Q. Wang et al.

Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, and BA.5

Nature, July 2022; doi.org/10.1038/s41586-022-05053-w

Abstract

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively1,2. These novel subvariants carrying additional mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

V.R. Emani et al.

Increasing SARS-CoV2 cases, hospitalizations and deaths among the vaccinated elderly populations during the Omicron (B.1.1.529) variant surge in UK

medRxiv, July 2022; doi.org/10.1101/2022.06.28.22276926

Abstract

BACKGROUND There were increased SARS-CoV2 hospitalizations and deaths noted during Omicron (B.1.1.529) variant surge in UK despite decreased cases, and the reasons are unclear.

METHODS In this retrospective observational study, we analyzed reported SARS-CoV2 cases, hospitalizations and deaths during the COVID-19 pandemic in the UK. We also analyzed variables (ethnic, deprivation score vaccination disparities and pre-existing conditions) that can affect the outcomes. The vaccine effectiveness among those ≥18 years of age (August 16, 2021 to March 27, 2022) was analyzed.

RESULTS Of the total cases (n= 22,072,550), hospitalizations (n=848,911) and deaths (n=175,070) due to COVID-19 in the UK; 51.3% of cases (n=11,315,793), 28.8% of hospitalizations (n=244,708), and 16.4% of deaths (n=28,659) occurred during the Omicron variant surge. When comparing the period of February 28 - May 1, 2022 with the prior 12-weeks, we observed a significant increase in the case fatality rate (0.19% vs 0.41%; RR 2.11 [2.06-2.16], p<0.001) and the risk of hospitalizations (1.58% vs 3.72%; RR 2.36[2.34-2.38]; p<0.001). During the same period, we also observed a significant increase in the proportion of cases (23.7% vs 40.3%; RR1.70 [1.70-1.71]; p<0.001) among ≥50 years of age and hospitalizations (39.3% vs 50.3%;RR1.28 [1.27-1.30]; p<0.001) and deaths (67.89% vs 80.07%;RR1.18 [1.16-1.20]; p<0.001) among ≥75 years of age. The vaccine effectiveness (VE) for the third dose was in negative since December 20, 2021, with a significantly increased proportion of SARS-CoV2 cases hospitalizations and deaths among the vaccinated; and a decreased proportion of cases, hospitalizations, and deaths among the unvaccinated. The pre-existing conditions were present in 95.6% of all COVID-19 deaths and we also observed various ethnic, deprivation score and vaccination rate disparities that can adversely affect hospitalization and deaths among the compared groups based on the vaccination status.

CONCLUSIONS There is no discernable optimal vaccine effectiveness among ≥18 years of age, vaccinated third dose population since December 20, 2021 during the beginning of the Omicron variant surge. Pre-existing conditions, ethnicity, deprivation score, and vaccination rate disparities data need to be adjusted by the development of validated models for evaluating VE for hospitalizations and deaths. The increased proportion of cases with significantly increased risk of hospitalizations and deaths among the elderly population during the Omicron variant surge underscores the need to prevent infections in the elderly irrespective of vaccination status with uniform screening protocols and protective measures.

S. Malhotra et al.

COVID-19 infection, and reinfection, and vaccine effectiveness against symptomatic infection among health care workers in the setting of omicron variant transmission in New Delhi, India

The Lancet Regional Health - Southeast Asia, June 2022; doi.org/10.1016/j.lansea.2022.100023

Abstract

Background

Surge of SARS CoV-2 infections ascribed to omicron variant began in December 2021 in New Delhi. We determined the infection and reinfection density in a cohort of health care workers (HCWs) along with vaccine effectiveness (VE) against symptomatic infection within omicron transmission period (considered from December 01, 2021 to February 25, 2022.

Methods

This is an observational study from the All India Institute of Medical Sciences, New Delhi. Data were collected telephonically. Person-time at risk was counted from November 30, 2021 till date of infection/ reinfection, or date of interview. Comparison of clinical features and severity was done with previous pandemic periods. VE was estimated using test-negative case-control design [matched pairs (for age and sex)]. Vaccination status was compared and adjusted odds ratios (OR) were computed by conditional logistic regression. VE was estimated as (1-adjusted OR)X100-.

Findings

11474 HCWs participated in this study. The mean age was 36⋅2 (±10⋅7) years. Complete vaccination with two doses were reported by 9522 (83%) HCWs [8394 (88%) Covaxin and 1072 Covishield (11%)]. The incidence density of all infections and reinfection during the omicron transmission period was 34⋅8 [95% Confidence Interval (CI): 33⋅5–36⋅2] and 45⋅6 [95% CI: 42⋅9–48⋅5] per 10000 person days respectively. The infection was milder as compared to previous periods. VE was 52⋅5% (95% CI: 3⋅9–76⋅5, p = 0⋅036) for those who were tested within 14–60 days of receiving second dose and beyond this period (61–180 days), modest effect was observed.

Interpretation

Almost one-fifth of HCWs were infected with SARS CoV-2 during omicron transmission period, with predominant mild spectrum of COVID-19 disease. Waning effects of vaccine protection were noted with increase in time intervals since vaccination.

M.T. Tsakok et al.

Chest CT and Hospital Outcomes in Patients with Omicron Compared with Delta Variant

SARS-CoV-2 Infection

Radiology, June 2022 ; doi : 10.1148/radiol.220533

Abstract

The SARS-Cov-2 Omicron variant demonstrates rapid spread but with reduced disease severity. Studies evaluating the lung imaging findings of Omicron infection versus non-Omicron variants remain lacking.

Purpose To compare Omicron and Delta variants of SARS-CoV-2 by their chest CT radiological pattern, biochemical parameters, clinical severity and hospital outcomes after adjusting for vaccination status.

Materials and Methods Retrospective study of hospitalized adult patients rt-PCR positive for SARS-CoV-2 with CT pulmonary angiography performed within 7 days of admission between December 1, 2021 and January 14, 2022. Blinded radiological analysis with multiple readers including RSNA CT classification, chest CT severity score (CT-SS, range 0 least severe to 25 most severe) and CT imaging features including bronchial wall thickening. Results 106 patients (Delta n=66, Omicron n=40) were evaluated (mean age, 58 years ± 18, 58 men). In the Omicron group, 37% (15/40) of CT pulmonary angiograms were categorized as normal compared with 15% (10/66) in the Delta group (p=.016). Using a generalized linear model to control for confounding variables, including vaccination status, Omicron variant infection was associated with a CT-SS that was lower by 7.2 points compared to infection with Delta variant.

Updated March 2022

COVID- 19. Self-Testing At Home or Anywhere

Centers for Disease Control and Prevention

https://www.cdc.gov/coronavirus/2019-ncov/testing/self-testing.html#:~:text=Positive%20results%20from%20self%2Dtests,symptoms%20associated%20with%20COVID%2D19

J. Skarbinski et al.

Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: A retrospective cohort study

The Lancet Regional Health - Americas, June 2022; doi.org/10.1016/j.lana.2022.100297

Abstract

Background

The incidence of and risk factors for severe clinical outcomes with the Omicron (B.1.1.529) SARS-CoV-2 variant have not been well-defined.

Methods

We conducted a retrospective cohort study to assess risks of severe clinical outcomes within 21 days after SARS-CoV-2 diagnosis in a large, diverse, integrated health system.

Findings

Among 118,078 persons with incident SARS-CoV-2 infection, 48,101 (41%) were during the Omicron period and 69,977 (59%) during the Delta (B.1.617.2) period. Cumulative incidence of any hospitalization (2.4% versus 7.8%; adjusted hazard ratio [aHR] 0.55; 95% confidence interval [CI] (0.51-0.59), with low-flow oxygen support (1.6% versus 6.4%; aHR 0.46; CI 0.43-0.50), with high-flow oxygen support (0.6% versus 2.8%; aHR 0.47; CI 0.41-0.54), with invasive mechanical ventilation (0.1% versus 0.7%; aHR 0.43; CI 0.33-0.56), and death (0.2% versus 0.7%; aHR 0.54; CI 0.42-0.70) were lower in the Omicron than the Delta period. The risk of hospitalization was higher among unvaccinated persons (aHR 8.34; CI 7.25-9.60) and those who completed a primary COVID-19 vaccination series (aHR 1.72; CI 1.49-1.97) compared with those who completed a primary vaccination series and an additional dose. The strongest risk factors for all severe clinical outcomes were older age, higher body mass index and select comorbidities.

