensor assay, and 66.2% for the GenScript assay con un tasso di concordanza tra l’86.6% (95% confdence interval [CI], 83.1% to 89.6%) e il 97.6% (95%CI, 95.7% to 98.8%). I dati hanno dimostrato dopo una singola dose di AZ un tasso di sieroconversione compreso tra il 66.2% ed il 92.5% con un elevato tasso di concordanza tra tutti i sistemi di rilevazione utilizzati, ed è il primo report da inizio pandemia che utilizza 5 diversi tipi di antibody assays tra cui neutralization antibody assays.
COMMENTO : Una utile comparazione di diversi saggi anticorpali.

Chekuri S et al

SARS-CoV-2 coinfection with additional respiratory virus does not predict severe disease: a retrospective cohort study

Journal of Antimicrobial Chemotherapy,

https://academic.oup.com/jac/article/76/Supplement_3/iii12/6374623

CONTENUTO: Studio retrospettivo su 306 pazienti con infezione da SARS-CoV-2 sottoposti anche a test con pannello per patogeni respiratori (RPP), al fine di determinare se la coinfezione tra SARS-CoV-2 e altri virus respiratori fosse associata ad un esordio o un outcome clinico più grave. I pazienti con una confezione tra SARS-CoV-2 e altri virus respiratori (diversi dal virus influenzale e dal VRS) avevano una presentazione clinica meno grave ma una minore probabilità di essere ricoverati. Non sono state osservate differenze significative in termini di outcome tra pazienti coinfetti e non.

COMMENTO: La casistica di questo studio è piuttosto piccola e quindi i risultati dovranno essere ulteriormente verificati e confermati. La coinfezione che determina un minor rischio ad essere ricoverati e a soffrire di forme gravi è legato ad una ridotta infiammazione come conseguenza della coinfezione.

Van Praet JT, et al.

Dynamics of the cellular and humoral immune response after BNT162b2 mRNA Covid-19 vaccination in Covid-19 naive nursing home residents.

J Infect Dis, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab458/6369254

CONTENUTO: Studio effettuato su 100 pazienti degenti in due case di riposo in Belgio sottoposti a vaccinazione con Pfizer-BioNTech, confrontati con un gruppo di controllo di 34 operatori sanitari. Mediante prelievo a 4, 8, 24 settimane sono stati valutati il titolo anticorpale e l’immunità cellulare misurata mediante la secrezione di interferon-gamma da parte delle cellule mononucleate dopo stimolazione con glicoproteina di SARS-CoV-2. Entrambi si riducevano significativamente nel corso delle 24 settimane e risultavano inferiori rispetto a quelli degli operatori sanitari, soprattutto tra i pazienti degenti COVID-19 naive nei quali l’emivita delle risposta anticorpale era di 47 giorni. Emerge una risposta immunitaria al vaccino quantitativamente più bassa e con una durata delle protezione inferiore rispetto a quella di adulti sani. La più giovane età è stata associata ad un più alto titolo anticorpale a 4 settimane, mentre diabete mellito e neoplasia attiva ad una inferiore risposta dell’immunità cellulo-mediata. Solo eventi avversi minori sono stati osservati, confermando un profilo di sicurezza della vaccinazione nel breve termine.

COMMENTO: Questo lavoro suggerisce che i soggetti anziani, popolazione particolarmente vulnerabile a diverse patologie metaboliche o neoplasie, sono un target prioritario per la terza dose di vaccino contro il virus del COVID-19. Infatti essi, sebbene vaccinati con le due dosi convenzionali del vaccino BNT162b2 mRNA Covid-19 (Pfizer-BioNTech), presentano un declino significativo, dopo 4 settimane, delle risposte immunitarie protettive contro il vaccino, rispetto ad operatori sanitari sani, usati come controllo.  In particolare, nei soggetti più anziani le risposte anticorpali neutralizzanti il virus si riducono significativamente, mentre nei pazienti anziani con neoplasie o diabete mellito si riducono anche le risposte dei linfociti T antivirali. Ricordiamo che queste ultime sono le più importanti ad evitare che una eventuale infezione (anche in soggetti vaccinati con due dosi) esiti in gravi sequele come gravi malattie, soprattutto a livello respiratorio, o morte, e quindi in ricoveri in reparti di terapia intensiva.  Il motivo delle deficitarie difese immunitarie negli anziani è dovuto a un progressivo invecchamento del sistema immunitario e ad una ridotta generazione di nuove cellule immunitarie che provengono dal modollo o dal timo (che nell’anziano è atrofizzato). Inoltre le difese immunitarie vengono ulteriormente rese inefficienti in corso di diabete, dove i linfociti sono meno attivi e funzionali a causa di processi dismetabolici, o in corso di tumori, in cui i linfociti non funzionano e diventano “esauriti” a causa della persistenza del tumore. Pertanto, l’anziano per se e ancora di più l’anziano diabetico e/o neoplastico, rispondono significativamente meno bene alle vaccinazioni in generale, e dovrebbero avere priorità alla terza dose del vaccino anti-virus del COVID-19, come indicato anche nel nuovo regolamento vaccinale del nostro SSN.

Mateus J. et al.

Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells

Science, https://www.science.org/doi/epdf/10.1126/science.abj9853

CONTENUTO : Studio clinico di fase 1 open-label condotto su 35 pazienti che hanno ricevuto due somministrazioni di una dose ridotta (25-ug) di vaccino per SARS-CoV2 mRNA-1273, al giorno 1 ed al giorno 28 dello studio. I pazienti sono stati suddivisi per fasce di età (18-55 aa n=15, 56-70 aa n=10 e >70 n=10). E’ stata valutata la risposta immunitaria specifica alla lower dose di vaccino (CD4+ T cell, CD8 T cell, anticopri neutralizzanti), ed è stata confrontata con la risposta generata in pazienti guariti dall’infezione da Sars-CoV2. E’ stata riscontrato una produzione di T cell CD8+ nell’88% dei soggetti, con un livello a 6 mesi dalla seconda dose comparabile a quello riscontrabile in pazienti guariti dall’infezione. Inoltre la presenza di cellule T della memoria cross-reattive pre-esistenti al vaccino hanno dimostrato di favorire una risposta CD4+ mediata e la produzione anticorpale in seguito alla somministrazione.

COMMENTO : Questo studio dei colleghi del La Jolla Institute of Immunologyfornisce  nuove e rilevanti informazioni sulle risposte immuni, in particolare quelle della memoria immunitaria ad un vaccino mRNA (Moderna), ed è importante  per le conseguenze che potrebbero avere queste informazioni sulla campagna di vaccinazione contro la pandemia . Lo studio primariamente dimostra che sia il  livello degli anticorpi neutralizzanti che  natura, entità e durata delle risposte anti-SARS-2-CoV mediate da linfociti B e T  ( in particolare i linfociti helper dei centri germinativi) generate dalla somministrazione di  un quarto della  dose vaccinale correntemente usata ( 25  invece dei 100 microgrammi di mRNA codificante la proteina trimerica spike di SARS-CoV-2) sono mediamente paragonabili a quelle presenti nei soggetti guariti dal COVID-19.Si noti che lo studio non parla di protezione e sarebbe errato dedurre da questi dati che i vaccinati con un quarto di dose hanno lo stesso grado di protezione dal Covid quanto i soggetti guariti dalla malattia. Secondo, ma non meno importante, lo studio dimostra che queste risposte immuni sono particolarmente potenti nei soggetti che hanno memoria di altre infezioni da Coronavirus o esposti ad antigeni diversi da quelli dei coronavirus ma cross reattivi con lo Spike di SARS-CoV-2. Quanto pesino queste immunità crociate e ben evidenziate nei sieri di soggetti pre-COVID-19 è materia di lungo dibattito ma potrebbe spiegare certe differenze, nella resistenza all’infezione e nel decorso della malattia, fra soggetti con simili fattori di rischio. In ogni caso, pare importante per la risposta al vaccino. Una potenziale ma importante conseguenza di questo studio è la possibilità di usare un basso dosaggio per la cosiddetta terza dose, con risparmio di vaccino e diminuzione degli effetti collaterali non del tutto trascurabili.

Bar-On Y. M. et al

Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2114255?articleTools=true

CONTENUTO : : Studio osservazionale (30 giugno-31 agosto 2021) condotto utilizzando dati estratti dal database del Ministero della salute israeliano, riguardanti 1135804 persone divise in due gruppi : booster e non-booster a seconda della ricezione o meno della terza dose. Criteri di inclusione : Età maggiore o uguale a 60 anni, aver completato il ciclo vaccinale entro il 1° marzo 2021, dati disponibili riguardanti il sesso, negatività al tampone molecolare per Sars-CoV2 prima del 30 giugno 2021, non precedenti viaggi all’estero nell’agosto 2021. Lo scopo dello studio è stato quello di valutare i tassi di infezione e malattia severa tra i due gruppi. E’stato riscontrato che una dose booster di vaccino BNT162b2 a 12 giorni ha ridotto sensibilmente il tasso di infezioni e di malattia severa da Sars-CoV2 rispetto al gruppo non-booster. Le stesse variabili sono state considerate confrontando i soli membri del gruppo booster a 4 e 6 giorni dalla somministrazione vs. 12 giorni dalla stessa. In questa analisi il tasso di infezioni è stato inferiore dopo 12 giorni dalla dose booster (estimated factor di 5.4), dimostrando un’efficacia di questa strategia vaccinale persino contro la variante delta, dominante in questo momento storico.

COMMENTO: C’è ancora un gran dibattito scientifico sulla reale necessità di una terza dose generalizzata, non limitata ai soli soggetti fragili. I  dati provenienti da Israele, dove una terza dose  con pieno dosaggio di mRNA è stata somministrata a tutti gli adulti senza aver fatto  alcuna sperimentazione clinica, sembrano tuttavia dimostrare  che dopo i 6 mesi comincia a perdersi un po' della protezione contro la malattia oltre quella contro l’infezione e che si possa rimediare effettivamente a questa perdita di immunità e di protezione con un buon richiamo (per inciso ricordo qui che lo studio israeliano è squisitamente  osservazionale, non controllato,  che come tutte queste osservazioni hanno essenzialmente natura pratica, perché piene di potenziali fattori confondenti non identificati). A questo punto, penso che rifare una terza dose, con pieno dosaggio (come è stato fatto in Israele col vaccino della Pfizer-BionTech) possa essere un inutile spreco di vaccino e di converso mi piace notare che Moderna ha invece ridotto, sia pure solo a metà, la dose del richiamo.

Shah ASV et al.

Effect of Vaccination on Transmission of SARS-CoV-2

N Engl J Med, https://www.nejm.org/doi/pdf/10.1056/NEJMc2106757?articleTools=true

CONTENUTO : Ancora non esistono dati derivati da trial clinici sull’effetto della vaccinazione sulla riduzione della trasmissione di SARS-CoV-2. Questo studio scozzese di real life su194,362 conviventi di 144,525 operatori sanitari dimostra che la vaccinazione porta non solo ad una diminuzione della malattia COVID-19 ma anche della trasmissione dell’infezione già a partire da due settimane dopo la prima dose.

COMMENTO : questo studio ci da una ulteriore conferma  sulla protezione vaccinale non solo più circa la protezione dalla malattia seria ma anche che la vaccinazione in doppia dose diminuisce la probabilita di infettarsi da parte delle persone . La grandezza campionaria è anche abbastanza importante per poter dare validità  statistica al lavoro.

Wu S et al

Safety, tolerability, and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in adults: preliminary report of an open-label and randomised phase 1 clinical trial

The Lancet, July 2021; doi.org/10.1016/S1473-3099(21)00396-0

COMMENTO :

Background

SARS-CoV-2 has caused millions of deaths, and, since Aug 11, 2020, 20 intramuscular COVID-19 vaccines have been approved for use. We aimed to evaluate the safety and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in adults without COVID-19 from China.

Method

This was a randomised, single-centre, open-label, phase 1 trial done in Zhongnan Hospital (Wuhan, China), to evaluate the safety and immunogenicity of the Ad5-nCoV vaccine by aerosol inhalation in adults (≥18 years) seronegative for SARS-CoV-2. Breastfeeding or pregnant women and people with major chronic illnesses or history of allergies were excluded. Participants were enrolled and randomly assigned (1:1:1:1:1) into five groups to be vaccinated via intramuscular injection, aerosol inhalation, or both. Randomisation was stratified by sex and age (18–55 years or ≥56 years) using computer-generated randomisation sequences (block sizes of five). Only laboratory staff were masked to group assignment. The participants in the two aerosol groups received an initial high dose (2 × 1010 viral particles; HDmu group) or low dose (1 × 1010 viral particles; LDmu group) of Ad5-nCoV vaccine on day 0, followed by a booster on day 28. The mixed vaccination group received an initial intramuscular (5 × 1010 viral particles) vaccine on day 0, followed by an aerosolised booster (2 × 1010 viral particles) vaccine on day 28 (MIX group). The intramuscular groups received one dose (5 × 1010 viral particles; 1Dim group) or two doses (10 × 1010 viral particles; 2Dim group) of Ad5-nCoV on day 0. The primary safety outcome was adverse events 7 days after each vaccination, and the primary immunogenicity outcome was anti-SARS-CoV-2 spike receptor IgG antibody and SARS-CoV-2 neutralising antibody geometric mean titres at day 28 after last vaccination. This trial is registered with ClinicalTrials.gov, number NCT04552366.

Findings

Between Sept 28, 2020, and Sept 30, 2020, 230 individuals were screened for inclusion, of whom 130 (56%) participants were enrolled into the trial and randomly assigned into one of the five groups (26 participants per group). Within 7 days after vaccination, adverse events occurred in 18 (69%) in the HDmu group, 19 (73%) in the LDmu group, 19 (73%) in the MIX group, 19 (73%) in the 1Dim group, and 15 (58%) in the 2Dim group. The most common adverse events reported 7 days after the first or booster vaccine were fever (62 [48%] of 130 participants), fatigue (40 [31%] participants), and headache (46 [35%] participants). More adverse events were reported in participants who received intramuscular vaccination, including participants in the MIX group (49 [63%] of 78 participants), than those who received aerosol vaccine (13 [25%] of 52 participants) after the first vaccine vaccination. No serious adverse events were noted within 56 days after the first vaccine. At days 28 after last vaccination, geometric mean titres of SARS-CoV-2 neutralising antibody was 107 (95% CI 47–245) in the HDmu group, 105 (47–232) in the LDmu group, 396 (207–758) in the MIX group, 95 (61–147) in the 1Dim group, and 180 (113–288) in the 2Dim group. The geometric mean concentrations of receptor binding domain-binding IgG was 261 EU/mL (95% CI 121–563) in the HDmu group, 289 EU/mL (138–606) in the LDmu group, 2013 EU/mL (1180–3435) in the MIX group, 915 EU/mL (588–1423) in the 1Dim group, and 1190 EU/mL (776–1824) in the 2Dim group.

Interpretation

Aerosolised Ad5-nCoV is well tolerated, and two doses of aerosolised Ad5-nCoV elicited neutralising antibody responses, similar to one dose of intramuscular injection. An aerosolised booster vaccination at 28 days after first intramuscular injection induced strong IgG and neutralising antibody responses. The efficacy and cost-effectiveness of aerosol vaccination should be evaluated in future studies.

Kozlov M

COVID vaccines have higher approval in less-affluent countries

Nature news, July 2021; doi.org/10.1038/d41586-021-01987-9

COMMENTO: Surveys show that people in ten low- and middle-income nations are generally more eager to receive the COVID-19 jab than are people in two wealthier nations where vaccine is plentiful.

Stumpf J et al

Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine

The Lancet, July 2021; DOI: 10.1016/j.lanepe.2021.100178

COMMENTO: Background : Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality.

Methods : We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273.

Results : SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients.

Conclusion : Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

Shotri M et al

Spike-antibody waning after second dose of BNT162b2 or ChAdOx1

The Lancet, July 2021 ; doi.org/10.1016/S0140-6736(21)01642-1

COMMENTO: To identify early indications of waning antibody levels to the spike protein (S-antibody) after complete two-dose vaccination, we did a cross-sectional analysis of fully vaccinated adults (aged ≥18 years) who submitted capillary blood samples for Virus Watch, a longitudinal community cohort study in England and Wales.4 The study received ethical approval from the Hampstead NHS Health Research Authority Ethics Committee (20/HRA/2320). Sera were tested using Elecsys Anti-SARS-CoV-2 S and N electro-chemiluminescent immunoassays (Roche Diagnostics, Basel, Switzerland); the S assay targets total antibodies to the S1 subunit of the spike protein (range 0·4–25 000 units per mL [U/mL]), whereas the N assay targets total antibodies to the full-length nucleocapsid protein, which we took as a proxy for previous SARS-CoV-2 infection (specificity 99·8% [99·3–100]).5 Serological results were linked with demographic and clinical information collected at enrolment and with weekly self-reported vaccination status.

Thomas SJ et al

Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine

MedRXiv, July 2021; doi.org/10.1101/2021.07.28.21261159

COMMENTO : Background: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine

encoding a prefusion-stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.

BNT162b2 is highly efficacious against COVID-19 and is currently authorized for emergency use or conditional approval worldwide. At the time of authorization, data beyond 2 months postvaccination were unavailable.

Methods: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study, 44,165 ≥16-year-old participants and 2,264 12-15-year-old participants were randomized

to receive 2 doses, 21 days apart, of 30 µg BNT162b2 or placebo. Study endpoints reported here are vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data, both up to 6

months post-vaccination.

Results: BNT162b2 continued to be safe and well tolerated. Few participants had adverse events leading to study withdrawal. VE against COVID-19 was 91% (95% CI 89.0‒93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection. VE of 86%‒100% was seen across countries and in populations with diverse haracteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% (95% CI 80.3‒ 99.9). In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed.