Interpretation

Persons with SARS-CoV-2 infection were significantly less likely to develop severe clinical outcomes during the Omicron period compared with the Delta period. COVID-19 primary vaccination and additional doses were associated with reduced risk of severe clinical outcomes among those with SARS-CoV-2 infection.

L. Yao et al.

Omicron subvariants escape antibodies elicited by vaccination and BA.2.2 infection

Lancet, June 2022; doi.org/10.1016/ S1473-3099(22)00410-8

Abstract

The BA.1, BA.2, and BA.3 omicron subvariants of SARS-CoV-2 showed similar but substantial resistance to vaccine-induced and infectioninduced serum neutralising activity. The new BA.2.12.1, BA.2.13, BA.4 and BA.5 omicron subvariants containing Leu452 substitutions show more infectious potential than BA.2. We examined neutralising activity against the BA.1, BA.2, BA.2.11, BA.2.12.1, BA.2.13, BA.4, and BA.5 omicron subvariants in serum from people who received BBIBP-CorV (Sinopharm) primary immunisation, people who received BBIBP-CorV or ZF2001 (Anhui Zhifei Longcom) boosters, and people with omicron breakthrough infections.

Callaway

What Omicron’s BA.4 and BA.5 variants mean for the pandemic

Nature, June 2022; https://www.nature.com/articles/d41586-022-01730-y

Abstract

Like a Hollywood franchise that churns out sequel after mind-numbing sequel, Omicron is back.

Mere weeks after the variant’s BA.2 lineage caused surges globally, two more Omicron spin-offs are on the rise worldwide. First spotted by scientists in South Africa in April and linked to a subsequent rise in cases there, BA.4 and BA.5 are the newest members of Omicron’s growing family of coronavirus subvariants. They have been detected in dozens of countries worldwide.

F. Caccuri et al.

Competition for dominance within replicating quasispecies during prolonged SARS-CoV-2 Infection in an immunocompromised host

Virus Evolution, May 2022 ; doi.org/10.1093/ve/veac042

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) emerge for their capability to better adapt to the human host aimed and enhance human-to-human transmission. Mutations in spike largely contributed to adaptation. Viral persistence is a prerequisite for intra-host virus evolution, and this likely occurred in immunocompromised patients who allow intra-host long-term viral replication. The underlying mechanism leading to the emergence of variants during viral persistence in the immunocompromised host is still unknown. Here, we show the existence of an ensemble of minor mutants in the early biological samples obtained from an immunocompromised patient and their dynamic interplay with the master mutant during a persistent and productive long-term infection. In particular, after 222 days of active viral replication, the original master mutant, named MB61 , was replaced by a minor quasispecies (MB61) expressing two critical mutations in spike, namely Q493K and N501T. Isolation of the two viruses allowed us to show that MB61 entry into target cells occurred mainly by the fusion at the plasma membrane (PM), whereas endocytosis characterized the entry mechanism used by MB61 . Interestingly, coinfection of two human cell lines of different origin with the SARS-CoV-2 isolates highlighted the early and dramatic predominance of MB61 over MB61 replication. This fnding may be explained by a faster replicative activity of MB61 as compared to MB61 as well as by the capability of MB61 to induce peculiar viral RNAsensing mechanisms leading to an increased production of interferons (IFNs) and, in particular, of IFN-induced transmembrane protein 1 (IFITM1) and IFITM2. Indeed, it has been recently shown that IFITM2 is able to restrict SARS-CoV-2 entry occurring by endocytosis. In this regard, MB61 may escape the antiviral activity of IFITMs by using the PM fusion pathway for entry into the target cell, whereas MB61 cannot escape this host antiviral response during MB61 coinfection, since it has endocytosis as the main pathway of entry. Altogether, our data support the evidence of quasispecies fghting for host dominance by taking beneft from the cell machinery to restrict the productive infection of competitors in the viral ensemble. This fnding may explain, at least in part, the extraordinary rapid worldwide turnover of VOCs that use the PM fusion pathway to enter into target cells over the original pandemic strain.

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 10.

Abstract

The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but 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 HCW 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. Komplas et al.

Association of Omicron vs Wild-type SARS-CoV-2 Variants With Hospital-Onset SARS-CoV-2 Infections in a US Regional Hospital System

JAMA, June  2022; doi:10.1001/jama.2022.9609

Abstract

The Omicron surge was associated with a significant increase in hospital-onset SARS-CoV-2 infections compared with the prior winter surge. Possible reasons include the Omicron surge’s very high community and health care worker incidence rates, as well as Omicron’s greater contagiousness. Sources of nosocomial infections include health care workers, visitors, and other patients.

Study limitations include possible underdetection of hospital-acquired cases owing to lack of serial testing, failure to test patients with asymptomatic or paucisymptomatic infections, or disease onset after discharge. Time since admission is a limited proxy for nosocomial infection. Some hospital-acquired cases may be misidentified as community acquired because the incubation period for SARS-CoV-2 can be fewer than 5 days, particularly for Omicron. Conversely, some community-acquired cases might only have been identified more than 5 days after admission because of a long incubation period or delayed testing. Findings may not be generalizable to hospitals with fewer baseline infection control measures (eg, vaccination requirements, testing all patients on admission and 72 hours after admission).

D.J. Pinato et al.

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study

Lancet, June 2022; doi.org/10.1016/ S1470-2045(22)00273-X

Abstract

Background The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe.

Methods In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing.

Findings As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57–77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19–0·61) and 28 days (0·34 [0·16–0·79]), complications due to COVID-19 (0·26 [0·17–0·46]), and hospitalisation due to COVID-19 (0·17 [0·09–0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15–0·34]) and oxygen therapy (0·24 [0·14–0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase.

Interpretation Despite time-dependent improvements in outcomes reported in the omicron phase. compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19.

D. Yamasoba et al.

Neutralisation sensitivity of SARSCoV-2 omicron subvariants to therapeutic monoclonal antibodiesLancertInfetc. Dis., June 2022; doi.org/10.1016/ S1473-3099(22)00365-6

Abstract

During the current pandemic, SARSCoV-2 has considerably diversified. The omicron variant (B.1.1.529) was identified at the end of November, 2021, and rapidly spread worldwide. As of May, 2022, the omicron BA.2 subvariant is the most dominant variant in the world. Other omicron subvariants have since emerged and some of them have begun to outcompete BA.2 in multiple countries. For instance, omicron BA.2.11 subvariant is spreading in France, and the BA.2.12.1 and BA.4/5 subvariants are becoming dominant in the USA and South Africa, respectively. Newly emerging SARS-CoV-2 variants need to be carefully monitored for a potential increase in transmission rate, pathogenicity, and resistance to immune responses.

E. Andreano et al.

Anatomy of Omicron BA.1 and BA.2 neutralizing antibodies in COVID-19 mRNA vaccinees

Nature Communications, June 2022; doi.org/10.1038/s41467-022-31115-8

Abstract

SARS-CoV-2 vaccines, administered to billions of people worldwide, mitigate the effects of the COVID-19 pandemic, however little is known about the molecular basis of antibody cross-protection to emerging variants, such as Omicron BA.1, its sublineage BA.2, and other coronaviruses. To answer this question, 276 neutralizing monoclonal antibodies (nAbs), previously isolated from seronegative and seropositive donors vaccinated with BNT162b2 mRNA vaccine, were tested for neutralization against the Omicron BA.1 and BA.2 variants, and SARS-CoV-1 virus. Only 14.2, 19.9 and 4.0% of tested antibodies neutralize BA.1, BA.2, and SARS-CoV-1 respectively. These nAbs recognize mainly the SARS-CoV-2 receptor binding domain (RBD) and target Class 3 and Class 4 epitope regions on the SARS-CoV-2 spike protein. Interestingly, around 50% of BA.2 nAbs did not neutralize BA.1 and among these, several targeted the NTD. Cross-protective antibodies derive from a variety of germlines, the most frequents of which were the IGHV1-58;IGHJ3-1, IGHV2-5;IGHJ4-1 and IGHV1-69;IGHV4-1. Only 15.6, 20.3 and 7.8% of predominant gene-derived nAbs elicited against the original Wuhan virus cross-neutralize Omicron BA.1, BA.2 and SARS-CoV-1 respectively. Our data provide evidence, at molecular level, of the presence of cross-neutralizing antibodies induced by vaccination and map conserved epitopes on the S protein that can inform vaccine design.