Conclusion: With up to 6 months of follow-up and despite a gradually declining trend in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19. (ClinicalTrials.gov number, NCT04368728).

Abbasi J

Überantibodies From Recovered COVID-19 Patients Could Spur New Therapeutics and Vaccines

JAMA, July 2021;  doi:10.1001/jama.2021.12915

COMMENTO: At least a few of the patients, all of whom had mild to moderate disease, produced 4 particularly potent antibodies against the strain that infected them and a diverse range of variants that since have been detected. Two of the antibodies were “ultrapotent” at tiny concentrations across all 23 of the variants the scientists tested, including the highly transmissible B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) versions, the researchers recently reported in Science. Combinations of some of these antibodies mitigated viral escape in laboratory experiments, a feature that could slow resistant strains from emerging in patients treated with the cocktails.

Yang S et al

Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials

The Lancet, March 2021; doi: 10.1016/S1473-3099(21)00127-4

COMMENTO:

 Background

Although several COVID-19 vaccines have been developed so far, they will not be sufficient to meet the global demand. Development of a wider range of vaccines, with different mechanisms of action, could help control the spread of SARS-CoV-2 globally. We developed a protein subunit vaccine against COVID-19 using a dimeric form of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as the antigen. We aimed to assess the safety and immunogenicity of this vaccine, ZF2001, and determine the appropriate dose and schedule for an efficacy study.

Methods

We did two randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials. Phase 1 was done at two university hospitals in Chongqing and Beijing, China, and phase 2 was done at the Hunan Provincial Center for Disease Control and Prevention in Xiangtan, China. Healthy adults aged 18–59 years, without a history of SARS-CoV or SARS-CoV-2 infection, an RT-PCR-positive test result for SARS-CoV-2, a history of contact with confirmed or suspected COVID-19 cases, and severe allergies to any component of the vaccine were eligible for enrolment. In phase 1, participants were randomly assigned (2:2:1) to receive three doses of the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart. In phase 2, participants were randomly assigned (1:1:1:1:1:1) to receive the vaccine (25 μg or 50 μg) or placebo intramuscularly, 30 days apart, in either a two-dose schedule or a three-dose schedule. Investigators, participants, and the laboratory team were masked to group allocation. For phase 1, the primary outcome was safety, measured by the occurrence of adverse events and serious adverse events. For phase 2, the primary outcome was safety and immunogenicity (the seroconversion rate and the magnitude, in geometric mean titres [GMTs], of SARS-CoV-2-neutralising antibodies). Analyses were done on an intention-to-treat and per-protocol basis. These trials are registered with ClinicalTrials.gov (NCT04445194 and NCT04466085) and participant follow-up is ongoing.

Findings

Between June 22 and July 3, 2020, 50 participants were enrolled into the phase 1 trial and randomly assigned to receive three doses of placebo (n=10), the 25 μg vaccine (n=20), or the 50 μg vaccine (n=20). The mean age of participants was 32·6 (SD 9·4) years. Between July 12 and July 17, 2020, 900 participants were enrolled into the phase 2 trial and randomly assigned to receive two doses of placebo (n=150), 25 μg vaccine (n=150), or 50 μg vaccine (n=150), or three doses of placebo (n=150), 25 μg vaccine (n=150), or 50 μg vaccine (n=150). The mean age of participants was 43·5 (SD 9·2) years. In both phase 1 and phase 2, adverse events reported within 30 days after vaccination were mild or moderate (grade 1 or 2) in most cases (phase 1: six [60%] of ten participants in the placebo group, 14 [70%] of 20 in the 25 μg group, and 18 [90%] of 20 in the 50 μg group; phase 2: 37 [25%] of 150 in the two-dose placebo group, 43 [29%] of 150 in the two-dose 25 μg group, 50 [33%] of 150 in the two-dose 50 μg group, 47 [31%] of 150 in the three-dose placebo group, 72 [48%] of 150 in the three-dose 25 μg group, and 65 [43%] of 150 in the three-dose 50 μg group). In phase 1, two (10%) grade 3 or worse adverse events were reported in the 50 μg group. In phase 2, grade 3 or worse adverse events were reported by 18 participants (four [3%] in the two-dose 25 μg vaccine group, two [1%] in the two-dose 50 μg vaccine group, two [1%] in the three-dose placebo group, four [3%] in the three-dose 25 μg vaccine group, and six [4%] in the three-dose 50 μg vaccine group), and 11 were considered vaccine related (two [1%] in the two-dose 25 μg vaccine group, one [1%] in the two-dose 50 μg vaccine group, one [1%] in the three-dose placebo group, two [1%] in the three-dose 25 μg vaccine group, and five [3%] in the three-dose 50 μg vaccine group); seven participants reported serious adverse events (one [1%] in the two-dose 25 μg vaccine group, one [1%] in the two-dose 50 μg vaccine group, two [1%] in the three-dose placebo group, one [1%] in the three-dose 25 μg vaccine group, and two [1%] in the three-dose 50 μg vaccine group), but none was considered vaccine related. In phase 2, on the two-dose schedule, seroconversion rates of neutralising antibodies 14 days after the second dose were 76% (114 of 150 participants) in the 25 μg group and 72% (108 of 150) in the 50 μg group; on the three-dose schedule, seroconversion rates of neutralising antibodies 14 days after the third dose were 97% (143 of 148 participants) in the 25 μg group and 93% (138 of 148) in the 50 μg group. In the two-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the second dose were 17·7 (95% CI 13·6–23·1) in the 25 μg group and 14·1 (10·8–18·3) in the 50 μg group. In the three-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the third dose were 102·5 (95% CI 81·8–128·5) in the 25 μg group and 69·1 (53·0–90·0) in the 50 μg group.

Interpretation

The protein subunit vaccine ZF2001 appears to be well tolerated and immunogenic. The safety and immunogenicity data from the phase 1 and 2 trials support the use of the 25 μg dose in a three-dose schedule in an ongoing phase 3 trial for large-scale evaluation of ZF2001's safety and efficacy.

Mendonca Guimaraes R et al

Younger Brazilians hit by COVID-19 – What are the implications?

The Lancet, July 2021 ; doi.org/10.1016/j.lana.2021.100014

COMMENTO : Once the older adults are mostly vaccinated, we expect that younger adults will gradually occupy more hospital wards and ICU beds. Although we recognize a higher prevalence of comorbidities among older adults8, many chronic diseases, such as hypertension and diabetes, have a high prevalence among those aged 40. Many adults in this age group might suffer from these diseases. However, they do not even have a diagnosis, since the often present an insidious course. They only discover these chronic conditions when hospitalized due to the acute – and severe – disease COVID-19.

Woolf K et al

Ethnic differences in SARS-CoV-2 vaccine hesitancy in United Kingdom healthcare workers: Results from the UK-REACH prospective nationwide cohort study

The Lancet, July 2021; DOI: 10.1016/j.lanepe.2021.100180

COMMENTO: Background : In most countries, healthcare workers (HCWs) represent a priority group for vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to their elevated risk of COVID-19 and potential contribution to nosocomial SARS-CoV-2 transmission. Concerns have been raised that HCWs from ethnic minority groups are more likely to be vaccine hesitant (defined by the World Health Organisation as refusing or delaying a vaccination) than those of White ethnicity, but there are limited data on SARS-CoV-2 vaccine hesitancy and its predictors in UK HCWs.

Methods : Nationwide prospective cohort study and qualitative study in a multi-ethnic cohort of clinical and non-clinical UK HCWs. We analysed ethnic differences in SARS-CoV-2 vaccine hesitancy adjusting for demographics, vaccine trust, and perceived risk of COVID-19. We explored reasons for hesitancy in qualitative data using a framework analysis.

Findings : 11,584 HCWs were included in the cohort analysis. 23% (2704) reported vaccine hesitancy. Compared to White British HCWs (21.3% hesitant), HCWs from Black Caribbean (54.2%), Mixed White and Black Caribbean (38.1%), Black African (34.4%), Chinese (33.1%), Pakistani (30.4%), and White Other (28.7%) ethnic groups were significantly more likely to be hesitant. In adjusted analysis, Black Caribbean (aOR 3.37, 95% CI 2.11 - 5.37), Black African (aOR 2.05, 95% CI 1.49 - 2.82), White Other ethnic groups (aOR 1.48, 95% CI 1.19 - 1.84) were significantly more likely to be hesitant. Other independent predictors of hesitancy were younger age, female sex, higher score on a COVID-19 conspiracy beliefs scale, lower trust in employer, lack of influenza vaccine uptake in the previous season, previous COVID-19, and pregnancy. Qualitative data from 99 participants identified the following contributors to hesitancy: lack of trust in government and employers, safety concerns due to the speed of vaccine development, lack of ethnic diversity in vaccine studies, and confusing and conflicting information. Participants felt uptake in ethnic minority communities might be improved through inclusive communication, involving HCWs in the vaccine rollout, and promoting vaccination through trusted networks.

Interpretation : Despite increased risk of COVID-19, HCWs from some ethnic minority groups are more likely to be vaccine hesitant than their White British colleagues. Strategies to build trust and dispel myths surrounding the COVID-19 vaccine in these communities are urgently required. Emphasis should be placed on the safety and benefit of SARS-CoV-2 vaccination in pregnancy and in those with previous COVID-19. Public health communications should be inclusive, non-stigmatising and utilise trusted networks.

Lim WW et al

Comparative immunogenicity of mRNA and inactivated vaccines against COVID-19

The Lancet, July 2021; doi.org/10.1016/S2666-5247(21)00177-4

COMMENTO: We enrolled a cohort of 1442 health-care workers from public and private hospitals and medical clinics in Hong Kong and arranged for longitudinal collection of blood samples after obtaining informed consent. Here we present our preliminary laboratory testing results on 93 participants for whom we have complete data on antibody concentrations before vaccination, after the first dose, and after the second dose. These included 63 participants (55·6% male, median age 37 years, range 26–60 years) who were fully vaccinated with the BNT162b2 vaccine and 30 participants (23·3% male, median age 47 years, range 31–65 years) who received both doses of the inactivated vaccine.

Butt AA et al

SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting

Annals of Internal Medicine, July 2021; DOI: 10.7326/M21-1577

COMMENTO: Background: With the emergency use authorization of multiple vaccines against SARS-CoV-2 infection, data are urgently needed to determine their effectiveness in a real-world setting.

Objective: To evaluate the short-term effectiveness of vaccines in preventing SARS-CoV-2 infection.

Design: Test-negative case–control study using conditional logistic regression.

Setting: U.S. Department of Veterans Affairs health care system.

Participants: All veterans who had testing for SARS-CoV-2 infection between 15 December 2020 and 4 March 2021 and no confirmed infection before 15 December 2020.

Intervention: SARS-CoV-2 vaccination with either the BNT-162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine as part of routine clinical care.

Measurements: Effectiveness of vaccination against confirmed SARS-CoV-2 infection.

Results: Among 54 360 persons who tested positive and 54 360 propensity score–matched control participants, the median age was 61 years, 83.6% were male, and 62% were White. Median body mass index was 31 kg/m2 among those who tested positive and 30 kg/m2 among those who tested negative. Among those who tested positive, 9800 (18.0%) had been vaccinated; among those who tested negative, 17 825 (32.8%) had been vaccinated. Overall vaccine effectiveness 7 or more days after the second dose was 97.1% (95% CI, 96.6% to 97.5%). Effectiveness was 96.2% (CI, 95.5% to 96.9%) for the Pfizer–BioNTech BNT-162b2 vaccine and 98.2% (CI, 97.5% to 98.6%) for the Moderna mRNA-1273 vaccine. Effectiveness remained above 95% regardless of age group, sex, race, or presence of comorbidities.

Limitations: Predominantly male population; lack of data on disease severity, mortality, and effectiveness by SARS-CoV-2 variants of concern; and short-term follow-up.

Conclusion: Currently used vaccines against SARS-CoV-2 infection are highly effective in preventing confirmed infection in a high-risk population in a real-world setting.

Brosh-Nissimov T et al

BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel

CMI, July 2021 ; DOI: 10.1016/j.cmi.2021.06.036

COMMENTO: Objectives

The mRNA coronavirus disease 2019 (COVID-19) vaccines have shown high effectiveness in the prevention of symptomatic COVID-19, hospitalization, severe disease and death. Nevertheless, a minority of vaccinated individuals might become infected and experience significant morbidity. Characteristics of vaccine breakthrough infections have not been studied. We sought to portray the population of Israeli patients, who were hospitalized with COVID-19 despite full vaccination.

Methods

A retrospective multicentre cohort study of 17 hospitals included patients fully vaccinated with Pfizer/BioNTech's BNT162b2 vaccine who developed COVID-19 more than 7 days after the second vaccine dose and required hospitalization. The risk for poor outcome, defined as a composite of mechanical ventilation or death, was assessed.

Results

A total of 152 patients were included, accounting for half of hospitalized fully vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notably, the cohort was characterized by a high rate of co-morbidities predisposing to severe COVID-19, including hypertension (108; 71%), diabetes (73; 48%), congestive heart failure (41; 27%), chronic kidney and lung diseases (37; 24% each), dementia (29; 19%) and cancer (36; 24%), and only six (4%) had no co-morbidities. Sixty (40%) of the patients were immunocompromised. Higher viral load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titres of anti-Spike IgG, but these differences did not reach statistical significance.

Conclusions

We found that severe COVID-19 infection, associated with a high mortality rate, might develop in a minority of fully vaccinated individuals with multiple co-morbidities. Our patients had a higher rate of co-morbidities and immunosuppression compared with previously reported non-vaccinated hospitalized individuals with COVID-19. Further characterization of this vulnerable population may help to develop guidance to augment their protection, either by continued social distancing, or by additional active or passive vaccinations.

Souza WM et al

Neutralisation of SARS-CoV-2 lineage P.1 by antibodies elicited through natural SARS-CoV-2 infection or vaccination with an inactivated SARS-CoV-2 vaccine: an immunological study

The Lancet, July 2021 ; doi.org/10.1016/S2666-5247(21)00129-4

COMMENTO : Background

Mutations accrued by SARS-CoV-2 lineage P.1—first detected in Brazil in early January, 2021—include amino acid changes in the receptor-binding domain of the viral spike protein that also are reported in other variants of concern, including B.1.1.7 and B.1.351. We aimed to investigate whether isolates of wild-type P.1 lineage SARS-CoV-2 can escape from neutralising antibodies generated by a polyclonal immune response.

Methods

We did an immunological study to assess the neutralising effects of antibodies on lineage P.1 and lineage B isolates of SARS-CoV-2, using plasma samples from patients previously infected with or vaccinated against SARS-CoV-2. Two specimens (P.1/28 and P.1/30) containing SARS-CoV-2 lineage P.1 (as confirmed by viral genome sequencing) were obtained from nasopharyngeal and bronchoalveolar lavage samples collected from patients in Manaus, Brazil, and compared against an isolate of SARS-CoV-2 lineage B (SARS.CoV2/SP02.2020) recovered from a patient in Brazil in February, 2020. Isolates were incubated with plasma samples from 21 blood donors who had previously had COVID-19 and from a total of 53 recipients of the chemically inactivated SARS-CoV-2 vaccine CoronaVac: 18 individuals after receipt of a single dose and an additional 20 individuals (38 in total) after receipt of two doses (collected 17–38 days after the most recent dose); and 15 individuals who received two doses during the phase 3 trial of the vaccine (collected 134–230 days after the second dose). Antibody neutralisation of P.1/28, P.1/30, and B isolates by plasma samples were compared in terms of median virus neutralisation titre (VNT50, defined as the reciprocal value of the sample dilution that showed 50% protection against cytopathic effects).

Findings

In terms of VNT50, plasma from individuals previously infected with SARS-CoV-2 had an 8·6 times lower neutralising capacity against the P.1 isolates (median VNT50 30 [IQR <20–45] for P.1/28 and 30 [<20–40] for P.1/30) than against the lineage B isolate (260 [160–400]), with a binominal model showing significant reductions in lineage P.1 isolates compared with the lineage B isolate (p≤0·0001). Efficient neutralisation of P.1 isolates was not seen with plasma samples collected from individuals vaccinated with a first dose of CoronaVac 20–23 days earlier (VNT50s below the limit of detection [<20] for most plasma samples), a second dose 17–38 days earlier (median VNT50 24 [IQR <20–25] for P.1/28 and 28 [<20–25] for P.1/30), or a second dose 134–260 days earlier (all VNT50s below limit of detection). Median VNT50s against the lineage B isolate were 20 (IQR 20–30) after a first dose of CoronaVac 20–23 days earlier, 75 (<20–263) after a second dose 17–38 days earlier, and 20 (<20–30) after a second dose 134–260 days earlier. In plasma collected 17–38 days after a second dose of CoronaVac, neutralising capacity against both P.1 isolates was significantly decreased (p=0·0051 for P.1/28 and p=0·0336 for P.1/30) compared with that against the lineage B isolate. All data were corroborated by results obtained through plaque reduction neutralisation tests.

Interpretation

SARS-CoV-2 lineage P.1 might escape neutralisation by antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2. Continuous genomic surveillance of SARS-CoV-2 combined with antibody neutralisation assays could help to guide national immunisation programmes.

Funding

São Paulo Research Foundation, Brazilian Ministry of Science, Technology and Innovation and Funding Authority for Studies, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health.

Reynolds CJ et al

Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose

Science, April 2021 ; DOI: 10.1126/science.abh1282

COMMENTO: SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

Goldshtein I et al

Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women

JAMA, July 2021; DOI: 10.1001/jama.2021.11035

COMMENTO: Importance  Data on BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) effectiveness and safety in pregnancy are currently lacking because pregnant women were excluded from the phase 3 trial.