European Centre for Disease Prevention and Control (ECDC)

Implications of the emergence and spread of the SARS-CoV-2 variants of concern BA.4 and BA.5 for the EU/EEA

https://www.ecdc.europa.eu/en/news-events/implications-emergence-spread-sars-cov-2-variants-concern-ba4-and-ba5

13 June 2022

P. Qu et al.

Neutralization of the SARS-CoV-2 Omicron BA.4/5 and BA.2.12.1 Subvariants

The New England J of Medicine, June 2022; doi: 10.1056/NEJMc2206725

Abstract

Emerging subvariants of the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have reignited concern about further immune escape. Specifically, BA.2.12.1, which is on the rise in the United States, has two more mutations (L452Q and S704L) than BA.2. In addition, BA.4 and BA.5 (hereafter, BA.4/5), which bear identical spike proteins, have become the dominant strains in South Africa.Here, we examine neutralizing-antibody titers in serum samples obtained from vaccinated persons who had received a single booster dose of the same vaccine used in the two-dose series and who had been previously infected with SARS-CoV-2.

Callaway E.

How months-long COVID infections could seed dangerous new variants

Nature, June 2022; doi.org/10.1038/d41586-022-01613-2

Abstract

Virologist Sissy Sonnleitner tracks nearly every COVID-19 case in Austria’s rugged eastern Tyrol region. So, when one woman there kept testing positive for months on end, Sonnleitner was determined to work out what was going on.

Before becoming infected with SARS-CoV-2 in late 2020, the woman, who was in her 60s, had been taking immune-suppressing drugs to treat a lymphoma relapse. The COVID-19 infection lingered for more than seven months, causing relatively mild symptoms, including fatigue and a cough.

I. Kimura et al.

Virological characteristics of the novel 1 SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5

biorXiv, May 2022; doi.org/10.1101/2022.05.26.493539

Abstract

After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.

Obermeyer F. et al.

Analysis of 6.4 million SARS-CoV-2 genomes identifies mutations associated with fitness

Science, May 2022; doi:10.1126/science.abm1208

Abstract

Repeated emergence of SARS-CoV-2 variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR0, a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR0 to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many non-spike mutations within the nucleocapsid and nonstructural proteins. PyR0 forecasts growth of new lineages from their mutational profile, ranks the fitness of lineages as new sequences become available, and prioritizes mutations of biological and public health concern for functional characterization.

K. Khan et al.

Omicron sub-lineages BA.4/BA.5 escape BA.1 infection elicited neutralizing immunity

medRxiv, May 2022; doi.org/10.1101/2022.04.29.22274477

Abstract

The SARS-CoV-2 Omicron (B.1.1.529) variant first emerged as the BA.1 sub-lineage, with extensive escape from neutralizing immunity elicited by previous infection with other variants, vaccines, or combinations of both1,2. Two new sub-lineages, BA.4 and BA.5, are now emerging in South Africa with changes relative to BA.1, including L452R and F486V mutations in the spike receptor binding domain. We isolated live BA.4 and BA.5 viruses and tested them against neutralizing immunity elicited to BA.1 infection in participants who were Omicron/BA.1 infected but unvaccinated (n=24) and participants vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV.2S with breakthrough Omicron/BA.1 infection (n=15). In unvaccinated individuals, FRNT50, the inverse of the dilution for 50% neutralization, declined from 275 for BA.1 to 36 for BA.4 and 37 for BA.5, a 7.6 and 7.5-fold drop, respectively. In vaccinated BA.1 breakthroughs, FRNT50 declined from 507 for BA.1 to 158 for BA.4 (3.2-fold) and 198 for BA.5 (2.6-fold). Absolute BA.4 and BA.5 neutralization levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants. The observed escape of BA.4 and BA.5 from BA.1 elicited immunity is more moderate than of BA.1 against previous immunity1,3. However, the low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection4.This may indicate that, based on neutralization escape, BA.4 and BA.5 have potential to result in a new infection wave.ct

L. Subissi et al.

An early warning system for emerging SARS-CoV-2 variants

Nature Medicine, May 2022; doi.org/10.1038/s41591-022-01836-w

Abstract

Global sequencing and surveillance capacity for SARS-CoV-2 must be strengthened and combined with multidisciplinary studies of infectivity, virulence and immune escape, in order to track the unpredictable evolution of the ongoing COVID-19 pandemic.

In June 2020, the World Health Organization (WHO) SARS-CoV-2 evolution working group was established to track SARS-CoV-2 variants and their specific genetic changes and to monitor viral characteristics and their impact on medical and non-medical countermeasures, including vaccines against COVID-19. In November 2021, this working group transitioned to a formal WHO Technical Advisory Group on Virus Evolution (TAG-VE), with the aim of developing and implementing a global risk-monitoring framework for SARS-CoV-2 variants, based on a multidisciplinary approach that includes in silico, virological, clinical and epidemiological data.

Q. Wang et al.  

SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion

bioRxiv, May 2022 ;doi.org/10.1101/2022.05.26.493517

Abstract

The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

P. Elliott et al.

Twin peaks: The Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England

Science, May 2022; doi: 10.1126/science.abq4411

Abstract

Rapid transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to record-breaking incidence rates around the world. The REal-time Assessment of Community Transmission-1 (REACT-1) study has tracked SARS-CoV-2 infection in England using reverse transcription polymerase chain reaction (RT-PCR) results from self-administered throat and nose swabs from randomly selected participants aged 5+ years, approximately monthly from May 2020 to March 2022. Weighted prevalence in March 2022 was the highest recorded in REACT-1 at6.37% (N=109,181) with Omicron BA.2 largely replacing BA.1. Prevalence was increasing overall with the greatest increase in those aged 65-74 and 75+ years. This was associated with increased hospitalizations and deaths but at much lower levels than in previous waves against a backdrop of high levels of vaccination.

K. Khan et al.

Omicron infection enhances Delta antibody immunity in vaccinated persons

Nature, May 2022 ;doi.org/10.1038/s41586-022-04830-x

Abstract

The extent to which Omicron infection1-9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. We measured SARS-CoV-2 variant neutralization capacity in 39 Omicron sub-lineage BA.1 infected individuals in South Africa starting at a median of 6 (IQR 3-9) days post-symptoms onset and continuing until a last follow-up sample a median of 23 (IQR 19-27) days post-symptoms to allow BA.1 elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer-BNT162b2 or J&J-Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean titer (GMT) FRNT50 of 42 at enrollment to 575 at the last follow-up time-point (13.6-fold) in vaccinated and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1091 (5.7-fold) in vaccinated and 28 to 91 (3.0-fold) in unvaccinated participants. At the last time-point, unvaccinated BA.1 infected individuals had 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization, and 4.8-fold lower Omicron sub-lineage BA.2 neutralization relative to vaccinated, with low absolute levels of neutralization for the non-BA.1 viruses. These results indicate that vaccination combined with Omicron/BA.1 infection hybrid immunity should be protective against Delta and other variants. In contrast, infection with Omicron/BA.1 alone offers limited cross-protection despite moderate enhancement.

M.R. Chang et al.

Analysis of a SARS-CoV-2 convalescent cohort identified a common strategy for escape of vaccineinduced anti-RBD antibodies by Beta and Omicron variants

eBioMedicine, May 2022; doi.org/10.1016/j. ebiom.2022.104025

Abstract

Background Evolutionary pressure has led to the emergence of SARS-CoV-2 variants, with the most recent Omicron variant containing an unparalleled 30 mutations in the spike protein. Many of these mutations are expected to increase immune evasion, thus making breakthrough cases and re-infection more common.

Methods From June 2020 to December 2021 serial blood samples (initial post recovery, 6 months, 12 months) were collected from a COVID-19 convalescent cohort in Boston, MA. Plasma was isolated for use in Mesoscale Discovery based antibody binding assays. Unvaccinated donors or those vaccinated prior to the primary blood draw were excluded from this analysis, as were those who did not have at least two blood draws. Wilcoxon signed rank tests were used to compare pre- and post-vaccination titers and antibody response against different variants, while McNemar tests were used to compare the proportions of achieving  4 fold increases against different variants.

Findings Forty-eight COVID convalescent donors with post-infection vaccination (hybrid immunity) were studied to evaluate the levels of cross-reactive antibodies pre- and post- vaccination against various SARS-CoV-2 Spike and receptor binding domain (RBD) proteins. Vaccination with BNT162b2, mRNA-1273 or Ad26.COV2.S led to a 6¢3 to 7¢8 fold increase in anti-Spike antibody titers and a 7¢0 to 7¢4 fold increase in anti-WT, Alpha and Delta RBD antbody. However, a lower response was observed for Beta and Omicron RBDs with only 7/48 (15%) and 15/48 (31%) donors having a 4 fold increase in post-vaccination titers against Beta and Omicron RBDs. Structural analysis of the Beta and Omicron RBDs reveal a shared immune escape strategy involving residues K417-E484-N501 that is exploited by these variants of concern.

Interpretation Through mutations of the K417-E484-N501 triad, SARS-CoV-2 has evolved to evade neutralization by the class I/II anti-RBD antibody fraction of hybrid immunity plasma as the polyclonal antibody response post-vaccination shows limitations in the ability to solve the structural requirements to bind the mutant RBDs.

F. Zuo et al.

Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant.

Nature Communications, May 2022; doi.org/10.1038/s41467-022-30340-5

Abstract

The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.

Gray et al.

Effectiveness of Ad26.COV2.S and BNT162b2 Vaccines against Omicron Variant in South Africa

The New England Journal of Medicine, May 2022; doi10.1056/NEJMc2202061

Abstract

The B.1.1.529 (omicron) strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become dominant among the variants of concern in the coronavirus disease 2019 (Covid-19) pandemic in all regions of the world. The omicron variant now accounts for 95.4% of genetic sequences of SARS-CoV-2 in Africa, 96.0% in North America, and 87.6% in South America. This variant has been shown to escape antibody neutralization by both the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) and the Ad26.COV2.S vaccine (Johnson & Johnson–Janssen),1,2 which are the only two Covid-19 vaccines that have been administered in South Africa. We established the early effectiveness of the two-dose BNT162b2 vaccine regimen during the omicron-driven fourth wave in South Africa.2 The national vaccine program in South Africa has distributed 26,262,060 doses of the BNT162b2 vaccine and 8,477,267 doses of the Ad26.COV2.S vaccine. As of May 1, 44.8% of adults in South Africa had been fully vaccinated with two doses of the BNT162b2 vaccine or a single dose of the Ad26.COV2.S vaccine. Assessing vaccine effectivenessiscritical for national vaccine programs.

Callaway

Are COVID surges becoming more predictable? New Omicron variants offer a hint

Nature News, May 2022; doi.org/10.1038/d41586-022-01240-x

Abstract

Omicron relatives called BA.4 and BA.5 are behind a fresh wave of COVID-19 in South Africa, and could be signs of a more predictable future for SARS-CoV-2.

Here we go again. Nearly six months after researchers in South Africa identified the Omicron coronavirus variant, two offshoots of the game-changing lineage are once again driving a surge in COVID-19 cases there.

Cao et al.

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

bioRxriv, May 2022; doi.org/10.1101/2022.04.30.489997

Abstract

The recently emerged SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.21. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we show that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 displays the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization evasion against the plasma of 3-dose vaccinees and, most strikingly, of vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure induced by Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2 due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab4) and COV2-2130 (Cilgavimab5) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirusNAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

The displacement of the SARS-CoV-2 variant Delta with Omicron: An investigation of hospital admissions and upper respiratory viral loads

The Lancet, April 2022; doi.org/10.1016/j. ebiom.2022.104008

Abstract

Background

The increase in SARS-CoV-2 infections in December 2021 was driven primarily by the Omicron variant, which largely displaced the Delta over a three-week span. Outcomes from infection with Omicron remain uncertain. We evaluated whether clinical outcomes and viral loads differed between Delta and Omicron infections during the period when both variants were co-circulating.

Methods

In this retrospective observational cohort study, remnant clinical specimens, positive for SARS-CoV-2 after standard of care testing at the Johns Hopkins Microbiology Laboratory, between the last week of November and the end of December 2021, were used for whole viral genome sequencing. Cycle threshold values (Ct) for viral RNA, the presence of infectious virus, and levels of respiratory IgG were measured, and clinical outcomes were obtained. Differences in each measure were compared between variants stratified by vaccination status.

Findings

The Omicron variant displaced Delta during the study period and constituted 95% of the circulating lineages by the end of December 2021. Patients with Omicron infections (N = 1,119) were more likely to be vaccinated compared to patients with Delta (N = 908), but were less likely to be admitted (0.33 CI 0.21–0.52), require ICU level care (0.38 CI 0.17–0.87), or succumb to infection (0.26 CI 0.06–1.02) regardless of vaccination status. There was no statistically significant difference in Ct values based on the lineage regardless of the vaccination status. Recovery of infectious virus in cell culture was reduced in boosted patients compared to fully vaccinated without a booster and unvaccinated when infected with the Delta lineage. However, in patients with Omicron infections, recovery of infectious virus was not affected by vaccination.

Interpretation

Compared to Delta, Omicron was more likely to cause breakthrough infections of vaccinated individuals, yet admissions were less frequent. Admitted patients might develop severe disease comparable to Delta. Efforts for reducing Omicron transmission are required as, though the admission risk might be lower, the increased numbers of infections cause large numbers of hospitalizations.

J. P. Evans et al.

Neutralization of SARS-CoV-2 Omicron Sub-lineages BA.1, BA.1.1, and BA.2

Cell Host and Microbe, April; 2022; doi.org/10.1016/j.chom.2022.04.014

Abstract

Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants, and provide insight into the immunity from natural infection against Omicron sub-lineages.

A. Lai et al.

Phylogeography and genomic epidemiology of SARSCoV2 in Italy and Europe with newly characterized Italian genomes between FebruaryJune 2020.

Nature, Scientific reports, April 2022; doi.org/10.1038/s41598-022-09738-0

Abstract

The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including < 80 Italian isolates, while most of the Italian strains were intermixed in the whole tree. Pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 (20B) most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 (20D) developed most probably in other European countries entering Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, within the limitations of phylogeographical reconstruction, the estimated ancestral scenario suggests an important role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

C. Menni et al.

Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study

The Lancet, April 2022; doi.org/10.1016/S0140-6736(22)00327-0

Abstract      

Background The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.

Methods In this prospective longitudinal observational study, we collected data from participants who were selfreporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16–99 years, based in the UK, with a body-mass index between 15 and 55 kg/m², had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence.

Findings: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16–0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43–1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57–0·98, p=0·03).

Interpretation: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work–health policies and pubblic health advice.

Antigenic evolution will lead to new SARS-CoV-2 variants with unpredictable severity

Nat Rev Microbiol., 2022 ; doi.org/10.1038/s41579-022-00722-z

Abstract

The comparatively milder infections with the Omicron variant and higher levels of population immunity have raised hopes for a weakening of the pandemic. We argue that the lower severity of Omicron is a coincidence and that ongoing rapid antigenic evolution is likely to produce new variants that may escape immunity and be more severe.