Objective  To assess the association between receipt of BNT162b2 mRNA vaccine and risk of SARS-CoV-2 infection among pregnant women.

Design, Setting, and Participants  This was a retrospective cohort study within the pregnancy registry of a large state-mandated health care organization in Israel. Pregnant women vaccinated with a first dose from December 19, 2020, through February 28, 2021, were 1:1 matched to unvaccinated women by age, gestational age, residential area, population subgroup, parity, and influenza immunization status. Follow-up ended on April 11, 2021.

Exposures  Exposure was defined by receipt of the BNT162b2 mRNA vaccine. To maintain comparability, nonexposed women who were subsequently vaccinated were censored 10 days after their exposure, along with their matched pair.

Main Outcomes and Measures  The primary outcome was polymerase chain reaction–validated SARS-CoV-2 infection at 28 days or more after the first vaccine dose.

Results  The cohort included 7530 vaccinated and 7530 matched unvaccinated women, 46% and 33% in the second and third trimester, respectively, with a mean age of 31.1 years (SD, 4.9 years). The median follow-up for the primary outcome was 37 days (interquartile range, 21-54 days; range, 0-70). There were 118 SARS-CoV-2 infections in the vaccinated group and 202 in the unvaccinated group. Among infected women, 88 of 105 (83.8%) were symptomatic in the vaccinated group vs 149 of 179 (83.2%) in the unvaccinated group (P ≥ .99). During 28 to 70 days of follow-up, there were 10 infections in the vaccinated group and 46 in the unvaccinated group. The hazards of infection were 0.33% vs 1.64% in the vaccinated and unvaccinated groups, respectively, representing an absolute difference of 1.31% (95% CI, 0.89%-1.74%), with an adjusted hazard ratio of 0.22 (95% CI, 0.11-0.43). Vaccine-related adverse events were reported by 68 patients; none was severe. The most commonly reported symptoms were headache (n = 10, 0.1%), general weakness (n = 8, 0.1%), nonspecified pain (n = 6, <0.1%), and stomachache (n = 5, <0.1%).

Conclusions and Relevance  In this retrospective cohort study of pregnant women, BNT162b2 mRNA vaccination compared with no vaccination was associated with a significantly lower risk of SARS-CoV-2 infection. Interpretation of study findings is limited by the observational design.

Rossi AH et al

Sputnik V Vaccine Elicits Seroconversion and Neutralizing Capacity to SARS CoV-2 after a Single Dose

Cell, July 2021; 10.1016/j.xcrm.2021.100359

COMMENTO: Massive vaccination offers great promise for halting the global COVID-19 pandemic. However, limited supply and uneven vaccine distribution create an urgent need to optimize vaccination strategies. We evaluate SARS-CoV-2-specific antibody responses after Sputnik V vaccination of healthcare workers in Argentina, measuring IgG anti-spike titers and neutralizing capacity after one and two doses in a cohort of naïve or previously infected volunteers. By 21 days after receiving the first dose of vaccine, 94% of naïve participants develop spike-specific IgG antibodies. A single Sputnik V dose elicits higher antibody levels and virus neutralizing capacity in previously infected individuals than in naïve ones receiving the full two-dose schedule. The high seroconversion rate after a single dose in naïve participants suggests a benefit of delaying second dose administration to increase the number of people vaccinated. The data presented provide information for guiding public health decisions in light of the current global health emergency.

Jara A et al

Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile

NEJM, July 2021 ; DOI: 10.1056/NEJMoa2107715

COMMENTO: BACKGROUND : Mass vaccination campaigns to prevent coronavirus disease 2019 (Covid-19) are occurring in many countries; estimates of vaccine effectiveness are urgently needed to support decision making. A countrywide mass vaccination campaign with the use of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (CoronaVac) was conducted in Chile starting on February 2, 2021.

METHODS : We used a prospective national cohort, including participants 16 years of age or older who were affiliated with the public national health care system, to assess the effectiveness of the inactivated SARS-CoV-2 vaccine with regard to preventing Covid-19 and related hospitalization, admission to the intensive care unit (ICU), and death. We estimated hazard ratios using the extension of the Cox proportional-hazards model, accounting for time-varying vaccination status. We estimated the change in the hazard ratio associated with partial immunization (≥14 days after receipt of the first dose and before receipt of the second dose) and full immunization (≥14 days after receipt of the second dose). Vaccine effectiveness was estimated with adjustment for individual demographic and clinical characteristics.

RESULTS : The study was conducted from February 2 through May 1, 2021, and the cohort included approximately 10.2 million persons. Among persons who were fully immunized, the adjusted vaccine effectiveness was 65.9% (95% confidence interval [CI], 65.2 to 66.6) for the prevention of Covid-19 and 87.5% (95% CI, 86.7 to 88.2) for the prevention of hospitalization, 90.3% (95% CI, 89.1 to 91.4) for the prevention of ICU admission, and 86.3% (95% CI, 84.5 to 87.9) for the prevention of Covid-19–related death.

CONCLUSIONS : Our results suggest that the inactivated SARS-CoV-2 vaccine effectively prevented Covid-19, including severe disease and death, a finding that is consistent with results of phase 2 trials of the vaccine.

Goldfarb JL et al

Beyond the First Dose — Covid-19 Vaccine Follow-through and Continued Protective Measures

NEJM, July 2021; DOI: 10.1056/NEJMp2104527

COMMENTO: Despite current efforts, many Americans, including many of those who have already received a first vaccine dose, remain confused about the timing of protection and the necessity of a second dose. Moreover, a large proportion of vaccinees report being uninformed about CDC guidance regarding the need to continue to take prophylactic measures including mask wearing and avoiding crowds. Finally, our results have identified demographic groups who are most reluctant to accept these measures who would benefit from targeted outreach.

al Jalali V et al

Improved immunogenicity against SARS-CoV-2 in a solid organ transplant recipient by switching vaccines

CMI, June 2021; DOI: 10.1016/j.cmi.2021.06.022 

COMMENTO: Because of the lack of a marked antibody response, on March 30th one shot of the AZD1222 vaccine was administered. Remarkably, twenty-eight days after this vaccination another anti-spike antibody test (SARS-CoV-2 spike antibody test by Roche) detected 1963 U/ml of antibodies and a neutralizing antibody test conducted on May 20th showed an antibody titer of 1:160.

Han B et al

Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial

The Lancet, June 2021; doi.org/10.1016/S1473-3099(21)00319-4

COMMENTO: Background

A vaccine against SARS-CoV-2 for children and adolescents will play an important role in curbing the COVID-19 pandemic. Here we aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in children and adolescents aged 3–17 years.

Methods

We did a double-blind, randomised, controlled, phase 1/2 clinical trial of CoronaVac in healthy children and adolescents aged 3–17 years old at Hebei Provincial Center for Disease Control and Prevention in Zanhuang (Hebei, China). Individuals with SARS-CoV-2 exposure or infection history were excluded. Vaccine (in 0·5 mL aluminum hydroxide adjuvant) or aluminum hydroxide only (alum only, control) was given by intramuscular injection in two doses (day 0 and day 28). We did a phase 1 trial in 72 participants with an age de-escalation in three groups and dose-escalation in two blocks (1·5 μg or 3·0 μg per injection). Within each block, participants were randomly assigned (3:1) by means of block randomisation to receive CoronaVac or alum only. In phase 2, participants were randomly assigned (2:2:1) by means of block randomisation to receive either CoronaVac at 1·5 μg or 3·0 μg per dose, or alum only. All participants, investigators, and laboratory staff were masked to group allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint assessed in the per-protocol population was seroconversion rate of neutralising antibody to live SARS-CoV-2 at 28 days after the second injection. This study is ongoing and is registered with ClinicalTrials.gov, NCT04551547.

Findings

Between Oct 31, 2020, and Dec 2, 2020, 72 participants were enrolled in phase 1, and between Dec 12, 2020, and Dec 30, 2020, 480 participants were enrolled in phase 2. 550 participants received at least one dose of vaccine or alum only (n=71 for phase 1 and n=479 for phase 2; safety population). In the combined safety profile of phase 1 and phase 2, any adverse reactions within 28 days after injection occurred in 56 (26%) of 219 participants in the 1·5 μg group, 63 (29%) of 217 in the 3·0 μg group, and 27 (24%) of 114 in the alum-only group, without significant difference (p=0·55). Most adverse reactions were mild and moderate in severity. Injection site pain was the most frequently reported event (73 [13%] of 550 participants), occurring in 36 (16%) of 219 participants in the 1·5 μg group, 35 (16%) of 217 in the 3·0 μg group, and two (2%) in the alum-only group. As of June 12, 2021, only one serious adverse event of pneumonia has been reported in the alum-only group, which was considered unrelated to vaccination. In phase 1, seroconversion of neutralising antibody after the second dose was observed in 27 of 27 participants (100·0% [95% CI 87·2–100·0]) in the 1·5 μg group and 26 of 26 participants (100·0% [86·8-100·0]) in the 3·0 μg group, with the geometric mean titres of 55·0 (95% CI 38·9–77·9) and 117·4 (87·8–157·0). In phase 2, seroconversion was seen in 180 of 186 participants (96·8% [93·1–98·8]) in the 1·5 μg group and 180 of 180 participants (100·0% [98·0–100·0]) in the 3·0 μg group, with the geometric mean titres of 86·4 (73·9–101·0) and 142·2 (124·7–162·1). There were no detectable antibody responses in the alum-only groups.

Interpretation

CoronaVac was well tolerated and safe and induced humoral responses in children and adolescents aged 3–17 years. Neutralising antibody titres induced by the 3·0 μg dose were higher than those of the 1·5 μg dose. The results support the use of 3·0 μg dose with a two-immunisation schedule for further studies in children and adolescents.

Lustig Y et al

Neutralizing Response against Variants after SARS-CoV-2 Infection and One Dose of BNT162b2

NEJM, June 2021 ; DOI: 10.1056/NEJMc2104036

COMMENTO: This study showed that, in our small cohort, one vaccine dose substantially increased neutralizing activity against all variants tested, with similar titers detected across patients for each variant. This highlights the importance of vaccination even in previously infected patients, given the added benefit of an increased antibody response to the variants tested. Limitations of the study include the small cohort of only women and the lack of evaluation of T-cell response. However, we think the fact that all six patients responded similarly to vaccination supports our conclusions. Further studies could investigate the effects of a second vaccine dose on neutralizing activity against variants of concern in persons who have and persons who have not been previously infected.

Hall S et al

COVID vaccines and breastfeeding: what the data say

Nature, June 2021; doi.org/10.1038/d41586-021-01680-x

COMMENTO: Unlike the yellow-fever vaccine, COVID-19 vaccines do not carry a risk of igniting an active infection. In addition, COVID-19 vaccines are extremely unlikely to cross into breast milk. The fragile messenger RNA used in the Pfizer–BioNTech and Moderna vaccines, for example, is designed to break down so quickly that it should never leave the cells where it was injected — let alone get into the bloodstream and then the breast. In fact, researchers don’t expect that any of the current vaccines will be excreted into breast milk.

Collier DA et al

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Nature, June 2021; doi.org/10.1038/s41586-021-03739-1

COMMENTO: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, data are scarce on vaccine efficacy against variants of concern (VOC) in individuals above 80 years of age1. Here we analysed immune responses following vaccination with mRNA vaccine BNT162b22 in elderly participants and younger health care workers. Serum neutralisation and binding IgG/IgA after the first vaccine dose diminished with increasing age, with a marked drop in participants over 80 years old. Sera from participants above 80 showed significantly lower neutralisation potency against B.1.1.7, B.1.351 and P.1. variants of concern as compared to wild type and were more likely to lack any neutralisation against VOC following the first dose. However, following the second dose, neutralisation against VOC was detectable regardless of age. Frequency of SARS-CoV-2 Spike specific B-memory cells was higher in elderly responders versus non-responders after first dose. Elderly participants demonstrated clear reduction in somatic hypermutation of class switched cells. SARS-CoV-2 Spike specific T- cell IFNγ and IL-2 responses decreased with increasing age, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high risk population that warrant specific measures to boost vaccine responses, particularly where variants of concern are circulating.

Wang Z et al

Vaccination boosts naturally enhanced neutralizing breadth to SARS-CoV-2 one year after infection

bioRXiv – not peer reviewed, May 2021; doi.org/10.1101/2021.05.07.443175

COMMENTO: Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naïve individuals. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants. Should memory responses evolve in a similar manner in vaccinated individuals, additional appropriately timed boosting with available vaccines could cover most circulating variants of concern.

Heath PT et al

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine

NEJM, June 2021; DOI: 10.1056/NEJMoa2107659

COMMENTO: BACKGROUND : Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.

METHODS : In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.

RESULTS : A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.

CONCLUSIONS : A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant.

Kamar N et al

Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients

NEJM, June 2021 ; DOI: 10.1056/NEJMc2108861

COMMENTO: Here, we report the humoral response in a group of 101 consecutive solid-organ transplant recipients (mean [±SD] age, 58±2 years; 69% were men) who were given three doses of the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). The group included 78 kidney-transplant recipients, 12 liver-transplant recipients, 8 lung-transplant or heart-transplant recipients, and 3 pancreas-transplant recipients.

Milman O et al

Community-level evidence for SARS-CoV-2 vaccine protection of unvaccinated individuals

Nature, June 2021; doi.org/10.1038/s41591-021-01407-5

COMMENTO: Mass vaccination has the potential to curb the current COVID-19 pandemic by protecting individuals who have been vaccinated against the disease and possibly lowering the likelihood of transmission to individuals who have not been vaccinated. The high effectiveness of the widely administered BNT162b vaccine from Pfizer–BioNTech in preventing not only the disease but also infection with SARS-CoV-2 suggests a potential for a population-level effect, which is critical for disease eradication. However, this putative effect is difficult to observe, especially in light of highly fluctuating spatiotemporal epidemic dynamics. Here, by analyzing vaccination records and test results collected during the rapid vaccine rollout in a large population from 177 geographically defined communities, we find that the rates of vaccination in each community are associated with a substantial later decline in infections among a cohort of individuals aged under 16 years, who are unvaccinated. On average, for each 20 percentage points of individuals who are vaccinated in a given population, the positive test fraction for the unvaccinated population decreased approximately twofold. These results provide observational evidence that vaccination not only protects individuals who have been vaccinated but also provides cross-protection to unvaccinated individuals in the community.

Bollyky TJ et al

Epidemiology, not geopolitics, should guide COVID-19 vaccine donations

The Lancet, June 2021; doi.org/10.1016/S0140-6736(21)01323-4

COMMENTO: Vaccine donations are not the only solution to the gap that has emerged between countries with and without sufficient doses of COVID-19 vaccines. Yet, the potential number of surplus vaccine doses purchased by G7 nations is likely to be in the hundreds of millions or more. Vaccine manufacturers based in those countries have also offered to sell more than a billion doses at cost for use in low-income and middle-income countries (LMICs) in 2021, which G7 governments could buy and donate. These supplies are sufficiently large to help with near-term vaccine demands while investments are made in technology transfer to LMICs and in scaling up global manufacturing capacity for vaccines and vaccine inputs to respond to SARS-CoV-2 and future pandemic threats.

Wang Z et al

Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection

Nature, June 2021 ; doi.org/10.1038/s41586-021-03696-9

COMMENTO: Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies1,2. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines3,4. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naive individuals2,5–8. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern4,9. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.

Herishanu Y et al

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia

Blood, June 2021 ;  DOI: 10.1182/blood.2021011568

COMMENTO: Patients with chronic lymphocytic leukemia (CLL) have an increased risk for severe COVID-19 disease and mortality. The goal of this study was to determine the efficacy of COVID-19 vaccine in patients with CLL. We evaluated humoral immune responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine in patients with CLL and compared responses with those obtained in age-matched healthy control subjects. Patients received 2 vaccine doses, 21 days apart, and antibody titers were measured by using the Elecsys Anti-SARS-CoV-2 S assay after administration of the second dose. In a total of 167 patients with CLL, the antibody response rate was 39.5%. A comparison between 52 patients with CLL and 52 sex- and aged-matched healthy control subjects revealed a significantly reduced response rate among patients (52% vs 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). The response rate was highest in patients who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients and 16.0% in patients under treatment at the time of vaccination. In patients treated with either Bruton’s tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, response rates were considerably low (16.0% and 13.6%). None of the patients exposed to anti-CD20 antibodies <12 months before vaccination responded. In a multivariate analysis, the independent predictors of response were younger age, female sex, lack of currently active treatment, immunoglobulin G levels ≥550 mg/dL, and immunoglobulin M levels ≥40 mg/dL. In conclusion, antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in patients with CLL is markedly impaired and affected by disease activity and treatment.

Sax P

We’re Allowed to Say that Some COVID-19 Vaccines Are Better than Others, Right?

HIV and ID Observations –NEJM, https://blogs.jwatch.org/hiv-id-observations/

COMMENTO: However, if someone asked me what COVID-19 vaccine I’d recommend, based on what we know now, my answer would not be “whichever one you prefer” or “whichever one you are offered first” — especially if it were a 35-year-old woman.

It would be an mRNA vaccine.

Bourguignon A et al

Adjunct Immune Globulin for Vaccine-Induced Thrombotic Thrombocytopenia

NEJM, June 2021 ; DOI: 10.1056/NEJMoa2107051

COMMENTO: The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients.