A. Rossler et al.

Neutralization Profile after Recovery from SARS-CoV-2 Omicron Infection

New England J of Medicine, March 2022; doi:10.1056/NEJMc2201607

Abstract

Serum samples obtained from unvaccinated persons after infection with the B.1.1.7 (alpha), B.1.351 (beta), or B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the B.1.1.529 (omicron) variant only occasionally.1 Similarly, levels of neutralizing antibodies against the omicron variant are low and only short-lived after one or two doses of a coronavirus disease 2019 (Covid-19) vaccine but are enhanced in persons who have been vaccinated and have also been infected (i.e., those with hybrid immunity) or in vaccinated persons who have received a booster dose.2,3

Little is known about neutralization profiles in persons who have recovered from infection with the omicron variant.4,5 Studies have focused primarily on either vaccinated persons who have had breakthrough infections with the omicron variant or unvaccinated persons whose history of previous infection is unknown. Here, we report the results of an analysis of neutralization profiles against six SARS-CoV-2 variants in serum samples obtained from persons who had recovered from infection with the omicron BA.1 variant, with or without preexisting SARS-CoV-2 immunity.

Sheward DJ et al.

Neutralisation sensitivity of the SARS-CoV-2 omicron (B.1.1.529) variant: a cross-sectional study

Lancet Infect Dis.,

https://reader.elsevier.com/reader/sd/pii/S1473309922001293?token=045A8DDD1975390F4756B9C37F35AD82438517884A3036DEB82E5326624F9E43A737A2C3C2FA357A7275844DA39C96A0&originRegion=eu-west-1&originCreation=20220325221634

CONTENUTO E COMMENTO: Studio cross-sectional che mira a valutare la sensibilità della variante omicron al test di neutralizzazione. E’ stato approntato uno specifico test di neutralizzazione del virus. Sono stati saggiati campioni di plasma convalescente, campioni di individui vaccinati, campioni di individui precedentemente infetti e campioni di donatori; è stata inoltre testata la capacità neutralizzante di cinque diversi anticorpi monoclonali di rilevanza clinica. E’ stata riscontrata una ridotta potenza di neutralizzazione verso omicron, rispetto al ceppo wild type, nei campioni raccolti poco dopo l’infezione o la vaccinazione; i sieri di individui con pregressa infezione e poi vaccinati sembrano invece mantenere una quasi sovrapponibile potenza di neutralizzazione rispetto a omicron e wild type. L’unico anticorpo monoclonale con attività neutralizzante verso omicron sembrerebbe essere S309, parente del sotrovimab (anche se con potenza ridotta rispetto al wild type).
Tale studio sembra confermare l’elevata capacità di omicron di evasione della risposta immunitaria; la combinazione più “immunogena” si conferma essere, come riportato anche in altri lavori di letteratura, anche nei confronti di omicron quella di pregressa infezione + successiva vaccinazione.

Tommy Nyberg et al.

Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2822%2900462-7

CONTENUTO E COMMENTO: Studio condotto in Inghilterra che quantifica il rischio di ospedalizzazione e morte a causa dell'infezione da Sars-CoV-2 da variante Omicron rispetto alla Delta sulla base di dati di circa 1.5 milioni di casi COVID-19, di cui circa 1 milione infettati con la variante Omicron. Il rischio complessivo di esiti gravi per l'infezione da Omicron è sostanzialmente inferiore rispetto alla variante Delta. Tuttavia, la riduzione del rischio di ospedalizzazione non è stata osservata tra i bambini di età inferiore ai 10 anni con Omicron rispetto a Delta. La riduzione del rischio di ospedalizzazione osservata a livello generale riflette una riduzione della gravità intrinseca della patologia.

La precedente infezione documentata da SARS-CoV-2 offriva una protezione contro il ricovero in ospedale ma soprattutto contro la morte in individui non vaccinati. La vaccinazione di richiamo con i vaccini a mRNA mantiene oltre il 70% di protezione contro l'ospedalizzazione e la morte nelle infezioni da Omicron.

WHO's Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE).

World Health Organization

Statement on Omicron sublineage BA.2

https://www.who.int/news/item/22-02-2022-statement-on-omicron-sublineage-ba.2

CONTENUTO E COMMENTO: Statement del gruppo di consulenza tecnica sull'evoluzione del virus SARS-CoV-2 (TAG-VE) dell'OMS riguardante i sotto-lignaggi della variante Omicron. La variante Omicron è composta da diverse sotto-varianti tra cui le più comuni sono BA.1 e BA.2. Entrambe sono sotto costante monitoraggio da parte dell’OMS. Attualmente BA.2 sta prevalendo su BA.1 in quanto più trasmissibile (anche se la differenza tra le due è molto meno netta rispetto ad esempio a quella tra la variante delta e omicron).  Nonostante siano stati segnalati casi di reinfezione da BA.2 dopo l'infezione da BA.1, i dati iniziali degli studi sulla reinfezione a livello di popolazione suggeriscono che l'infezione da BA.1 fornisce un’importante protezione contro la reinfezione da BA.2, almeno per il periodo limitato per il quale i dati sono disponibili.

Sebbene dati preliminari su modelli animali senza alcuna immunità per SARS-CoV-2 abbiano evidenziato che BA.2 può causare malattie più gravi rispetto a BA.1, i dati di real life sulle infezioni provenienti da Sud Africa, Regno Unito e Danimarca, mostrano che non vi sarebbe alcuna differenza di gravità tra BA.2 e BA.1 nei contesti dove l'immunità da vaccinazione o da infezione naturale è elevata.

Maher MC et al.

Predicting the mutational drivers of future SARS-CoV-2 variants of concern

Sci Transl Med., https://www.science.org/doi/epdf/10.1126/scitranslmed.abk3445

CONTENUTO E COMMENTO : Una delle più grandi minacce del virus SARS-CoV-2 è rappresentata dalla sua capacità di evolvere e di conseguenza eludere la risposta immunitaria generata dalle precedenti esposizioni al virus o dai vaccini. In questo studio gli autori concepiscono e validano un modello per tentare di predire le future “variant of concern” del virus, attraverso l’analisi delle mutazioni degli aminoacidi di SARS-CoV-2. E’ stato testato il valore predittivo di caratteristiche epidemiologiche, evolutive, immunologiche, nonché modelli di sequenziamento di proteine basati su reti neurali per identificare i principali driver dell’evoluzione di SARS-CoV-2. Sono state identificate retrospettivamente con elevata accuratezza tutte le mutazioni che si sono susseguite nel corso delle varie fasi della pandemia ed è stato costruito un modello apparentemente in grado di predire le future mutazioni che si diffonderanno. Gli autori avrebbero validato tale modello nei confronti di Omicron, ottenendo un elevato score predittivo.

Identificare con alcuni mesi di anticipo le future varianti virali circolanti potrebbe avere un enorme impatto sulla profilassi e terapia dell’infezione virale: sarebbe infatti possibile approntare in anticipo vaccini e farmaci, specialmente anticorpi monoclonali, il più possibile mirati.

Madhi SA et al.

Decoupling of omicron variant infections and severe COVID-19

Lancet., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8856666/pdf/main.pdf

CONTENUTO E COMMENTO : Articolo della sezione “Commentary” della prestigiosa rivista “The Lancet” sulla crescente evidenza di divergenza fra il tasso di infezioni da variante Omicron e il tasso di forme severe di COVID-19. Secondo gli autori infatti, nonostante le multiple mutazioni a carico della proteina spike riscontrate in Omicron responsabili dell’evasione della risposta umorale neutralizzante, le precedenti infezioni da SARS-CoV-2 e la vaccinazione con doppia dose o con dose booster potrebbero conferire comunque una robusta protezione nei confronti delle forme severe della malattia causata da questa variante. Alla base di questa ipotesi si collocherebbero infatti la risposta cellulare T-mediata e la risposta umorale non neutralizzante, che sembrerebbero meno influenzate dalle multiple mutazioni della proteina spike e pertanto potrebbero conferire protezione nei confronti della Omicron.