Thakkar A et al

Seroconversion rates following COVID-19 vaccination amongst patients with cancer

Cancer Cell, June 2021;  DOI: 10.1016/j.ccell.2021.06.002

COMMENTO : As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. Comparing to solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematological malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post-vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post-vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

Istituto Superiore di Sanità

Impatto della vaccinazione COVID-19 sul rischio di infezione da SARS-CoV-2 e successivo ricovero e decesso in Italia (27.12.2020 - 03.05.2021)

https://www.epicentro.iss.it/vaccini/pdf/report-valutazione-impatto-vaccinazione-covid-19-15-mag-2021.pdf

COMMENTO : Questo è il primo report di analisi congiunta dei datidell’anagrafe nazionale vaccini e della sorveglianza integrata COVID-19. Tale attività è stata possibile attraverso il Decreto-legge 14 gennaio 2021 n. 2, che disciplina i sistemi informativi funzionali all'implementazione del piano strategico dei vaccini per la prevenzione delle infezioni da SARS-CoV-2 (comma 7, art 3).

  • La gran parte delle persone vaccinate contro COVID-19 (95%) è stata aderente alla schedula vaccinale(seconda dose 21 + 4 giorni per Comirnaty e 28 + 2 giorni per Moderna).
  • L’analisi congiunta ha evidenziato che il rischio di infezione da SARS-CoV-2, ricovero e decesso diminuisce progressivamente dopo le prime due settimane e fino a circa 35 giorni dopo la somministrazione della prima dose. Dopo i 35 giorni si osserva una stabilizzazione della riduzione che ècirca dell’80% per il rischio di diagnosi, del 90% per il rischio di ricovero e del 95% per il rischio didecesso.

Questi effetti sono simili sia negli uomini che nelle donne e in persone in diverse fasce di età.

Takuva S et al

Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study

NEJM, June 2021; DOI: 10.1056/NEJMc2107920

COMMENTO : Here, we report interim safety data from the first 288,368 participants who were vaccinated with Ad26.COV2.S in the Sisonke study — an open label, single-group, phase 3b implementation study to monitor the effectiveness of the single-dose Ad26.COV2.S vaccine among 500,000 health care workers in South Africa (ClinicalTrials.gov number, NCT04838795. opens in new tab). Enrollment in the study began on February 17, 2021, and as of April 12, 2021, a total of 288,368 health care workers had received the Ad26.COV2.S vaccine, among whom 5898 (2%) reported adverse events.

Harrington P et al

Single dose of BNT162b2 mRNA vaccine against SARS-CoV-2 induces high frequency of neutralising antibody and polyfunctional T-cell responses in patients with myeloproliferative neoplasms

Leukemia, May 2021; doi.org/10.1038/s41375-021-01300-7

COMMENTO: Patients with a WHO defined diagnosis of an MPN presenting to our clinic were recruited in accordance with the regional research and ethics review board, with sampling at baseline and median of 21 days (IQR 21–21) following first injection of 30 μg BNT162b2. Clinical characteristics and adverse events are summarised in Table 1, with all adverse events reported within 7 days after administration of the vaccine considered to be related to the vaccine. The vaccine was safe and generally well tolerated with 57.1% (12) patients reporting localised inflammation and 47.6% (10) of patients reporting systemic side effects including flu-like illness, fatigue and gastrointestinal symptoms, following injection.

Hodgson D et al

The potential for vaccination-induced herd immunity against the SARS-CoV-2 B.1.1.7 variant

Eurosurveillance, May 2021 ;  DOI: 10.2807/1560-7917.ES.2021.26.20.2100428

COMMENTO: Initial reports of vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease (COVID-19), have suggested a substantial reduction of the risk of infection [1]. Nevertheless, with the emergence of more transmissible variants such as B.1.1.7 [2], how large-scale immunisation programmes against SARS-CoV-2 will perform is currently unclear. This study assesses the potential of COVID-19 vaccination to generate herd immunity and takes into account vaccine effectiveness, naturally-acquired immunity and achievable vaccination coverage (depending on the population age structure), as well as two transmissibility scenarios ((i) with pre-B.1.1.7, and (ii) with exclusively B.1.1.7 variants).

Bboum Y et al

Africa needs local solutions to face the COVID-19 pandemic

The Lancet, March 2021 ; doi.org/10.1016/S0140-6736(21)00719-4

COMMENTO: An important conclusion from the Article by Salyer and colleagues is the need for country-specific solutions. No one-size-fits-all approach will succeed within a continent as diverse as Africa. Countries with a high number of COVID-19 deaths desperately need vaccination to prevent further illness and deaths from severe COVID-19. Some countries might not request the vaccines because of their COVID-19 epidemiology, whereas other countries have a greater need but will be limited by the 20% allowance. By contrast, countries with low case fatality ratios could instead invest in community engagement, health system strengthening, surveillance, and case reporting to adequately handle high case counts during this wave and beyond.

Nawal AK et al

Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults A Randomized Clinical Trial

JAMA, May 2021; doi:10.1001/jama.2021.8565

COMMENTO: Importance  Although effective vaccines against COVID-19 have been developed, additional vaccines are still needed.

Objective  To evaluate the efficacy and adverse events of 2 inactivated COVID-19 vaccines.

Design, Setting, and Participants  Prespecified interim analysis of an ongoing randomized, double-blind, phase 3 trial in the United Arab Emirates and Bahrain among adults 18 years and older without known history of COVID-19. Study enrollment began on July 16, 2020. Data sets used for the interim analysis of efficacy and adverse events were locked on December 20, 2020, and December 31, 2020, respectively.

Interventions  Participants were randomized to receive 1 of 2 inactivated vaccines developed from SARS-CoV-2 WIV04 (5 µg/dose; n = 13 459) and HB02 (4 µg/dose; n = 13 465) strains or an aluminum hydroxide (alum)–only control (n = 13 458); they received 2 intramuscular injections 21 days apart.

Main Outcomes and Measures  The primary outcome was efficacy against laboratory-confirmed symptomatic COVID-19 14 days following a second vaccine dose among participants who had no virologic evidence of SARS-CoV-2 infection at randomization. The secondary outcome was efficacy against severe COVID-19. Incidence of adverse events and reactions was collected among participants who received at least 1 dose.

Results  Among 40 382 participants randomized to receive at least 1 dose of the 2 vaccines or alum-only control (mean age, 36.1 years; 32 261 [84.4%] men), 38 206 (94.6%) who received 2 doses, contributed at least 1 follow-up measure after day 14 following the second dose, and had negative reverse transcriptase–polymerase chain reaction test results at enrollment were included in the primary efficacy analysis. During a median (range) follow-up duration of 77 (1-121) days, symptomatic COVID-19 was identified in 26 participants in the WIV04 group (12.1 [95% CI, 8.3-17.8] per 1000 person-years), 21 in the HB02 group (9.8 [95% CI, 6.4-15.0] per 1000 person-years), and 95 in the alum-only group (44.7 [95% CI, 36.6-54.6] per 1000 person-years), resulting in a vaccine efficacy, compared with alum-only, of 72.8% (95% CI, 58.1%-82.4%) for WIV04 and 78.1% (95% CI, 64.8%-86.3%) for HB02 (P < .001 for both). Two severe cases of COVID-19 occurred in the alum-only group and none occurred in the vaccine groups. Adverse reactions 7 days after each injection occurred in 41.7% to 46.5% of participants in the 3 groups; serious adverse events were rare and similar in the 3 groups (WIV04: 64 [0.5%]; HB02: 59 [0.4%]; alum-only: 78 [0.6%]).

Conclusions and Relevance  In this prespecified interim analysis of a randomized clinical trial, treatment of adults with either of 2 inactivated SARS-CoV-2 vaccines significantly reduced the risk of symptomatic COVID-19, and serious adverse events were rare. Data collection for final analysis is pending.

Wallace M et al

The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine in Adolescents Aged 12–15 Years — United States, May 2021

MMWR, https://www.cdc.gov/mmwr/volumes/70/wr/mm7020e1.htm

COMMENTO : What is already known about this topic?

On May 10, 2021, the Food and Drug Administration expanded Emergency Use Authorization for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12–15 years.

What is added by this report?

On May 12, 2021, after a systematicreview of all available data, the Advisory Committee on Immunization Practices made an interimrecommendation for use of the Pfizer-BioNTech COVID-19 vaccine in adolescents aged 12–15 years for the prevention of COVID-19.

What are the implications for public health practice?

The Pfizer-BioNTech COVID-19 vaccine is the first COVID-19 vaccine approved for use in adolescents and has high efficacy against symptomatic COVID-19. Vaccination will be important to protect adolescents against symptomatic COVID-19 disease and to reduce community transmission of SARS-CoV-2.

Roeker LE et al

COVID-19 vaccine efficacy in patients with chronic lymphocytic leukemia

Leukemia, May 2021; doi.org/10.1038/s41375-021-01270-w

COMMENTO : While randomized controlled trials demonstrated 94–95% efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike messenger RNA (mRNA) vaccines, efficacy in immunocompromised patients has not been established. We aimed to understand serologic response to mRNA vaccination in patients with chronic lymphocytic leukemia (CLL), a population of interest given the immunocompromised state associated with this malignancy and disease-directed therapies, as well as incomplete immune responses following other vaccinations.

Shinde V et al

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

NEJM, May 2021; DOI: 10.1056/NEJMoa2103055

COMMENTO: BACKGROUND : The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1–2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission.

METHODS : In this phase 2a–b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)–negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points weresafety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection.

RESULTS : Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, −0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups.

CONCLUSIONS : The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant.

Saunders KO et al

Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses

Nature, May 2021; doi.org/10.1038/s41586-021-03594-0

COMMENTO : Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and the SARS-CoV-2 pandemic. Vaccines that elicit protective immunity against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that macaque immunization with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052/Alum elicited cross-neutralizing antibody (cross-nAb) responses against batCoVs, SARS-CoV-1, SARS-CoV-2, and SARS-CoV-2 variants B.1.1.7, P.1, and B.1.351. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization ID50 titer of 47,216, and protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD alsoinduced SARS-CoV-1 and batCoV cross-nAbs, albeit at lowertiters. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV vaccines.

Johnston MS et al

Delayed Localized Hypersensitivity Reactions to the Moderna COVID-19 Vaccine

A Case Series

JAMA ; May 2021 ; doi:10.1001/jamadermatol.2021.1214

COMMENTO : Importance  In response to the coronavirus disease 2019 (COVID-19) pandemic, 2 mRNA vaccines (Pfizer-BioNTech and Moderna) received emergency use authorization from the US Food and Drug Administration in December 2020. Some patients in the US have developed delayed localized cutaneous vaccine reactions that have been dubbed “COVID arm.”

Objective  To describe the course of localized cutaneous injection-site reactions to the Moderna COVID-19 vaccine, subsequent reactions to the second vaccine dose, and to characterize the findings of histopathologic examination of the reaction.

Design, Setting, and Participants  This retrospective case series study was performed at Yale New Haven Hospital, a tertiary medical center in New Haven, Connecticut, with 16 patients referred with localized cutaneous injection-site reactions from January 20 through February 12, 2021.

Main Outcomes and Measures  We collected each patient’s demographic information, a brief relevant medical history, clinical course, and treatment (if any); and considered the findings of a histopathologic examination of 1 skin biopsy specimen.

Results  Of 16 patients (median [range] age, 38 [25-89] years; 13 [81%] women), 14 patients self-identified as White and 2 as Asian. The delayed localized cutaneous reactions developed in a median (range) of 7 (2-12) days after receiving the Moderna COVID-19 vaccine. These reactions occurred at or near the injection site and were described as pruritic, painful, and edematous pink plaques. None of the participants had received the Pfizer-BioNTech vaccine. Results of a skin biopsy specimen demonstrated a mild predominantly perivascular mixed infiltrate with lymphocytes and eosinophils, consistent with a dermal hypersensitivity reaction. Of participants who had a reaction to first vaccine dose (15 of 16 patients), most (11 patients) developed a similar localized injection-site reaction to the second vaccine dose; most (10 patients) also developed the second reaction sooner as compared with the first-dose reaction.

Conclusions and Relevance  Clinical and histopathologic findings of this case series study indicate that the localized injection-site reactions to the Moderna COVID-19 vaccine are a delayed hypersensitivity reaction. Thesereactionsmayoccursoonerafter the second dose, but they are self-limited and not associatedwithserious vaccine adverse effects. In contrast to immediate hypersensitivity reactions (eg, anaphylaxis, urticaria), these delayed reactions (dubbed “COVID arm”) are not a contraindication to subsequent vaccination.

Reynolds CJ et al

Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose

Science, April 2021 ; DOI: 10.1126/science.abh1282

COMMENTO: SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

Fabiani M et al

Effectiveness of the Comirnaty (BNT162b2, BioNTech/Pfizer) vaccine in preventing SARS-CoV-2 infection among healthcare workers, Treviso province, Veneto region, Italy, 27 December 2020 to 24 March 2021 separator commenting unavailable

Eurosurveillance , April 2021, doi.org/10.2807/1560-7917.ES.2021.26.17.2100420

COMMENTO: Data on effectiveness of the BioNTech­/Pfizer COVID-19 vaccine in real-world settings are limited. In a study of 6,423 healthcare workers in Treviso Province, Italy, we estimated that, within the time intervals of 14–21 days from the first and at least 7 days from the second dose, vaccine effectiveness in preventing SARS-CoV-2 infection was 84% (95% confidence interval (CI): 40–96) and 95% (95% CI: 62–99), respectively. These results could support the ongoing vaccination campaigns by providing evidence for targeted communication.

Boyarski BJ et al

Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients

JAMA, May 2021 ; doi:10.1001/jama.2021.7489

COMMENTO: In contrast to immunocompetent participants in vaccine trials, a low proportion (17%) of solid organ transplant recipients mounted a positive antibody response to the first dose of SARS-CoV-2 messenger RNA (mRNA) vaccines, with those receiving anti–metabolite maintenance immunosuppression less likely to respond.3 In this study, we assessed antibody response after the second dose.

Shinde V et al

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

NEJM, May 2021 ; DOI: 10.1056/NEJMoa2103055

COMMENTO: BACKGROUND : The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1–2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission.

METHODS : In this phase 2a–b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)–negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection.

RESULTS : Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, −0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups.

CONCLUSIONS : The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant.

Butt AA et al

Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants

NEJM, May 2021; DOI: 10.1056/NEJMc2104974

COMMENTO: The estimated effectiveness of the vaccine against any documented infection with the B.1.1.7 variant was 89.5% (95% confidence interval [CI], 85.9 to 92.3) at 14 or more days after the second dose. The effectiveness against any documented infection with the B.1.351 variant was 75.0% (95% CI, 70.5 to 78.9). Vaccine effectiveness against severe, critical, or fatal disease due to infection with any SARS-CoV-2 (with the B.1.1.7 and B.1.351 variants being predominant within Qatar) was very high, at 97.4% (95% CI, 92.2 to 99.5). Sensitivity analyses confirmed these results.

Menni C et al

Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study

The Lancet, April 2021; doi.org/10.1016/S1473-3099(21)00224-3

COMMENTO : Background : The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and effectiveness of these vaccines in a UK community setting.

Methods : In this prospective observational study, weexamined the proportion and probability of self-reportedsystemic and local side-effectswithin 8 days of vaccination in individualsusing the COVID SymptomStudy app whoreceived one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses wereadjusted by age (≤55 years vs >55 years), sex, health-care workerstatus (binary variable), obesity (BMI <30 kg/m2 vs ≥30 kg/m2), and comorbidities (binary variable, with or without comorbidities).

Findings : Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemicside-effectswerereported by 13·5% (38 155 of 282 103) of individualsafter the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effectswerereported by 71·9% (150 023 of 208 767) of individualsafter the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemicside-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49–68) for ChAdOx1 nCoV-19 and 69% (66–72) for BNT162b2 at 21–44 days and 72% (63–79) for BNT162b2 after 45–59 days.

Interpretation : Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days.

Paul Sax

The decision on the Johnson and Johnson COVID-19 vaccine surprised me, here’s why

HIV and ID Observations – NEJM,

https://blogs.jwatch.org/hiv-id-observations/?p=10069&preview=true

COMMENTO : The “pause” on the one-shot Johnson & Johnson (J&J) COVID-19 vaccine is over. Based on a furtherreview of safety data thatoccurred on April 23, both the CDC and the FDA said the vaccine mayresumehere in the U.S., provided the label includes a warning about a serious, but rare, sideeffect — thrombosis with thrombocytopenia syndrome (TTS).

I confess this decision surprised me. Myhunch was that they would advise limiting the vaccine in the U.S. to women older than 50, with no age criterion for men. Instead, it’s now available for all.

This was no doubt a trickydecision, one reflected in the 10-4 vote of the Advisory Committee on Immunization Practices (ACIP).

Chappell KJ et al

Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial

The Lancet, April 2021; doi.org/10.1016/S1473-3099(21)00200-0

COMMENTO : Background

Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]).

Methods

Wedid a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclampsubunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 daysapart of either placebo, sclamp vaccine at 5 μg, 15 μg, or 45 μg, or one dose of sclamp vaccine at 45 μg followed by placebo. Participants and study personnel, except the dose administration personnel, weremasked to treatment. The primary safety end points included solicited local and systemic adverse events in the 7 day safter each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up untilday 57. Primary immunogenicity end points were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation as says assessed at 28 days after each dose. The study isongoing and registered with ClinicalTrials.gov, NCT04495933.

Findings

Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 μg dose (geometric mean titre [GMT] 6400, 95% CI 3683–11 122), with 15 μg dose (7492, 4959–11 319), and the two 45 μg dose cohorts (8770, 5526–13 920 in the two-dose 45 μg cohort; 8793, 5570–13 881 in the single-dose 45 μg cohort); 4 weeks after the second dose (day 57) with two 5 μg doses (102 400, 64 857–161 676), with two 15 μg doses (74 725, 51 300–108 847), with two 45 μg doses (79 586, 55 430–114 268), only a single 45 μg dose (4795, 2858–8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 μg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 μg doses (GMT 228, 95% CI 146–356), two 15 μg doses (230, 170–312), and two 45 μg doses (239, 187–307).