Sebbene tali conclusioni debbano essere confermate da altri studi, tale articolo rappresenta un’ulteriore ipotesi immunopatologica a sostegno della presunta ridotta virulenza della variante Omicron e dell’importanza di produrre nuovi vaccini da distribuire estensivamente.

 Yamasoba D. et al.

Virological characteristics of SARS-CoV-2 BA.2 variant

BioRxiv, https://www.biorxiv.org/content/10.1101/2022.02.14.480335v1.full.pdf

CONTENUTO E COMMENTO : Studio che descrive le caratteristiche del nuovo lineage BA.2 della variante Omicron. BA.2, rispetto al lineage BA.1, sembrerebbe essere più trasmissibile, tanto da iniziare a competere nell’ambiente con essa. Sembrerebbe anch’essa sfuggire al’immunità umorale indotta, come dimostrato dagli esperimenti di neutralizzazione. BA.2 sembrerebbe inoltre essere pressochè completamente resistente agli anticorpi monoclonali casirivimab/indevimab e sembrerebbe essere 35 volte più resistente al sotrovimab, l’anticorpo monoclonale cardine del trattamento precoce dell’infezione da SARS-CoV-2 variante Omicron. La BA.2 sembrerebbe avere una maggior tendenza a replicare nell’epitelio nasale umano e, da aluni esperimenti su criceti, sembrerebbe essere più patogena dell’altra.

Questo studio evidenzia come nuove varianti e lineage emergenti possano, seppur differendo di poco le une dalle altre, possedere caratteristiche virologiche peculiari che possono tradursi in difficoltà epidemiologiche, profilattiche e terapeutiche sempre maggiori. E’ pertanto fondamentale un sistema di attento monitoraggio delle varianti e dei loro differenti lineage, al fine di intercettare precocemente quelle emergenti per poter attuare strategie diagnostico-terapeutiche sempre più mirate.

Tarke A. et al.

SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron

Cell, https://doi.org/10.1016/j.cell.2022.01.015

CONTENUTO E COMMENTO: : studio cheindaga l’immunita’ adattativa verso un estesospettro di varianti di SARS-CoV2, comprese Delta ed Omicron, in soggettivaccinati con i vaccini mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373. Sono statiarruolati 96 adultivaccinati, studiati a duesettimanedopo la prima dose, 2 dopo la seconda, 3,5 mesi e 5-6 mesidopol’ultima dose.

I datidimostranoche la maggior parte degliepitopi delle cellule T sono conservati, non solo per le varianti « precoci », ma anche per le piu’ recenti, suggerendoche l’evoluzione continua delle varianti non e’ stata associata ad un aumentato escape immune dalle risposte delle cellule T.

A livelloproteomico, il 95% degliepitopiriportati di classe II e 98% di quelli di classe I eranocompletamenteconservatiall’analisicomputazionale sui dati IEDB (www.IEDB.org), estratti a luglio 2021. Nelcaso di Omicron, la frazionedegliepitopiconservatitotalmentee’diminuita ad 88% per la classe II e 95% per la classe I in tutto il proteoma. Focalizzandosisullaproteinaspike, in contesto vaccinale, il 91% degliepitopi di classe II e il 94% di quelli di classe I eranoconservati, mentre la frazione di epitopispikeconservati per Omicron e’diminuita a 72% per la classe II e 86% per la classe I. Questo alto numero di epitopimutati per le cellule T per spikeeraattesa in quanto moltemutazionidefinentivarianti sono localizzate proprio sullaproteinaspike. Va pero’ enfatizzatocheunamutazionedell’epitopo non preclude il riconoscimentocrossreattivodellasequenzamutata.

Il legame HLA era ben conservatonellamaggioranzadegliepitopimutati e non si e’osservatoimpatto del legame HLA sugliepitopi omicron.

Il riconoscimento delle cellule T per numerosevarianti, incluse Delta ed Omicron e’statomisuratoneidonatorivaccinati con mRNA-1273, BNT162b2, Ad26.COV2.S. Il riconoscimentodella variante ancestrale e’statosimile per i 3 differentivaccini: si e’pero’ riscontrataunaaltavariabilita’ neisoggettivaccinati con Ad26.COV2.S, possibilmente legato al fattochequestovaccinoinduceunarisposta T spikespecificachecolpisceprincipalmente la regione S1, mentreglialtrivaccinievocanounarisposta piu’ amplia.

Misurando la produzionecitochinica come outcome, e’ stata notataun’importanteriduzionenellamemoria a 3,5 mesi per la variante Delta. Le risposte delle cellule T dellamemoria verso le variantitestate, incluso Omicron, sono state descritte in unacoorte di donatorifino a 6-7 mesidopo la vaccinazione : i daticonfermanoche la maggioranza delle risposte delle cellule CD4+ e CD8+ rilevatetramite AIM assayeranopreservatefino alla fine delle rilevazione, anche per la variante omicron.

LIMITAZIONI : esperimentieffettuati con unaconcentrazione importante di peptidi il chepuo’ sottostimare l’impatto delle mutazionisulle cellule T; non e’noto se il livello di conservazionedegliepitopiconservirisposte T funzionali in vivo; impatto delle risposte delle cellule T sullaprotezionecontro SARS-CoV2 non noto; lo studio ha analizzatorispostepeptidichepiuttostocherisposte in vivo; non analisi di soggetti con infezionenaturale.

Marcotte H et al.

Immunity to SARS-CoV-2 up to 15 months after infection

IScience, https://www.sciencedirect.com/science/article/pii/S258900422200013X

CONTENUTO E COMMENTO : Studio espIorante la durata dell’immunità umorale e cellulare fino a 15 mesi dopo la diagnosi di infezione da SARS-CoV2. In questa analisi, condotta su campioni raccolti tra gennaio e giugno 2021 in Italia e Svezia, la risposta anticorpale IgG mediata ha raggiunto il suo picco dopo 15-28 giorni dall’infezione, per poi ridursi gradualmente e raggiungere il suo plateau a distanza di 6 mesi. A differenza della variante G614, i titoli di anticorpi neutralizzanti prodotti in risposta alle infezioni da variante Beta, Gamma e Delta si sono dimostrati fino a 8 volte inferiori. Per quanto riguarda l’immunità cellulare, invece, il numero delle cellule T, ma non delle cellule B, si è ridotto significativamente tra i mesi 6 e 15.

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

Science, https://www.science.org/doi/epdf/10.1126/science.abn8652

CONTENUTO E COMMENTO : Questo studio si focalizza sulla variante Omicron, determinandone la struttura cristallina della proteina spike e del “receptor-binding domain” che si lega all’anticorpo monoclonale S309 (simile al sotrovimab) che neutralizza i sarbecovirus e al recettore ACE2 umano. Tale lavoro fornisce le basi molecolari per comprendere più adeguatamente il motivo per cui la variante Omicron sia in grado di evadere estensivamente la risposta immunitaria. Permette inoltre di comprendere l’importanza di disegnare e modellare terapie e vaccini contro quegli epitopi del virus che tendono maggiormente a conservarsi: sarebbe di fondamentale importanza sviluppare delle strategie che possano non solo risolvere l’attuale pandemia, ma anche prepararci nei confronti di future pandemie da sarbecovirus.

Bhattacharyya RP et al

Challenges in Inferring Intrinsic Severity of the SARS-CoV-2 Omicron Variant

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMp2119682

CONTENUTO E COMMENTO : L’apparente minore gravità e letalità della variante omicron di SARS-CoV-2 potrebbero dipendere dalle caratteristiche della popolazione (sudafricana) da cui derivano i primi dati, una popolazione giovane e priva di comorbidità, e dal maggior numero di soggetti testati rispetto alle scorse « ondate ».

Glocker, M.O.; et al.