Interpretation

This first-in-human trial shows that a subunit vaccine comprisingmammaliancell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike proteinelicitsstrong immune responseswith a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assayinterference, a possible barrier to widespread use highlighting the criticality of potential non-spike directedimmunogenicityduring vaccine development. Studies are ongoingwith alternative molecular clamp trimerisationdomains to amelioratethisresponse.

EuropeanMedicines Agency

COVID-19 Vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets

https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood

COMMENTO : At its meeting of 20 April 2021, EMA’s safety committee (PRAC) concluded that a warning about unusual blood clots with low blood platelets should be added to the product information for COVID-19 Vaccine Janssen. PRAC alsoconcludedthattheseeventsshouldbelisted as very rare sideeffects of the vaccine.

Taquet M et al

Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID-19 cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine

https://osf.io/a9jdq/

COMMENTO: Using  an  electronic  health  records  network  we  estimated  the  absolute  incidence  of  cerebral  venous thrombosis  (CVT)  in  the  two  weeks  following  COVID-19  diagnosis(N=513,284),or  influenza (N=172,742),or  receipt  of  the  BNT162b2  or  mRNA-1273  COVID-19  vaccines(N=489,871).Theincidence of portal vein thrombosis (PVT) was also assessed in these groups, as well asthe baselineCVTincidence over a two-week period. The incidence of CVT after COVID-19 diagnosis was 39.0 per million people (95% CI, 25.2–60.2). This washigher thanthe CVT incidenceafter influenza (0.0 per million people, 95% CI 0.0–22.2, adjusted RR=6.73, P=.003) or after receiving BNT162b2 or mRNA-1273 vaccine (4.1 per million people, 95% CI 1.1–14.9, adjusted RR=6.36, P<.001). The relative risks were similar if a broader definition of CVT was used. For PVT, the incidence was 436.4 per million people  (382.9-497.4)  after  COVID-19,  98.4  (61.4-157.6)  after  influenza,  and  44.9  (29.7-68.0)  after BNT162b2 or mRNA-1273. The incidence of CVT following COVID-19 was higher than the incidence observed across the entire health records network (0.41 per million people over any 2-week period). Laboratory test results, availablein a subsetof the COVID-19 patients,provide preliminary evidence suggestive  of raised  D-dimer,  lowered  fibrinogen,  and  an  increased  rate  of  thrombocytopenia  in  the CVT and PVT groups. Mortality was 20% and 18.8% respectively. These data show that the incidence of CVT issignificantly increased after COVID-19,andgreater than that observed with BNT162b2 and mRNA-1273 COVID-19 vaccines. The risk of CVT following COVID-19 isalsohigherthan the latestestimatefrom the EuropeanMedicines Agency for theincidenceassociated withChAdOx1 nCoV-19 vaccine (5.0 per million people, 95% CI 4.3–5.8). Although requirin greplication and corroboration, the present data highlight the risk of serious thrombotic events in COVID-19, and can help contextualize the risks and benefits of vaccination in this regard.

Gresele P et al

Management of cerebral and splanchnic vein thrombosis associated with thrombocytopenia in subjects previously vaccinated with Vaxzevria (AstraZeneca): a position statement from the Italian Society for the Study of Haemostasis and Thrombosis (SISET)

Blood transfusion, April 2021; DOI 10.2450/2021.0117-21

COMMENTO : ChAdOx1 nCOV-19 (Vaxzevria) is a vaccine against SARS-CoV-2 infection (COVID-19) developed by Oxford University and AstraZeneca that uses a replication-deficient chimpanzee adenoviral vector (ChAdOx1) containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene.

Over the last few weeks, there have been several reports of thromboembolicevents in subjectswhohad been administeredVaxzevria in the previousweeks. This ledseveralEuropean countries to decide to suspend its administration or, more recently, to limitit to subjects over 60 years of age.

Sadoff J et al

Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

NEJM, April 2021;  DOI: 10.1056/NEJMoa2101544

COMMENTO : BACKGROUND : The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.

METHODS :In an international, randomized, double-blind, placebo-controlled, phase 3 trial,we randomly assigned adult participants in a 1:1 ratio to receive a single dose ofAd26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccineefficacyagainstmoderate to severe–critical coronavirus disease 2019 (Covid-19) withan onset at least 14 days and at least 28 daysafter administration among participants in the per-protocol population whohadtestednegative for SARS-CoV-2.Safetywasalsoassessed.

RESULTS :The per-protocol population included 19,630 SARS-CoV-2–negative participants whoreceived Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protectedagainst moderate to severe–critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy,66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 daysafter administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to74.8). Vaccine efficacy was higher against severe–critical Covid-19 (76.7% [adjusted95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9]for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and64.0% against moderate to severe–critical Covid-19 with onset at least 14 days andat least 28 days after administration, respectively, and efficacy against severe–critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higherwith Ad26.COV2.S than with placebo but was generally mild to moderate andtransient. The incidence of serious adverse eventswasbalancedbetween the twogroups. Threedeathsoccurred in the vaccine group (none were Covid-19–related),and 16 in the placebo group (5 were Covid-19–related).

CONCLUSIONS :A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease,includinghospitalization and death. Safetyappeared to besimilar to that in otherphase 3 trials of Covid-19 vaccines.

Mmarks P

Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine

https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine

COMMENTO: Right now, these adverse events appear to be extremely rare. COVID-19 vaccine safety is a top priority for the federal government, and we take all reports of health problems following COVID-19 vaccination very seriously. People who have received the J&J vaccine who develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider. Health care providers are asked to report adverse events to the Vaccine Adverse Event Reporting System at https://vaers.hhs.gov/reportevent.html.

European Medicines Agency

COVID-19 Vaccine Janssen: assessment of very rare cases of unusual blood clots with low platelets continues

https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-assessment-very-rare-cases-unusual-blood-clots-low-platelets-continues

COMMENTO: As announced last week, EMA’s safety committee (PRAC) is reviewing very rare cases of unusual blood clots that occurred in the United States following the use of Janssen’s COVID-19 vaccine. The type of blood clot reported, cerebral venous sinus thrombosis (CVST), occurred in most cases in combination with low levels of blood platelets (thrombocytopenia).

Anichini G et al

SARS-CoV-2 Antibody Response in Persons with Past Natural Infection

NEJM, April 2021; DOI: 10.1056/NEJMc2103825

COMMENTO : Whether or not persons who have already been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be vaccinated is unclear. Only a few studies have shown that vaccinees who were previously infected with SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccinees.In an observational cohort study, we enrolled 100 health care workers, including 38 (9 men and 29 women) with a documented history of SARS-CoV-2 infection (mean duration between infection and vaccination, 111 days). The mean age of these previously infected participants was 35.1 years (95% confidence interval [CI], 31.7 to 38.6). Our study also included 62 participants (25 men and 37 women) who had not been previously infected. The mean age of those participants was 44.7 years (95% CI, 41.0 to 47.6).

Dagan N et al

BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting

NEJM, April 2021; DOI: 10.1056/NEJMoa2101765

COMMENTO : BACKGROUND : As mass vaccination campaigns against coronavirus disease 2019 (Covid-19) commence worldwide, vaccine effectiveness needs to be assessed for a range of outcomes across diverse populations in a noncontrolled setting. In this study, data from Israel’s largest health care organization were used to evaluate the effectiveness of the BNT162b2 mRNA vaccine.

METHODS : All persons who were newly vaccinated during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics. Study outcomes included documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symptomatic Covid-19, Covid-19–related hospitalization, severe illness, and death. We estimated vaccine effectiveness for each outcome as one minus the risk ratio, using the Kaplan–Meier estimator.

RESULTS : Each study group included 596,618 persons. Estimated vaccine effectiveness for the study outcomes at days 14 through 20 after the first dose and at 7 or more days after the second dose was as follows: for documented infection, 46% (95% confidence interval [CI], 40 to 51) and 92% (95% CI, 88 to 95); for symptomatic Covid-19, 57% (95% CI, 50 to 63) and 94% (95% CI, 87 to 98); for hospitalization, 74% (95% CI, 56 to 86) and 87% (95% CI, 55 to 100); and for severe disease, 62% (95% CI, 39 to 80) and 92% (95% CI, 75 to 100), respectively. Estimated effectiveness in preventing death from Covid-19 was 72% (95% CI, 19 to 100) for days 14 through 20 after the first dose. Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions.

CONCLUSIONS : This study in a nationwide mass vaccination setting suggests that the BNT162b2 mRNA vaccine is effective for a wide range of Covid-19–related outcomes, a finding consistent with that of the randomized trial.

Muir K et al

Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination

NEJM, April 2021; DOI: 10.1056/NEJMc2106075

COMMENTO : Thrombosis and thrombocytopenia have been reported after vaccination with the ChAdOx1 nCoV-19 vaccine (Oxford–AstraZeneca), a recombinant chimpanzee adenoviral vector encoding the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2 To date, such reactions have not been associated with other vaccines against coronavirus 2019 (Covid-19). We describe a case of extensive thrombosis associated with severe thrombocytopenia and disseminated intravascular coagulation that resembled autoimmune heparin-induced thrombocytopenia3 in a patient who had received the Ad26.COV2.S vaccine (Johnson & Johnson/Janssen), a recombinant adenovirus serotype 26 vector encoding the SARS-CoV-2 spike glycoprotein.

Jentsch PC et al

Prioritising COVID-19 vaccination in changing social and epidemiological landscapes: a mathematical modelling study

The Lancet, March 2021; doi.org/10.1016/S1473-3099(21)00057-8

COMMENTO : Background : During the COVID-19 pandemic, authorities must decidewhich groups to prioritise for vaccination in a shifting social–epidemiologicallandscape in which the success of large-scale non-pharmaceutical interventions requiresbroad social acceptance. Weaimed to compare projected COVID-19 mortalityunder four differentstrategies for the prioritisation of SARS-CoV-2 vaccines.

Methods : We developed a coupled social–epidemiological model of SARS-CoV-2 transmission in which social and epidemiological dynamics interact with one another. We modelled how population adherence to non-pharmaceutical interventions responds to case incidence. In the model, schools and workplaces are also closed and reopened on the basis of reported cases. The model was parameterised with data on COVID-19 cases and mortality, SARS-CoV-2 seroprevalence, population mobility, and demography from Ontario, Canada (population 14·5 million). Disease progression parameters came from the SARS-CoV-2 epidemiologicalliterature. Weassumed a vaccine with 75% efficacyagainstdisease and transmissibility. Wecomparedvaccinatingthoseaged 60 years and older first (oldest-first strategy), vaccinatingthoseyoungerthan 20 years first (youngest-first strategy), vaccinatinguniformly by age (uniformstrategy), and a novel contact-basedstrategy. The latter threestrategiesinterrupt transmission, whereas the first targets a vulnerable group to reducedisease. Vaccination rates rangedfrom 0·5% to 5% of the population per week, beginning on either Jan 1 or Sept 1, 2021.

Findings : Case notifications, non-pharmaceutical intervention adherence, and lockdown undergo successive waves that interact with the timing of the vaccine programme to determine the relative effectiveness of the four strategies. Transmission-interruptingstrategiesbecomerelatively more effective with time as herdimmunitybuilds. The model predictsthat, in the absence of vaccination, 72 000 deaths (95% credibleinterval 40 000–122 000) wouldoccur in Ontario from Jan 1, 2021, to March 14, 2025, and at a vaccination rate of 1·5% of the population per week, the oldest-first strategywouldreduce COVID-19 mortality by 90·8% on average (followed by 89·5% in the uniform, 88·9% in the contact-based, and 88·2% in the youngest-first strategies). 60 000 deaths (31 000–108 000) wouldoccurfrom Sept 1, 2021, to March 14, 2025, in the absence of vaccination, and the contact-basedstrategywouldreduce COVID-19 mortality by 92·6% on average (followed by 92·1% in the uniform, 91·0% in the oldest-first, and 88·3% in the youngest-first strategies) at a vaccination rate of 1·5% of the population per week.

Interpretation : The most effective vaccination strategy for reducingmortality due to COVID-19 depends on the time course of the pandemic in the population. For later vaccination start dates, use of SARS-CoV-2 vaccines to interrupt transmission mightprevent more deathsthanprioritisingvulnerableage groups.

The Lancet Microbe Editorial Board

Vaccine certificates: does the end justify the means?

The Lancet, April 2021; doi.org/10.1016/S2666-5247(21)00067-7

COMMENTO : As COVID-19 vaccination programmes proceed in many countries, governments worldwide are considering issuing so-called vaccine certificates to facilitate the re-opening of their stumped economies by easing some restrictions for individuals who have been vaccinated against SARS-CoV-2. But are such certificates justified? Are they likely to be useful? And, mostimportantly, are theyfair?

Wang L et al

Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization

NEJM, April 2021; DOI: 10.1056/NEJMc2103022

COMMENTO : Our findingssuggestthat B.1.1.7 showedlittleresistance to the neutralizingactivity of convalescent or vaccineeserum, whereas B.1.351 showed more resistance to the neutralization of both convalescent serum (by a factor of 2) and vaccineeserum (by a factor of 2.5 to 3.3) than the wild-type virus. Most of the vaccineeserumsamplesthatweretestedlostneutralizingactivity, a findingthatwas consistent with the results of otherrecentstudies of neutralization by convalescent serum or serumobtainedfromrecipients of messenger RNA or BBIBP-CorV vaccines. Our findingsalso highlight the importance of sustained viral monitoring and evaluation of the protective efficacy of vaccines in areas where variants are circulating.

Doria-Rose N et al

Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19

NEJM, April 2021; DOI: 10.1056/NEJMc2103916

COMMENTO: Wedescribe mRNA1273-elicited binding and neutralizingantibodiesin 33 healthyadult participants in an ongoing phase 1 trial,stratifiedaccording to age, at 180 daysafter the second dose of 100 μg (day 209).Antibodyactivityremained high in all age groups at day 209.

EuropeanMedicines Agency

AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets

https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood

COMMENTO : EMA’s safety committee (PRAC) has concluded today that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).

In reachingits conclusion, the committe etookintoconsideration all currentlyavailableevidence, including the advicefrom an ad hoc expert group.

EMA isremindinghealthcareprofessionals and people receiving the vaccine to remainaware of the possibility of very rare cases of bloodclotscombinedwithlowlevels of bloodplateletsoccurringwithin 2 weeks of vaccination. So far, most of the cases reported have occurred in womenunder 60 years of agewithin 2 weeks of vaccination. Based on the currentlyavailableevidence, specificriskfactors have not been confirmed.

Van Praet JT et al

Humoral and cellular immunogenicity of the BNT162b2 mRNA Covid-19 Vaccine in nursing home residents

Clinical Infectious Diseases, April 2021; doi.org/10.1093/cid/ciab300

COMMENTO : One-hundred consecutive residents from 2 Belgian long-term care facilities were studied after vaccination with 2 doses, administered with a 3-week interval. This study was approved by the local institutional review board, and written informed consent was obtained. We determined both humoral (antibodies against the receptor binding domain of S1 subunit of the spike protein, CMIA on Architect-I System from Abbott) and cellular (QuantiFERON SARS-CoV-2 Antigen 2, Qiagen) responses, as current evidence indicates that the immunological correlate of protective immunity requires a balance between neutralizing anti-S antibodies and Th1  responses. COVID-19-experienced and COVID-19-naïve residentsweresegregated bypresence (n=64) or absence (n=46) of antibodiesagainst SARS-CoV-2 nucleocapsid(CMIA on Architect-I System from Abbott), based on the observations by Capetti etal. Fifteenconsecutivehealthcareworkerswithout spike antibodiesbeforevaccination wereused as controls

Van Praet JT et al

Humoral and cellular immunogenicity of the BNT162b2 mRNA Covid-19 Vaccine in nursing home residents

Clinical Infectious Diseases, April 2021; doi.org/10.1093/cid/ciab300      

COMMENTO: One-hundred consecutive residents from 2 Belgian long-term care facilities were studied after vaccination with 2 doses, administered with a 3-week interval. This study was approved by the local institutional review board, and written informed consent was obtained. We determined both humoral (antibodies against the receptor binding domain of S1 subunit of the spike protein, CMIA on Architect-I System from Abbott) and cellular (QuantiFERON SARS-CoV-2 Antigen 2, Qiagen) responses, as current evidence indicates that the immunological correlate of protective immunity requires a balance between neutralizing anti-S antibodies and Th1  responses. COVID-19-experienced and COVID-19-naïve residentsweresegregated bypresence (n=64) or absence (n=46) of antibodiesagainst SARS-CoV-2 nucleocapsid(CMIA on Architect-I System from Abbott), based on the observations by Capetti etal. Fifteenconsecutivehealthcareworkerswithout spike antibodiesbeforevaccination wereused as controls.

Westholter D et al

SARS-CoV-2 outbreak in a long-term care facility after vaccination with BNT162b2

Clinical Infectious Diseases, April 2021; doi.org/10.1093/cid/ciab299

COMMENTO: In earlyJanuary 2021 73/76 (96%) residents and about 90% of the employeesreceived a first dose ofBNT162b2. SARS-CoV-2 rapidantigen tests were all negativeamongresidents and participatingemployees the daybefore. However, a member of the mobilevaccination team as well as an employe e reported respiratory symptoms one and four days after vaccination, respectively and tested positive for SARS-CoV-2 by PCR. There upon, local health authoritiesordered serial PCtestings of all residents 7, 14, 20, 23, 27, 30 and 35 daysafter the first vaccination and imposedintensifiedquarantinemeasures. A boosting dose of BNT162b2 wasoffered to all asymptomaticresidents 21 daysafter the first vaccination.The medianage of all residentswas 88 years and 61/76 (80%) werefemale. The vaccination itselfwas not associatedwithanyserious adverse events in thiscohort. Serial PCR testingsidentifiedSARS-CoV-2 infections in 26/76 (34%) residents. Positive cases weredetected 7 days (1), 14 days(10), 20 days (12) and 23 days (3) after the first vaccination. Only 3/26 (12%) residentsweresymptomatic at the time of diagnosiswhile 12/26 (46%) positivelytestedresidentsdevelopedsymptoms in the further course. Overall case fatality rate was 9/26 (35%). Of note, 5 of the 9 patients with fatal outcomewerediagnosed on day 20 after vaccination.

Glover RE et al

Vaccinating against covid-19 in people who report allergies

BMJ, January 2021; doi.org/10.1136/bmj.n120 

COMMENTO: Importantly, history of severe allergy does not preclude vaccination unless that allergy is to the vaccine or its components. Only one of the excipients in the Pfizer-BioNTech vaccine is a known potential allergen, polyethylene glycol (PEG 2000), and this is an inactive ingredient in over 1000 medications. The Oxford-AstraZeneca vaccine does not contain PEG 2000 so remains an alternative for people with a history of allergy to this ingredient. However, there is some cross-reactivity between PEG and polysorbate 80, an ingredient in the Oxford-AstraZeneca vaccine, so evaluation by an allergy specialist may be advisable before vaccination in anyone with a suspected PEG allergy history.Allergy is antigen specific, although people with one drug allergy may be more susceptible to other drug allergies than the general population.

Greinacher A et al

A Prothrombotic Thrombocytopenic Disorder Resembling Heparin-Induced Thrombocytopenia Following Coronavirus-19 Vaccination

Preprint- not peer reviewed, March 2021; DOI: 10.21203/rs.3.rs-362354/v1

COMMENTO: Background. Vaccines are important for managing the COVID-19 pandemic caused by SARS-CoV-2. However, following widespread vaccination using a recombinant adenoviral vector encoding the spike protein antigen of SARS-CoV-2 (AZD1222, AstraZeneca), reports have emerged of some vaccine recipients developing unusual thrombotic events and thrombocytopenia. We investigated whether such patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against platelet factor 4 (PF4), as is known to be caused by heparin and sometimes other environmental triggers.

Methods. We summarized the clinical and laboratory features of 9 patients in Germany and Austria who developed thrombosis and thrombocytopenia events following AZD1222 vaccination. Serum from four patients was used to test for anti-PF4/heparin antibodies, both by immunoassay and by platelet activation assays performed in the presence of heparin, PF4, or both.

Results. The 9 patients (8 female; median age, 36 [range, 22—49) presented with thrombosis beginning 4 to 16 days post-vaccination: 7 patients had cerebral venous thrombosis (CVT), 1 had pulmonary embolism, and 1 had splanchnic vein thrombosis and CVT; 4 patients died. None had received heparin prior to symptom onset. All four patients tested strongly positive for anti-PF4/heparin antibodies by immunoassay; all 4 patients tested strongly positive in the platelet activation assay in the presence of PF4 independently of heparin. Platelet activation was inhibited by high concentrations of heparin, Fc receptor-blocking monoclonal antibody, and intravenous immunoglobulin.

Conclusions. The AZD1222 vaccine is associated with development of a prothrombotic disorder that clinically resembles heparin-induced thrombocytopenia but which shows a different serological profile.

Gesellschaft für Thrombose- und Hämostaseforschung

Updated GTH statement on vaccination with the AstraZeneca COVID-19vaccine, as of March 22, 2021

https://gth-online.org/wp-content/uploads/2021/03/GTH_Stellungnahme_AstraZeneca_engl._3_22_2021.pdf

COMMENTO : An important pathomechanism has been clarified within the GTHunder the leadership of the Greifswald working group around AndreasGreinacher. The vaccination is likely to lead to the formation of antibodiesagainst platelet antigens as part of the inflammatory reaction and immunestimulation. Depending on or independently of heparin, these antibodies theninduce massive platelet activation via the Fc receptor in analogy to heparininduced thrombocytopenia (HIT). This mechanism (HIT mimicry) could bedemonstrated in four patients with a sinus / cerebral vein thrombosis aftervaccination with the AstraZeneca COVID-19 vaccine in the laboratory of AndreasGreinacher incooperation with other GTH members. As with classical HIT, theseantibodies appear 4–16 days after vaccination. This athomechanism does notrule out that the sinus / cerebral vein thromboses after vaccination with theAstraZeneca COVID-19 vaccine also have other causes.

Kupferschmidt K et al

A rare clotting disorder may cloud the world’s hopes for AstraZeneca’s COVID-19 vaccine

Science, https://www.sciencemag.org/news/2021/03/rare-clotting-disorder-may-cloud-worlds-hopes-astrazenecas-covid-19-vaccine

COMMENTO: Now, a group of researchers led by German clotting specialist Andreas Greinacher of the University of Greifswald says the highly unusual combination of symptoms—widespread blood clots and a low platelet count, sometimes with bleeding—resembles a rare side effect of the blood thinner heparin called heparin-induced thrombocytopenia (HIT).

Thompson MG et al

Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health CarePersonnel, First Responders, and Other Essential and Frontline Workers —Eight U.S. Locations, December 2020–March 2021

https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm

COMMENTO : What is already known about this topic? Messenger RNA (mRNA) COVID-19 vaccines have been shown to be effective in preventing symptomatic SARS-CoV-2 infection in randomized placebo-controlled Phase III trials.

What is added by this report? Prospective cohorts of 3,950 health care personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing for 13 consecutive weeks. Under real-world conditions, mRNA vaccine effectiveness of full immunization (≥14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥14 days after first dose but before second dose) was 80%.

What are the implications for public health practice? Authorized mRNA COVID-19 vaccines are effective for preventing SARS-CoV-2 infection in real-world conditions. COVID-19 vaccination is recommended for all eligible persons.

Stamatato L et al

mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection

Science, Marchc 2021; DOI: 10.1126/science.abg9175

COMMENTO: Emerging SARS-CoV-2 variants have raised concerns about resistance to neutralizing antibodies elicited by previous infection or vaccination. We examined whether sera from recovered and naïve donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants. Pre-vaccination sera from recovered donors neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351, but a single immunization boosted neutralizing titers against all variants and SARS-CoV-1 by up to 1000-fold. Neutralization was due to antibodies targeting the receptor binding domain and was not boosted by a second immunization. Immunization of naïve donors also elicited cross-neutralizing responses, but at lower titers. Our study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.

Blumenthal KG et al

Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-C

NEJM, April 2021, DOI: 10.1056/NEJMc2102131

COMMENTO : We have also observed delayed large local reactions to the mRNA-1273 vaccine, with a median onset on day 8 (range, 4 to 11) after the first dose. These reactions had a variable appearance (Figure 1). Here, we report on a series of 12 patients with these reactions, all of which appeared near the injection site after complete resolution of the initial local and systemic symptoms associated with vaccination. Five of the reactions were grade 3 plaques (≥10 cm in diameter) (Table 1). Some patients had concurrent systemic adverse effects, and among these patients, 2 had additional skin findings. Most patients received treatment for their symptoms (e.g., with ice and antihistamines). Some patients received glucocorticoids (topical, oral, or both), and 1 patient received antibiotic therapy for presumptive cellulitis. The symptoms resolved a median of 6 days after onset (range, 2 to 11).

Hall MA et al

“Vaccine Passport” Certification — Policy and Ethical Considerations

NEJM, March 2021 ; DOI: 10.1056/NEJMp2104289

COMMENTO : Using Covid-19 vaccine passports to tailor restrictions, however, has drawn staunch opposition based on several weighty concerns.1 First, while vaccine supply remains limited, privileging people who are fortunate enough to have gained early access is morally questionable. Second, even after supply constraints ease, rates of vaccination among racial minorities and low-income populations seem likely to remain disproportionately low; relatedly, if history is a guide, programs that confer social privilege on the basis of “fitness” can lead to invidious discrimination. Third, the extent of protection conferred by vaccination, particularly against new variants, is not yet well understood, nor is the potential for viral transmission by people who have been vaccinated. Fourth, privileging the vaccinated will penalize people with religious or philosophical objections to vaccination. Finally, we lack a consensus approach to accurately certifying vaccination.

Meyer MN et al

Trends in Health Care Worker Intentions to Receive a COVID-19 Vaccine and Reasons for Hesitancy

JAMA, March 2021 ; doi:10.1001/jamanetworkopen.2021.5344

COMMENTO: Although health care workers (HCWs) can serve as ambassadors of COVID-19 vaccine acceptance, surveys have found low acceptance rates among HCWs (eg, 33.5%).1 However, those surveys were conducted before the issuance of vaccine emergency use authorizations (EUAs) by the US Food and Drug Administration (FDA). We surveyed all employees of a health care system on the eve of vaccine distribution to encourage them to receive a COVID-19 vaccine, assess their intentions to do so, and understand reasons for hesitancy.

Sax P

COVID-19 vaccines FAQs: Are there minimum or maximum ages for patients to receive the vaccine?

https://www.nejm.org/covid-vaccine/faq

COMMENTO: The Pfizer/BioNTech vaccine is authorized for patients ≥16 years and the Moderna vaccine for ≥18 years. Studies in children are under way, but neither vaccine should be administered to children at this point. There is no maximum age restriction. Given the disproportionate toll that Covid-19 has taken on the elderly — essentially every study finds that older age is a risk factor for severe disease — older people should be strongly encouraged to be immunized.

One important unknown based solely on the clinical trial results is how effective the vaccines will be in the frail older population, especially those of extremely advanced age or who live in nursing homes. While this is a target population for early immunization, this particular subset of older people did not participate in the phase 3 clinical trials, because study participants had to be ambulatory and clinically stable. Since the release of the vaccines, however, we now have population-based studies showing a substantial decline in hospitalizations due to Covid-19 among people over 70, including data from nursing homes. These encouraging data suggest that even though older vaccinated people have lower antibody levels than younger recipients, they still experience significant protection.

Keehner J et al

SARS-CoV-2 Infection after Vaccination in Health Care Workers in California

NEJM, March 2021 ; DOI: 10.1056/NEJMc2101927

COMMENTO: In the initial 31 days of the vaccination campaign, 59% of 23,234 UTSW employees received a first dose of either one of the mRNA vaccines and 30% received a second dose. Between December 15, 2020, and January 28, 2021, a total of 350 of the 23,234 employees (1.5%) who were eligible to receive the vaccine were identified as being newly infected with SARS-CoV-2.

Benenson S et al

BNT162b2 mRNA Covid-19 Vaccine Effectiveness among Health Care Workers

NEJM, March 2021 ; DOI: 10.1056/NEJMc2101951

COMMENTO: From the beginning of the epidemic through January 31, 2021, of the 6680 health care workers, 689 (10.3%) were infected, mostly due to exposure to Covid-19 in the community; the trends in incidence among health care workers were similar to that in the Jerusalem population (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Vaccination with two doses of the Pfizer–BioNtech vaccine, given 21 days apart,4 began on December 20, 2020. Within 8 weeks, 5297 of 6252 (84.7%) health care workers who had not been previously infected by December 20 were vaccinated. Most of the health care workers (98.9%) who had received the first dose of vaccine and were not infected by day 21 received the second dose.

The Lancet Infectious Diseases Editorial Board

The COVID-19 exit strategy—why we need to aim low

The Lancet Infectious Diseases, February 2021; DOI: 10.1016/s1473-3099(21)00080-3 

COMMENTO: As we find ourselves in the second year of a global pandemic, the question on everyone's mind is: when will this end? Much of the narrative around the pandemic last year was that all hopes for a return to normal hinged on development of an effective vaccine. This rhetoric was deaf to the concerns of vaccine and public health experts, and for many a SARS-CoV-2 vaccine has become the magic bullet to deliver us from endless cycles of lockdown and economic decline. Against all precedent, going into 2021, the world had several vaccines with demonstrated efficacy against symptomatic COVID-19 in its armamentarium. Yet a magic bullet they are not.

Agenzia Italiana del Farmaco

AIFA: sospensione precauzionale del vaccino AstraZeneca

https://www.aifa.gov.it/-/aifa-sospensione-precauzionale-del-vaccino-astrazeneca

COMMENTO : L’AIFA ha deciso di estendere in via del tutto precauzionale e temporanea, in attesa dei pronunciamenti dell’EMA, il divieto di utilizzo del vaccino AstraZeneca Covid19 su tutto il territorio nazionale. Tale decisione è stata assunta in linea con analoghi provvedimenti adottati da altri Paese europei

Ulteriori approfondimenti sono attualmente in corso. L’AIFA, in coordinamento con EMA e gli altri Paesi europei, valuterà congiuntamente tutti gli eventi che sono stati segnalati a seguito della vaccinazione.

European Medicines Agency

Investigation of COVID-19 Vaccine AstraZeneca and thromboembolic events continues Share

https://www.ema.europa.eu/en/news/investigation-covid-19-vaccine-astrazeneca-thromboembolic-events-continues

COMMENTO : EMA’s safety committee (PRAC) made further progress today, Tuesday 16 March, in its detailed evaluation of cases of blood clots, some with unusual features such as low numbers of platelets, in recipients of COVID-19 Vaccine AstraZeneca. As previously stated, while its investigation is ongoing, EMA currently remains of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalisation and death, outweigh the risks of side effects.

Medicines & Healthcare products Regulatory Agency – United Kingdom

Coronavirus vaccine - weekly summary of Yellow Card reporting

https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-card-reporting

COMMENTO : This safety update report is based on detailed analysis of data up to 28 February 2021. At this date, an estimated 10.7 million first doses of the Pfizer/BioNTech vaccine and 9.7 million doses of the Oxford University/AstraZeneca vaccine had been administered, and around 0.8 million second doses, mostly the Pfizer/BioNTech vaccine, had been administered. This represents an increase of 2.8 million on the previous week.

Conclusions :

  • The increases in number of ADR reports reflects the increase in vaccine deployment as new vaccination centres have opened across the UK.
  • The number and nature of suspected adverse reactions reported so far are not unusual in comparison to other types of routinely used vaccines.
  • The overall safety experience with both vaccines is so far as expected from the clinical trials.
  • Based on current experience, the expected benefits of both COVID-19 vaccines in preventing COVID-19 and its serious complications far outweigh any known side effects.

As with all vaccines and medicines, the safety of COVID-19 vaccines is being continuously monitored.

Madhi SA et al

Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant

NEJM, March 2021; DOI: 10.1056/NEJMoa2102214

COMMENTO: BACKGROUND : Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa.

METHODS : We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose.

RESULTS : Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], −49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (92.9%) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, −76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups.

CONCLUSIONS : A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant.

Boyarsky BJ et al

Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients

JAMA, March 2021 ; doi:10.1001/jama.2021.4385

COMMENTO: Immunocompromised individuals have been excluded from studies of SARS-CoV-2 messenger RNA (mRNA) vaccines. In such patients, the immune response to vaccination may be blunted. To better understand the immunogenicity of mRNA vaccines in immunocompromised individuals, we quantified the humoral response to the first dose in solid organ transplant recipients.

Krutikov M et al

Spread of a Variant SARS-CoV-2 in Long-Term Care Facilities in England

NEJM, March 2021 ; DOI: 10.1056/NEJMc2035906

COMMENTO: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and hospital admissions for coronavirus disease 2019 (Covid-19) increased rapidly in the South East region of England in November and December 2020, despite lockdown measures.1,2 More than half of these infections were associated with a distinct phylogenetic cluster that is estimated to be 40 to 70% more transmissible than previous variants and is driving the growth of infections across England.3 Given the excess deaths seen in long-term care facilities during the pandemic, preventing further spread of this variant, known as B.1.1.7, to long-term care facilities is a public health priority.

Luchsinger LL et al

Vaccine efficacy probable against COVID-19 variants

Science, March 2021 ; DOI: 10.1126/science.abg9461

COMMENTO : The U.S. Food and Drug Administration (FDA) emergency use authorization of three vaccines, all of which have shown greater than 85% effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has provided the public with the hope of ending the global COVID-19 pandemic. However, recent outbreaks of more transmissible variant SARS-CoV-2 strains that harbor mutations in the spike protein—the critical viral target of immune responses produced by the vaccines —has invited a dour outlook on the vaccines' continued efficacy. The trepidation is based on the prompt compilation of in vitro data that demonstrate as much as 10-fold reduction in neutralization antibody (NAb) activity in vaccinated samples against mutant spike protein pseudovirus, which is thought to be an important metric of acquired immunity. Although reports of NAb reduction are alarming in magnitude, the proof of vaccine effectiveness can only be measured definitively by challenging vaccinated subjects with infection.

European Medicines Agency

COVID-19 Vaccine AstraZeneca: benefits still outweigh the risks despite possible link to rare blood clots with low blood platelets

https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots

COMMENTO: EMA’s safety committee, PRAC, concluded its preliminary review of a signal of blood clots in people vaccinated with COVID-19 Vaccine AstraZeneca at its extraordinary meeting of 18 March 2021. The Committee confirmed that:

  • the benefits of the vaccine in combating the still widespread threat of COVID-19 (which itself results in clotting problems and may be fatal) continue to outweigh the risk of side effects;
  • the vaccine is not associated with an increase in the overall risk of blood clots (thromboembolic events) in those who receive it;
  • there is no evidence of a problem related to specific batches of the vaccine or to particular manufacturing sites;

however, the vaccine may be associated with very rare cases of blood clots associated with thrombocytopenia, i.e. low levels of blood platelets (elements in the blood that help it to clot) with or without bleeding, including rare cases of clots in the vessels draining blood from the brain (CVST).