Compared with SARS-CoV2 wild type´s spike protein, the SARS-CoV2 omicron´s receptor binding motif (RBM) has adopted a more SARS-CoV1 and/or bat/civet-like structure

file:///C:/Users/00122705/Downloads/Glocker.pdf

CONTENUTO E COMMENTO: Lavoro non ancora peer-reviewed che sottolinea come il legame più debole della proteina spike di SARS- CoV-2 variante omicron al suo recettore sembrerebbe rallentare l'assorbimento del virus nelle cellule e, quindi, ritardare la risposta immunitaria innata. Ciò potrebbe essere responsabile di una maggiore carica virale nel tratto respiratorio superiore.

L'assunto che ci sia un legame recettoriale più debole di omicron rispetto a quelli di virus wild type, alfa o delta corrobora le osservazioni cliniche di esiti di malattie meno gravi dell'infezione da omicron rispetto alle infezioni con altri SARS- CoV-2.

Gli autori inoltre ipotizzano che la somministrazione del vaccinonei soggetti infettati con SARS-CoV-2 omicron potrebbe indurre un'immunità più generale e di lunga durata estendendo i repertori di anticorpi protettivi e migliorando contemporaneamente l'immunità mediata dai linfociti T, in definitiva preparando, in tal modo, un individuo a sconfiggere più varianti di virus patogeni in futuro.

Singanayagam, A., et al.

Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

Lancet Infect Dis, https://www.thelancet.com/action/showPdf?pii=S1473-3099%2821%2900648-4

CONTENUTO E COMMENTO: La vaccinazione riduce il rischio di infezione della variante delta e accelera la clearance virale. Tuttavia, gli individui completamente vaccinati con infezione hanno un picco di carica virale simile ai non vaccinati e possono trasmettere efficacemente l'infezione in ambienti domestici, anche ai contatti completamente vaccinati.

Jansen, L.., et al

Investigation of a SARS-CoV-2 B.1.1.529 (Omicron) Variant Cluster —Nebraska, November–December 2021

MMWR, https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm705152e3-H.pdf

CONTENUTO E COMMENTO: Sebbene si tratti di uno studio su un piccolo numero di pazienti si evidenzia come Omicron sia caratterizzata da :

-un periodo di incubazione più breve,

-una sindrome clinica simile o più lieve di quella associata con varianti precedentemente descritte in persone che sono state vaccinate o precedentemente infettate,

-un aumento del potenziale di reinfezione.

Considerando che per la variante Delta (SARS-CoV-2 B.1.617.2) il periodo di incubazione mediano è stato descritto come ≥ 5 giorni e più vicino a 4, il periodo di incubazione mediano osservato in questo cluster di Omicron è stato di circa 3 giorni.

Pulliam, J.R.C., et al.

Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa 2021-12-01

Medrxiv.org ,https://www.medrxiv.org/content/10.1101/2021.11.11.21266068v2.full.pdf

CONTENUTO E COMMENTO: Studio ancora non peer reviewed svolto in Sudafrica. Viene evidenziato come la recente diffusione della variante Omicron è stata associata ad una diminuzione del coefficiente di rischio per l'infezione primaria ma ad un aumento del coefficiente di rischio di reinfezione. L'evidenza a livello di popolazione suggerisce che la variante Omicron è associata a una sostanziale capacità di eludere l'immunità da una precedente infezione.

The origin of SARS-CoV-2 variants of concern

Lancet Infect Dis., https://www.thelancet.com/action/showPdf?pii=S1473-3099%2822%2900015-9

CONTENUTO E COMMENTO : Articolo della sezione « newsdesk » della prestigiosa rivista Lancet Infectious Diseases nel quale vengono esposte le tre principali teorie dell’origine della variante omicron. La prima teoria sostiene che la variante omicron si sarebbe generata in una comunità chiusa, con scarsa possibilità di sequenziamento genico, poco plausibile, considerata la straordinaria trasmissibilità della variante e tenuto conto dell’interconnessione del mondo. Una seconda teoria prevede che una popolazione di animali sia stata infettata, il virus sia mutato e abbia di nuovo infettato l’uomo, tuttavia è estremamente difficile stabilire quanto comune sia la trasmissione animale-uomo, dato che molti animali sono stati infettati da SARS-CoV-2. La teoria più accreditata prevede un’infezione persistente in un paziente immunocompromesso : nell’ospite immunocompromesso il virus può infatti continuare a replicarsi e a mutare, sviluppando meccanismi per penetrare più efficacemente nella cellula e per evadere il sistema immunitario.

Gruell H. et al.

mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant

https://www.nature.com/articles/s41591-021-01676-0.pdf

CONTENUTO E COMMENTO : Studio in vitro sull’attivita’ neutralizzante indotta da vaccino sul siero di una coorte di 30 individui senza evidenza di pregressa infezione, vaccinato con 2 dosi di BNT162b2, sul siero di 30 individui convalescenti che hanno poi ricevuto una dose di BNT162b2, studiati mediante un pseudovirus assay basato su lentivirus. I sieri sono stati quindi testati sull’espressione sugli pseudovirus delle protein spike dei ceppi Wu01, Alpha (B.1.1.7), Delta (B.1.617.2), Beta (B.1.351) e Omicron.

Tutti i campioni dei vaccinati hanno mostrato attivita’ neutralizzante contro il ceppo Wu01 con una media geometrica al 50% di diluzione inibitoria sierica (GeoMean ID50) di 546. L’attivita’ neutralizzante sierica per le varianti Alpha, Delta, and Beta e’ stata minore (GeoMean ID50s di 331, 172 e 40, rispettivamente). Solo 9 sieri sui 30 dei vaccinati (30%) aveva attivita’ neutralizzante sierica contro Omicron, con una GeoMean ID50 di 8, significativamente minore che con la variante Beta (P < 0.0001), una delle varianti note per la sua maggiore evasione immune.

Dopo il completamento del ciclo vaccinale con due dosi di vaccino BNT162b2 vaccine, l’attivita’ neutralizante sierica contro il ceppo Wu01 e’ diminuita di 4 volte lungo un periodo di 5 mesi (GeoMean ID50 da 546 a 139), ma e’ incrementata in maniera robusta dopo il booster (GeoMean ID50 6,241). 

Dopo il completamento del ciclo vaccinale (due dosi di vaccino BNT162b2), solo il 30–37% dei campioni aveva attivita’ neutralizzante determinabile contro la variante Omicron (GeoMean ID50s di 8 e 9 in tempo precoce e tardivo): quest’ultima e’ aumentata di 100 volte dopo la somministrazione di dose booster con BNT162b2 (GeoMean ID50 di 1,195 in tutti I 30 partecipanti)

Analizzando la risposta neutralizzante sierica contro omicron in una coorte longitudinale di 30 individui non vaccinati con pregressa infezione, successivamente vaccinati con una singola dose di BNT162b2, si e’ osservato invece che, nell’immediato periodo post infezione (1 mese e mezzo dopo), l’attivita’ neutralizzante verso il ceppo Wu01 era variabile (ID50s 37 - 11,008, GeoMean ID50 494, con decremento fino a 93 dopo 12 mesi). Dopo una singola dose di BNT162b2, si e’ documentato un forte incremento dell’attivita’ neutralizzante sierica (GeoMean ID50 7,997 contro il ceppo Wu01). Contro la variante Omicron, nell’immediato period post infezione e tardive (12 mesi dopo), si e’ mostrata scarsa attivita’ neutralizzante sierica, con un modesto incremento nel periodo tardivo per alcuni soggetti (possibile indice di una maturazione dell’affinita’ anticorpale in atto). Dopo una singola dose di vaccino BNT162b2, si e’ osservato un forte aumento dell’attivita’ neutralizzante sierica nei precedentemente infetti (GeoMean ID50 1,549 1 mese dopo la vaccinazione)

L’attivita’ neutralizzante contro omicron e’ stata inoltre studiata sugli anticorpi monoclonali maggiormente usati (bamlanvimab, etesevimab, REGN10933 (casirivimab), REGN10987 (imdevimab), S309 (sotrovimab)), un anticorpo attualmente studiato (DZIF-10c)) si e’ assistito ad una marcata riduzione dell’attivita’ in 7 anticorpi su 9 (conservata per sotrovimab e DZIF-10c).