Agenzia Italiana del Farmaco

Dopo parere EMA, domani riprendono vaccinazioni con AstraZeneca

https://www.aifa.gov.it/web/guest/-/dopo-parere-ema-domani-riprendono-vaccinazioni-con-astrazeneca

COMMENTO: La raccomandazione del Comitato di Valutazione dei rischi per la Farmacovigilanza (PRAC) dell’Agenzia Europea per i Medicinali (EMA), nella riunione di oggi, 18 marzo 2021, ha confermato il favorevole rapporto beneficio/rischio del vaccino antiCovid19 AstraZeneca, escludendo una associazione tra i casi di trombosi e il vaccino COVID19. Ha inoltre escluso, sulla base dei dati disponibili, problematiche legate alla qualità e alla produzione.

Paul Erlich Institut

FAQ – Temporary suspension of COVID-19 vaccine AstraZeneca

http://www.quotidianosanita.it/allegati/allegato947417.pdf

COMMENTO:  A specific form of severe cerebral venous thrombosis associated with

platelet deficiency (thrombocytopenia) and bleeding has been identified in seven cases (as of 15 March 2021) in temporal association with vaccination with COVID-19 Vaccine AstraZeneca.

Blumenthal KG et al

Acute Allergic Reactions to mRNA COVID-19 Vaccines

JAMA, March 2021 ; doi:10.1001/jama.2021.3976

COMMENTO: Anaphylaxis to the mRNA COVID-19 vaccines is currently estimated to occur in 2.5 to 11.1 cases per million doses, largely in individuals with a history of allergy. Allergic concerns contribute to vaccine hesitancy; we investigated acute allergic reaction incidence after more than 60 000 mRNA COVID-19 vaccine administrations.

Capetti AF et al

Impressive boosting of anti-S1/S2 IgG production in COVID-19-experienced patients after the first shot of the BNT162b2 mRNA COVID-19 Vaccine

Clinical Infectious Diseases, March 2021; doi.org/10.1093/cid/ciab214

COMMENTO : Our pilot study was aimed to describe anti-spike production after the first dose of the BNT162b2 mRNA COVID-19 Vaccine in COVID-19-naïve and COVID-19-experienced subjects, using the DiaSorin‟s LIAISON-CLIAS1/S2® IgG solution, which has a 94.4% positive agreement to Plaque Reduction Neutralization Test (PRNT).

Rapaka RR et al

Are some COVID vaccines better than others? Interpreting and comparing estimates of efficacy in trials of COVID-19 vaccines

Clinical Infectious Diseases, March 2021 ; doi.org/10.1093/cid/ciab213

COMMENTO: COVID-19 vaccine trials provide valuable insight into the safety and efficacy of vaccines, with individually-randomized, placebo-controlled trials being the gold standard in trial design. However, a myriad of variables must be considered as clinical trial data are interpreted and used to guide policy decisions. These variables include factors such as the characteristics of the study population and circulating SARS-CoV-2 strains, the force of infection, the definition and ascertainment of endpoints, the timing of vaccine efficacy assessment, and the potential for performance bias. In this Viewpoint, we discuss critical variables to consider when comparing efficacy measurements across current and future COVID-19 vaccine trials.

Saad-Roy CM et al

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes

Science, March 2021 ; DOI: 10.1126/science.abg8663

COMMENTO: In the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to SARS-CoV-2. Two critical issues arise: how will the timing of delivery of the second dose affect both infection dynamics and prospects for the evolution of viral immune escape via a build-up of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection and find that a one-dose policy may increase the potential for antigenic evolution under certain conditions of partial population immunity. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.

Raches E et al

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial

The Lancet, March 2021 ; doi.org/10.1016/S1473-3099(21)00070-0

COMMENTO: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28.

Methods : We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519.

Findings : Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group.

Interpretation : In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial.

The Centers for Disease Control and Prevention

Guidance for Fully Vaccinated People

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated-guidance.htm:

COMMENTO: Fully vaccinated people can:

Visit with other fully vaccinated people indoors without wearing masks or physical distancing

Visit with unvaccinated people from a single household who are at low risk for severe COVID-19 disease indoors without wearing masks or physical distancing

Refrain from quarantine and testing following a known exposure if asymptomatic

For now, fully vaccinated people should continue to:

Take precautions in public like wearing a well-fitted mask and physical distancing

Wear masks, practice physical distancing, and adhere to other prevention measures when visiting with unvaccinated people who are at increased risk for severe COVID-19 disease or who have an unvaccinated household member who is at increased risk for severe COVID-19 disease

Wear masks, maintain physical distance, and practice other prevention measures when visiting with unvaccinated people from multiple households

Avoid medium- and large-sized in-person gatherings

Get tested if experiencing COVID-19 symptoms

Follow guidance issued by individual employers

Follow CDC and health department travel requirements and recommendations

Christie A et al

CDC Interim Recommendations for Fully Vaccinated People An Important First Step

JAMA, March 2021 ; doi:10.1001/jama.2021.4367

COMMENTO: n addition, preliminary but rapidly increasing evidence suggests that fully vaccinated people likely pose little risk of transmission to unvaccinated people. Studies from the US, UK, and Israel found that 2 doses of Pfizer-BioNTech or Moderna vaccines were 86% to 92% effective against asymptomatic and symptomatic SARS-CoV-2 infection. More specifically, studies from Israel demonstrated that the Pfizer-BioNTech COVID-19 vaccine was 90% effective against asymptomatic infection, and vaccinated people who developed COVID-19 had a substantially lower viral load than unvaccinated people. Viral load has been identified as a key driver of transmission and this observation may indicate reduced transmissibility. Collectively, these findings demonstrate that vaccination has the potential to substantially reduce the COVID-19 disease burden in the US.

Stephenson KE et al

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19

JAMA, March 2021 ; doi:10.1001/jama.2021.3645

COMMENTO: Importance  Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.

Objective  To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.

Design, Setting, and Participants  Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.

Interventions  Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).

Main Outcomes and Measures  Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.

Results  Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.

Conclusion and Relevance  In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

Rinott E et al

Reduction in COVID-19 patients requiring mechanical ventilation following implementation of a national COVID-19 vaccination program – Israel, December 2020-February 2021

Morbidity and Mortality Weekly Report, https://www.cdc.gov/mmwr/volumes/70/wr/mm7009e3.htm

COMMENTO : Considering the vaccination rate and the expected vaccine efficacy, this study provides preliminary evidence at the population level for the reduction in risk for severe COVID-19, as manifested by need for mechanical ventilation, after vaccination with the Pfizer-BioNTech COVID-19 vaccine. These data are consistent with preliminary reports showing a reduction in COVID-19 cases and severe cases in the vaccinated population and a reduction in viral load in vaccinated persons compared with that in unvaccinated persons. Taken together, these results suggest reduced rates of severe COVID-19 following vaccination.

Public Health England

New data show vaccines reduce severe COVID-19 in older adults

https://www.gov.uk/government/news/new-data-show-vaccines-reduce-severe-covid-19-in-older-adults

COMMENTO: Today Public Health England (PHE) has submitted a pre-print of a real-world study that shows that both the Pfizer and Oxford-AstraZeneca vaccines are highly effective in reducing COVID-19 infections among older people aged 70 years and over. Since January, protection against symptomatic COVID, 4 weeks after the first dose, ranged between 57 and 61% for one dose of Pfizer and between 60 and 73% for the Oxford-AstraZeneca vaccine.

Bernal JL et al

Early effectiveness of COVID-19 vaccination with vBNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in the UK: a test negative case control study

Preprint, not peer- reviewed, March 2021; DOI: 10.1101/2021.03.01.21252652 

COMMENTO: Objectives : To estimate the real-world effectiveness of the Pfizer/BioNTech BNT162b2 vaccine and Astrazeneca ChAdOx1 vaccine against Confirmed COVID-19, hospitalisations and deaths. To estimate effectiveness on the UK variant of concern.

Design : Test negative case control design

Setting : Community COVID-19 PCR testing in England

Participants : All adults in England aged 70 years and older (over 7.5 million). All COVID-19 testing in the community among eligible individuals who reported symptoms between 8th December 2020 and 19 th February 2021 was included in the analysis.

Interventions : One and two doses of BNT162b2 vaccine. One dose of ChAdOx1 vaccine.

Main outcome measures : Symptomatic PCR confirmed SARS-CoV-2 infection, hospitalisations and deaths with COVID-19.

Results : Individuals aged >=80 years vaccinated with BNT162b2 prior to 4th January, had a higher odds of testing positive in the first 9 days after vaccination (odds ratio up to 1.48, 95%CI 1.23-1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore estimated relative to the baseline post-vaccination period. Vaccine effects were noted from 10-13 days after vaccination, reaching an effectiveness of 70% (95% CI 59-78%) from 28-34 days, then plateauing. From 14 days after the second dose a vaccine effectiveness of 89% (95%CI: 85-93%) was seen. Individuals aged >=70 years vaccinated from 4 th January had a similar underlying risk of COVID-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (95%CI 51-69%) from 28-34 days after vaccination then plateaued. With the ChAdOx1 vaccine, vaccine effects were seen from 14-20 days after vaccination reaching an effectiveness of 60% (95%CI 41-73%) from 28-34 days and further increasing to 73% (95%CI 27-90%) from day 35 onwards. On top of the protection against symptomatic disease, cases who had been vaccinated with one dose of BNT162b2 had an additional 43% (95%CI 33-52%) lower risk of emergency hospitalisation and an additional 51% (95%CI 37-62%) lower risk of death. Cases who had been vaccinated with one dose of ChAdOx1 had an additional 37% (95% CI 3-59%) lower risk of emergency hospitalisation. There was insufficient follow-up to assess the effect of ChAdOx1 on mortality due to the later rollout of this vaccine. Combined with the effect against symptomatic disease, this indicates that a single dose of either vaccine is approximately 80% effective at preventing hospitalisation and a single dose of BNT162b2 is 85% effective at preventing death with COVID-19.

Conclusion : Vaccination with either a single dose of BNT162b2 or ChAdOx1 COVID-19 vaccination was associated with a significant reduction in symptomatic SARS-CoV2 positive cases in older adults with even greater protection against severe disease. Both vaccines show similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 provides further protection against symptomatic disease but second doses of ChAdOx1 have not yet been rolled out in England. There is a clear effect of the vaccines against the UK variant of concern.

Saadat S et al

Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2

JAMA, March 2021 ; doi:10.1001/jama.2021.3341

COMMENTO: Current shortages in COVID-19 vaccine production and distribution have led some experts to suggest untested regimens. Persons who have had COVID-19 are thought to have protective immunity and memory responses. for at least 6 months; however, neither recall responses nor ideal vaccine dosing regimens have been studied in those previously infected with SARS-CoV-2. We assessed whether health care workers with previous COVID-19 infection could mount recall responses to a single dose of an mRNA-based COVID-19 vaccine.

Mainsty C et al

Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals

The Lancet, February 2021; doi.org/10.1016/S0140-6736(21)00501-8

COMMENTO: We reasoned that previous infection could be analogous to immune priming. As such, a first prime vaccine dose would effectively act as boost, so a second dose might not be needed. To test this, we undertook a nested case-control analysis of 51 participants of COVIDsortium, an ongoing longitudinal observational study of health-care workers (HCWs) in London who underwent weekly PCR and quantitative serology testing from the day of the first UK lockdown on March 23, 2020, and for 16 weeks onwards. 24 of 51 HCWs had a previous laboratory-confirmed mild or asymptomatic SARS-CoV-2 infection, as confirmed by positive detection of antibodies against the SARS-CoV-2 nucleocapsid (Elecsys Anti-SARS-CoV-2 N ECLIA, Roche Diagnostics, Burgess Hill, UK) or the receptor binding domain of the SARS-CoV-2 S1 subunit of the spike protein (anti-S; Elecsys anti-SARS-CoV-2 spike ECLIA, Roche Diagnostics), whereas 27 HCWs remained seronegative. A median of 12·5 sampling timepoints per participant permitted the identification of peak antibody titres in seropositive individuals while avoiding false negatives.

Ooliver SE et al

The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen  COVID-19 Vaccine

Morbidity and Mortality Weekly Report, https://www.cdc.gov/mmwr/volumes/70/wr/mm7009e4.htm

COMMENTO: What is already known about this topic? On February 27, 2021, the Food and Drug Administration issued an Emergency Use Authorization (EUA) for the Janssen COVID-19 vaccine.

What is added by this report? On February 28, 2021, after a transparent evidence-based review of all available data, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of the Janssen COVID-19 vaccine in persons aged ≥18 years for the prevention of COVID-19.

What are the implications for public health practice? The Janssen COVID-19 vaccine has high efficacy against COVID-19–associated hospitalization and death. Persons may receive any ACIP-recommended COVID-19 vaccine and are encouraged to receive the earliest vaccine available to them. Use of all EUA-authorized COVID-19 vaccines is critical in controlling the pandemic.

Blumenthal KG et al

Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2

NEJM, March 2021 ; DOI: 10.1056/NEJMc2102131

COMMENTO: Baden et al. report on a phase 3 clinical trial of the mRNA-1273 vaccine against SARS-CoV-2, and they provide information on immediate injection-site reactions, which were observed in 84.2% of the participants after the first dose. The trial also showed that delayed injection-site reactions (defined in that trial as those with an onset on or after day 8) occurred in 244 of the 30,420 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose. These reactions included erythema, induration, and tenderness. The reactions typically resolved over the following 4 to 5 days. However, these reactions were not further characterized, and links between reactions after the first dose and those after the second dose were not provided to inform clinical care.

Pasin L et al

Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies

European Journal of Internal Medicine, February 2021; doi.org/10.1016/j.ejim.2021.01.016

COMMENTO: INTRODUCTION: Severe COVID-19 cases have a detrimental hyper-inflammatory host response and different cytokine-blocking biologic agents were explored to improve outcomes. Anakinra blocks the activity of both IL-1alpha and IL1beta and is approved for different autoinflammatory disorders, but it is used off-label for conditions characterized by an excess of cytokine production. Several studies on anakinra in COVID-19 patients reported positive effects. We performed a meta-analysis of all published evidence on the use of anakinra in COVID19 to investigate its effect on survival and need for mechanical ventilation. METHODS: We searched for any study performed on adult patients with acute hypoxemic failure related to 2019-nCoV infection, receiving anakinra versus any comparator. Primary endpoint was mortality at the longest available follow-up. Adverse effects, need for mechanical ventilation and discharge at home with no limitations were also analysed. RESULTS: Four observational studies involving 184 patients were included. Overall mortality of patients treated with anakinra was significantly lower than mortality in the control group (95% CI 0.14-0.48, p<0.0001). Moreover, patients treated with anakinra had a significantly lower risk of need for mechanical ventilation than controls (95% CI 0.250.74, p=0.002). No difference in adverse events and discharge at home with no limitations was observed. The Trial Sequential Analysis z-cumulative line reached the monitoring boundary for benefit and the required sample size. CONCLUSIONS: Administration of anakinra in COVID-19 patients was safe and might be associated with reductions in both mortality and need for mechanical ventilation. Randomized clinical trials are warranted to confirm these findings.

FDA Briefing Document

Janssen Ad26.COV2.S Vaccine for the Prevention of COVID-19

https://www.fda.gov/media/146217/download

COMMENTO: On February 4, 2021, Janssen Biotech, Inc. (the Sponsor) submitted an Emergency Use Authorization (EUA) request to FDA for an investigational vaccine intended to prevent COVID19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine, known as Ad26.COV2.S, is a replication-incompetent adenovirus type 26 (Ad26) vectored vaccine encoding a stabilized variant of the SARS-CoV-2 S protein. The proposed use under an EUA is for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. The proposed dosing regimen is a single intramuscular injection at the dose level of 5×1010 viral particles (vp).

Dagan N et al

BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting

NEJM, February 2021 ; DOI: 10.1056/NEJMoa2101765

COMMENTO: BACKGROUND : As mass vaccination campaigns against coronavirus disease 2019 (Covid-19) commence worldwide, vaccine effectiveness needs to be assessed for a range of outcomes across diverse populations in a noncontrolled setting. In this study, data from Israel’s largest health care organization were used to evaluate the effectiveness of the BNT162b2 mRNA vaccine.

METHODS : All persons who were newly vaccinated during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics. Study outcomes included documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symptomatic Covid-19, Covid-19–related hospitalization, severe illness, and death. We estimated vaccine effectiveness for each outcome as one minus the risk ratio, using the Kaplan–Meier estimator.

RESULTS : Each study group included 596,618 persons. Estimated vaccine effectiveness for the study outcomes at days 14 through 20 after the first dose and at 7 or more days after the second dose was as follows: for documented infection, 46% (95% confidence interval [CI], 40 to 51) and 92% (95% CI, 88 to 95); for symptomatic Covid-19, 57% (95% CI, 50 to 63) and 94% (95% CI, 87 to 98); for hospitalization, 74% (95% CI, 56 to 86) and 87% (95% CI, 55 to 100); and for severe disease, 62% (95% CI, 39 to 80) and 92% (95% CI, 75 to 100), respectively. Estimated effectiveness in preventing death from Covid-19 was 72% (95% CI, 19 to 100) for days 14 through 20 after the first dose. Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions.

CONCLUSIONS : This study in a nationwide mass vaccination setting suggests that the BNT162b2 mRNA vaccine is effective for a wide range of Covid-19–related outcomes, a finding consistent with that of the randomized trial.

Katz MH et al

How to Advise Persons Who Are Antibody Positive for SARS-CoV-2 About Future Infection Risk

JAMA, February 2021 ;  doi:10.1001/jamainternmed.2021.0374

COMMENTO: Underlying the question of whether the presence of antibodies provides protection against future infections are 3 questions: are antibodies protective, how good are the available tests for accurately detecting antibodies, and how long does protection last? To address the first question, we know that most patients who recover from COVID-19 have antibodies and that reinfection (as opposed to extended symptoms or ongoing viral shedding) is rare, at least at this date. However, even if antibodies are protective, there remains a question of how accurate commercial tests are for detecting antibodies.

Hodgson SH et al                                                                                                                                         

What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2

The Lancet, October 2020; doi.org/10.1016/S1473-3099(20)30773-8

COMMENTO : The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 1 million deaths in the first 6 months of the pandemic and huge economic and social upheaval internationally. An efficacious vaccine is essential to prevent further morbidity and mortality. Although some countries might deploy COVID-19 vaccines on the strength of safety and immunogenicity data alone, the goal of vaccine development is to gain direct evidence of vaccine efficacy in protecting humans against SARS-CoV-2 infection and COVID-19 so that manufacture of efficacious vaccines can be selectively upscaled. A candidate vaccine against SARS-CoV-2 might act against infection, disease, or transmission, and a vaccine capable of reducing any of these elements could contribute to disease control. However, the most important efficacy endpoint, protection against severe disease and death, is difficult to assess in phase 3 clinical trials. In this Review, we explore the challenges in assessing the efficacy of candidate SARS-CoV-2 vaccines, discuss the caveats needed to interpret reported efficacy endpoints, and provide insight into answering the seemingly simple question, “Does this COVID-19 vaccine work?”

Wu K et al                                               

Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine — Preliminary Report

NEJM, February 2021; DOI: 10.1056/NEJMc2102179

COMMENTO: The mRNA-1273 vaccine against SARS-CoV-2 elicited high neutralizing-antibody titers in phase 1 trial participants and has been shown to be highly efficacious in preventing symptomatic Covid-19 disease and severe disease.The recent emergence of SARS-CoV-2 variants in the United Kingdom (the B.1.1.7 lineage) and in South Africa (the B.1.351 lineage) has led to concerns about increased transmission and the potential of these variants to circumvent immunity elicited by natural infection or vaccination.

Voysey M et al

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

The Lancet, February 2021; doi.org/10.1016/S0140-6736(21)00432-3

COMMENTO : Background : The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4–12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.

Methods : We present data from three single-blind randomised controlled trials—one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)—and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primaryoutcomewasvirologicallyconfirmedsymptomatic COVID-19 disease, defined as a nucleicacid amplification test (NAAT)-positive swabcombinedwith at least one qualifyingsymptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 daysafter the second dose. Secondaryefficacy analyses included cases occuring at least 22 daysafter the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation wereexploratoryoutcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent end point review committee. The primary analysis included all participants whowere SARS-CoV-2 N protein seronegative at baseline, hadhad at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005).

Findings : Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4–74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3–85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59–0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3–91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0–69·9] at <6 weeks). These observations are supported by immunogenicity data thatshowed binding antibodyresponses more thantwo-foldhigherafter an interval of 12 or more weekscomparedwith an interval of lessthan 6 weeks in thosewhowereaged 18–55 years (GMR 2·32 [2·01–2·68]).

Interpretation : The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose.

Kadire SR et al

Delayed Second Dose versus Standard Regimen for Covid-19 Vaccination

NEJM, February 2021; DOI: 10.1056/NEJMclde2101987

COMMENTO:  You chair the Governor’s task force on rollout of the Covid-19 vaccine. Given concerns about the limited availability of the two-dose mRNA vaccine, you have been asked to weigh in on the debate regarding the most effective use of the currently available doses. Should people who have already received a first dose of vaccine have their second dose delayed by a number of months until there is a greater supply, so that more people can receive a first dose? Or should those who have gotten the first dose receive the second dose according to the standard schedule, 3 to 4 weeks after the first dose, as recommended by the Food and Drug Administration (FDA)? You must consider the benefits and risks of the twoapproaches, on bothindividual and population levels, and decidewhat to recommend to the task force.

Amit S et al

Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients

The Lancet, February 2021; doi.org/10.1016/ S0140-6736(21)00448-7

COMMENTO: In December, 2020, the IsraeliGovernmentapproved the BNT162b2 COVID-19 vaccine and initiated a national immunisation campaignprioritisinghealth-care workers (HCWs), as in other countries. This campaigncoincidedwith a thirdwave of COVID-19, peaking at 10 116 daily new cases by mid-January, 2021. The ShebaMedical Centre, Israel'slargesthospitalwith 9647 HCWs, began staff vaccination on Dec 19, 2020. All HCWs, excludingthosewithprevious SARS-CoV-2 infection, wereeligible for vaccination. Clinical trial data of BNT162b2 vaccine estimated an early vaccine efficacy in preventing COVID-19 of 52·4% before dose two, and 90.5% on days 2–7 after dose two. A recentanalysis of BNT162b2 vaccine data estimated vaccine efficacy of 89–91% duringdays 15–28 after the first dose. Weexaminedearlyreductions in SARS-CoV-2 infection and COVID-19 rates in vaccinatedHCWs.

Olliaro P

What does 95% COVID-19 vaccine efficacy really mean?

The Lancet, February 2021; doi.org/10.1016/S1473-3099(21)00075-X

COMMENTO: Simple mathematics helps. If we vaccinated a population of 100 000 and protected 95% of them, that would leave 5000 individuals diseased over 3 months, which is almost the current overall COVID-19 case rate in the UK. Rather, a 95% vaccine efficacy means that instead of 1000 COVID-19 cases in a population of 100 000 without vaccine (from the placebo arm of the abovementioned trials, approximately 1% would be ill with COVID-19 and 99% would not) we would expect 50 cases (99·95% of the population is disease-free, at least for 3 months).

Mallapaty S

Can COVID vaccines stop transmission? Scientists race to find answers

Nature, February 2021; doi.org/10.1038/d41586-021-00450-z

COMMENTO: As countries roll out vaccines thatprevent COVID-19, studies are underway to determinewhether shots can also stop people fromgettinginfected and passing on the SARS-CoV-2 virus. Vaccines thatprevent transmission could help to bring the pandemicunder control if they are given to enough people.

Robertson JFR et al

Delayed second dose of the BNT162b2 vaccine: innovation or misguided conjecture?

The Lancet, February 2021; doi.org/10.1016/ S0140-6736(21)00455-4

COMMENTO: Westrongly support vaccination against COVID-19 with the Pfizer-BioNTech COVID-19 mRNA vaccine BNT162b2 when adhering to the 3-week dosing schedule that was found highly effective in the phase 3 randomised clinical trial—regarded as the gold standard. However we do not support the second dose beingdelayed to 12 weeks, as implemented by UK Chief Medical Officers. The latter followed recommendations by the Joint Committee on Vaccination and Immunisation (JCVI), based on unplanned, retrospective analysis and unwarranted assumptions.

The UK is currently the only country to have adopted a maximal 12 weeks delay. How science-led is the UK strategy? Is it innovative and world-leading, or scientifically fallacious, resulting in an unproven dosing schedule introduced without fully informed patient consent? What are the potential risks, for individuals and the population?

Pfizer.com/ News

Pfizer and BioNTech Submit COVID-19 Vaccine Stability Data at Standard Freezer Temperature to the U.S. FDA

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-covid-19-vaccine-stability-data

COMMENTO: NEW YORK and MAINZ, GERMANY, February 19, 2021 — Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) today announced the submission of new data to the U.S. Food and Drug Administration (FDA) demonstrating the stability of their COVID-19 vaccine whenstored at -25°C to -15°C (-13°F to 5°F), temperatures more commonly found in pharmaceutical freezers and refrigerators. The data have been submitted to the FDA to support a proposed update to the U.S. Emergency Use Authorization (EUA) Prescribing Information, which would allow for vaccine vials to bestored at these temperatures for a total of twoweeks as an alternative or complement to storage in an ultra-low temperature freezer.

Amit S et al

Post-Vaccination COVID-19 among Healthcare Workers, Israel

Emerging Infectious Diseases, Febraury 2021; https://doi.org/10.3201/eid2704.210016

COMMENTO : Coronavirus disease (COVID-19) symptoms can be mistaken for vaccine-related side effects during initial days after immunization. Among 4,081 vaccinated healthcare workers in Israel, 22 (0.54%) developed COVID-19 from 1–10 days (median 3.5 days) after immunization. Clinicians should not dismiss postvaccination symptoms as vaccine-related and should promptly test for COVID-19.

Xie X et al

Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera

Nature, February 2021 ; doi.org/10.1038/s41591-021-01270-4

COMMENTO: We engineered three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion + N501Y + D614G from UK; and E484K + N501Y + D614G from SA. Neutralization geometric mean titers (GMTs) of 20 BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.

University of Oxford

ChAdOx1 nCov-19 provides minimal protection against mild-moderate COVID-19 infection from B.1.351 coronavirus variant in young South African adults

https://www.ox.ac.uk/news/2021-02-07-chadox1-ncov-19-provides-minimal-protection-against-mild-moderate-covid-19-infection

COMMENTO: In an analysis, submitted as a pre-print prior to peer-review publication, a two-dose regimen of the ChAdOx1 nCoV-19 vaccine provides minimal protection against mild-moderate COVID-19 infection from the B.1.351 coronavirus variant first identified in South Africa.

Logunov DY et al

Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia

The Lancet, February 2021 ; doi.org/10.1016/S0140-6736(21)00234-8

COMMENTO: Background : A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial.

Methods : We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396).

Findings : Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6–95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine.

Interpretation : This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort.

Krammer F et al

Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine

medRXiv – not peer reviewed, February 2021; doi.org/10.1101/2021.01.29.21250653

COMMENTO: An important question is arising as COVID-19 vaccines are getting rolled out: Should individuals who already had a SARS-CoV-2 infection receive one or two shots of the currently authorized mRNA vaccines. In this short report, we show that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naïve individuals after the second dose. We also show that the reactogenicity is significantly higher in individuals who have been infected with SARS-CoV-2 in the past. Changing the policy to give these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses.

Mahase E et al

Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant

BMJ, February 2021;  doi: https://doi.org/10.1136/bmj.n296

COMMENTO: The SARS-CoV-2 vaccine produced by the US biotechnology company Novavax is 95.6% effective against the original variant of SARS-CoV-2 but also provides protection against the newer variants B.1.1.7 (85.6%) and B.1.351 (60%), preliminary data from clinical trials show.

Interim results have been released from a phase III trial carried out in the UK with more than 15 000 participants aged between 18 and 84, including 27% over the age of 65. The trial tested two doses of the vaccine administered three weeks apart and reported 62 symptomatic cases of covid-19, of which 56 were in the placebo group (saline) and six in the vaccine group. Of the 62 cases, only one was severe (in the placebo group), and 32 were with the UK variant.

A phase II trial of the Novavax vaccine is also ongoing in South Africa with 4400 volunteers, in which 29 cases have been seen in the placebo group (one severe) and 15 in the vaccine group. Preliminary sequencing data of 27 of these cases found that 93% (25) involved the South Africa variant.

Baden LR et al

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

NEJM, February 2021; DOI: 10.1056/NEJMoa2035389

COMMENTO : BACKGROUND : Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.

METHODS : This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2.

RESULTS : The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.

CONCLUSIONS : The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified.

Rappuoli R et al

Vaccinology in the post−COVID-19 era

Proceedings of the National Academy of Sciences, January 2021; doi.org/10.1073/pnas.2020368118

COMMENTO : The COVID-19 pandemicis a shocking reminder of how our world would look in the absence of vaccination. Fortunately, new technologies, the pace of understanding new and existingpathogens, and the increasedknowledge of the immune system allow us today to develop vaccines at an unprecedented speed. Some of the vaccine technologies that are fast-tracked by the urgency of COVID-19 mayalsobe the answer for otherhealthpriorities, such as antimicrobialresistance, chronic infections, and cancer, that the post-COVID-19 world willurgentlyneed to face. This perspective analyzes the way COVID-19 istransformingvaccinology and the opportunities for vaccines to have an increasingly important role in health and well-being.

Muik A et al

Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera

bioRXiv – not peer reviewed, January 2021; doi.org/10.1101/2021.01.18.426984

COMMENTO : Recently, a new SARS-CoV-2 lineage called B.1.1.7 has emerged in the United Kingdom that was reported to spread more efficiently than other strains. This variant has an unusually large number of mutations with 10 amino acid changes in the spike protein, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we investigated SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 16 participants in a previously reported trial with the mRNA-based COVID-19 vaccine BNT162b2. The immune sera hadequivalentneutralizingtiters to both variants. These data, togetherwith the combinedimmunityinvolving humoral and cellular effectorsinduced by this vaccine, makeitunlikelythat the B.1.1.7 lineagewill escape BNT162b2-mediated protection.

Wu K et al

mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants

bioRXiv– not peer reviewed, January 2021; doi.org/10.1101/2021.01.25.427948

COMMENTO: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative infection of a global pandemic that has led to more than 2 million deaths worldwide. The Moderna mRNA-1273 vaccine has demonstrated ~94% efficacy in a Phase 3 study and has been approved under Emergency Use Authorization. The emergence of SARS-CoV-2 variants with mutations in the spike protein, mostrecentlycirculatingisolatesfrom the United Kingdom (B.1.1.7) and Republic of South Africa (B.1.351), has led to lowerneutralizationfrom convalescent serum by pseudovirus neutralization (PsVN) assays and resistance to certain monoclonal antibodies. Here, usingtwo orthogonal VSV and lentivirus PsVNassaysexpressing spike variants of 20E (EU1), 20A.EU2, D614G-N439, mink cluster 5, B.1.1.7, and B.1.351 variants, weassessed the neutralizingcapacity of sera fromhumansubjects or non-human primates (NHPs) thatreceived mRNA-1273. No significant impact on neutralizationagainst the B.1.1.7 variant wasdetected in either case, howeverreducedneutralizationwasmeasuredagainst the mutations present in B.1.351. Geometricmeantiter (GMT) of human sera fromclinical trial participants in VSV PsVNassayusing D614G spike was 1/1852. VSV pseudoviruseswith spike containing K417N-E484K-N501Y-D614G and full B.1.351 mutations resultedin 2.7 and 6.4-fold GMT reduction, respectively, whencompared to the D614G VSV pseudovirus. Importantly, the VSV PsVN GMT of thesehuman sera to the full B.1.351 spike variant wasstill 1/290, with all evaluated sera able to fullyneutralize. Similarly, sera fromNHPsimmunizedwith 30 or 100μg of mRNA-1273 had VSV PsVNGMTs of ~ 1/323 or 1/404, respectively, against the full B.1.351 spike variant with a ~ 5 to 10-fold reductioncompared to D614G. Individual mutations that are characteristic of the B.1.1.7 and B.1.351 variants had a similar impact on neutralizationwhentested in VSV or in lentivirus PsVNassays. Despite the observeddecreases, the GMT of VSV PsVNtiters in humanvaccinee sera against the B.1.351 variant remained at ~1/300. Takentogetherthese data demonstratereduced but stillsignificantneutralizationagainst the full B.1.351 variant following mRNA-1273 vaccination.

Mahase E

Covid-19: What new variants are emerging and how are they being investigated?

BMJ, January 2021; doi.org/10.1136/bmj.n158

COMMENTO: The new, more transmissible variant of SARS-CoV-2 found in England is just one of many variations of the virus being detected around the world. Elisabeth Mahase looks at whatwe know so far.

Connors M et al

SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn

Annals of Internal Medicine, 19 January 2021; doi.org/10.7326/M21-0111

COMMENTO : Over the next weeks and months, physicians will face questions regarding the science, safety, and efficacy of the first wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines to be authorized and distributed. In most cases these vaccine platforms will be new technologies that have not previously been administered other than through clinical trials. Although the initial data on efficacy and safety are extraordinarily encouraging, many questions remain regarding who should receive these vaccines and the immediate, intermediate, and long-term impact of the vaccination program on the pandemic.

Klass P et al

Vaccinating Children against Covid-19 — The Lessons of Measles

NEJM, 20 January 2021; DOI: 10.1056/NEJMp2034765

COMMNETO : Imagine a highly contagious virus circulating in the community. Many infected children have fever and some general misery but recover without incident. Rarely, devastating complications occur, leading to hospitalization, severe illness, and occasional deaths. Susceptible adults fare worse, with higher rates of poor outcomes. Would you want your child vaccinated against this disease?

You guessed we were talking about measles, right?

Greaney AJ et al

Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

BioRXiv, 4 January 2021; doi.org/10.1101/2020.12.31.425021

COMMENTO: The evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.

Sadoff J et al

Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine

NEJM, 13 January 2021 ; doi: 10.1056/NEJMoa2034201

COMMENTO : BACKGROUND : Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein.

METHODS : In this multicenter, placebo-controlled, phase 1–2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule.

RESULTS : After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 224 to 354) and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488), regardless of vaccine dose or age group. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 14, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3.

CONCLUSIONS : The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate.

Pollard A et al

How the Oxford-AstraZeneca covid-19 vaccine was made

BMJ, 12 January 2021 ; doi.org/10.1136/bmj.n86

COMMENTO: Andrew Pollard has been leading the Oxford vaccine clinical trials in the UK, Brazil, and South Africa. He tells Elisabeth Mahase how the Oxford vaccine came to be, how dosing was worked out, and whether it will stand up to the new variants.

Topol EJ et al

Messenger RNA vaccines against SARS-CoV-2

Cell, 13 January 2021 ; doi.org/10.1016/j.cell.2020.12.039

COMMENTO : The first two vaccines proven to be effective for inhibiting COVID-19 illness were both mRNA, achieving 95% efficacy (and safety) among 74,000 participants (half receiving placebo) after intramuscular delivery of two shots, 3–4 weeks apart.

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