Wolter N et al

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2822%2900017-4

CONTENUTO E COMMENTO: Studio retrospettivo nazionale di data linkages condotto in Sud-Africa con l’obiettivo di valutare la gravità clinica delle infezioni da variante omicron a confronto con infezioni da variante delta, utilizzando la perdita del gene S al test PCR per COVID-19 (SGTF) come proxy di variante omicron.

I risultati dell’analisi suggeriscono che pazienti con SGTF hanno un ridotto rischio di ospedalizzazione e di malattia severa, probabilmente come risultato di una precedente immunità.

Araf Y et al.

Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines

J Med Virol., https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.27588

CONTENUTO E COMMENTO: Review sulla famigerata « Variant Of Concern » Omicron, che ne mette a fuoco la genomica, la trasmissibilità e l’efficacia dei vaccini contro di essa. In primo luogo la variante Omicron possiede un elevatissimo numero di mutazioni, 30 delle quali sono nella sequenza genomica che codifica per la proteina spike, responsabili dell’alterazione strutturale della stessa e pertanto della capacità di Omicron di sfuggire al sistema immunitario. La variante Omicron possiede inoltre un’incredibile trasmissibilità, circa 4 volte maggiore del ceppo « wild type » e 2 volte maggiore della variante Delta, caratteristica che le ha permesso una diffusione rapidissima nel mondo. Infine Omicron è stata riscontrata anche in pazienti vaccinati per SARS-CoV-2, suggerendo che la nuova variante presenta un certo grado di resistenza ai vaccini attualmente disponibili.

Nemet I. et al.

Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 Omicron Infection

The NEJM, https://www.nejm.org/doi/full/10.1056/NEJMc2119358?query=featured_coronavirus

CONTENUTO E COMMENTO: Studio analitico in vitro, condotto in Israele, sulla neutralizzazione di cellule infettate con diverse varianti di SARS-CoV2 su campioni di siero ottenuto da operatori sanitari vaccinati con il vaccino BNT162b2, divisi in due gruppi (20 operatori ciascuno), uno comprendente coloro che hanno ricevuto 2 e l’altro 3 dosi di vaccino.

I risultati mostrano una significante minore efficacia della neutralizzazione del virus wild-type e delle tre varianti di interesse (beta, delta, omicron) dai sieri ottenuti da operatori che hanno ricevuto 2 dosi del vaccino BNT162b2. Una minore efficacia di neutralizzazione contro le varianti beta ed omicron rispetto al virus wild-type e’ stato osservato in entrambi i gruppi in modo simile.

Limitazioni : campione piccolo, studio in vitro, maggiore distanza temporale dall’ultima dose nel gruppo con 2 dosi.

Interessante notare come la vaccinazione, sia essa con due o tre dosi, sembra associarsi una ridotta efficacia della neutralizzazione in vitro per le varianti non wild-type.

Pengcheng H et al

Receptor binding and complex structures of human ACE2 to spike RBD from Omicron and Delta SARS-CoV-2

Cell , https://www.cell.com/cell/fulltext/S0092-8674(22)00001-0

CONTENUTO E COMMENTO : Studio della struttura cristallina dell’interazione fra la porzione legante il recettore (RBD) della proteina S (spike) della variante omicron di SARS-CoV-2 e il recettore cellulare ACE-2. Pare che le mutazioni della porzione RBD di omicron consentano una affinità simile a quella della RBD wild-type, pur conferendo un vantaggio in termini di « fuga » dal sistema immunitario. La conoscenza dettagliata dei meccanismi molecolari alla base dell’infezione da SARS-CoV-2 è alla base di una comprensione sempre più approfondita della malattia e dello sviluppo di nuove possibilità terapeutiche.

Dr. Francis Collins

Latest on Omicron Variant and COVID-19 Vaccine Protection

NIH.gov,

https://directorsblog.nih.gov/2021/12/14/the-latest-on-the-omicron-variant-and-vaccine-protection/

CONTENUTO E COMMENTO: Risultati preliminari sembrano documentare un calo significativo degli anticorpi neutralizzanti contro questa variante nelle persone che hanno ricevuto un ciclo di due dosi  di vaccino mRNA.

Tuttavia, i risultati iniziali degli studi condotti sia in laboratorio che nel mondo reale mostrano che le persone che ricevono una dose booster, possono essere meglio protette. Sebbene questi dati siano preliminari, suggeriscono che la dose di richiamo aiuterà a proteggere le persone già vaccinate da possibili infezioni gravi da Omicron durante i mesi invernali.

Vale anche la pena notare che la variante Omicron per lo più non ha mutazioni in porzioni del suo genoma che sono target di altri componenti dell'immunità indotta dal vaccino, comprese le cellule T. Queste cellule fanno parte della seconda linea di difesa del nostro organismo e sono generalmente più difficili da evitare per i virus. Sebbene le cellule T non possano prevenire l'infezione, aiutano a proteggere dalla malattia più grave.

Abdullah F., et al.

Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in Tshwane, South Africa

Int J Infect Dis, https://www.ijidonline.com/action/showPdf?pii=S1201-9712%2821%2901256-X

CONTENUTO E COMMENTO:  Dai dati emersi in questo studio condotto in una città del Sud Africa la polmonite COVID-19 causata dalla variante Omicron sarebbe presente solo in circa un terzo dei pazienti ricoverati e in oltre il 70% di questi pazienti sarebbe di grado lieve-moderato. La mortalità confrontata con l’ondata precedente (prevalentemente causata dalla variante Delta) sarebbe del 4.5% vs. 21.3%.

Torjesen I. 

Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear

BMJ, https://www.bmj.com/content/bmj/375/bmj.n2943.full.pdf

CONTENUTO: Articolo della prestigiosa rivista BMJ sulla nuova variante Omicron: viene fatto riferimento alle numerose mutazioni del virus, alla sua presunta ridotta sensibilità ai vaccini e alle modalità per poterlo diagnosticare.

COMMENTO: La variante Omicron di SARS-CoV-2 è responsabile di un cluster di casi in Sud Africa che si sta rapidamente diffondendo in tutto il mondo. Essa è la variante più mutata emersa finora tra tutte quelle sequenziate tanto che è diventata immediatamente una “variante di preoccupazione“ per l’OMS per i possibili problemi di elevata trasmissibilità e resistenza alla protezione indotta dai vaccini.  Al di là delle legittime preoccupazioni, nella new pubblicata su BMJ viene espressa una considerazione importante, almeno a giudizio di chi scrive.

Quando emerge una variante virale antigenicamente molto distante dalle precedenti si può assistere ad una riduzione significativa del titolo protettivo degli anticorpi; tuttavia esiste la possibilità concreta che alti titoli di anticorpi siano comunque efficaci nel controllo dell’infezione. Ne consegue che un titolo elevato, eventualmente elicitato da una ulteriore somministrazione di vaccino, potrebbe compensare la distanza antigenica della variante omicron rispetto alle variante circolanti finora. Quindi, anche se i vaccini dovessero rilevarsi meno efficaci contro la variante omicron, essi potrebbero comunque fornire una certa protezione soprattutto nei vaccinati dopo il booster.

Patone M et al

Mortality and critical care unit admission associated with the SARS-CoV-2 lineage B.1.1.7 in England: an observational cohort study

The Lancet, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00318-2/fulltext?dgcid=raven_jbs_etoc_email

CONTENUTO : Studio osservazionale su due coorti di oltre 200.000 pazienti complessivi condotto nel Regno Unito, in cui si osserva un rischio doppio per chi ha l’infezione da «variante» B.1.1.7 (cosiddetta inglese) di SAS-CoV-2 di essere ricoverato in rianimazione e morire a 28 giorni, anche se si tratterebbe di pazienti più giovani rispetto a quelli infettati da virus non-B.1.1.7. Per i pazienti ricoverati in rianimazione invece non si osserva alcuna associazione fra l’infezione da variante e il rischio di morte o un’aumentata necessità di cure intensive. Da notare che la diagnosi di infezione da variante si basa sulla supposizione che se il test molecolare non amplifica il gene S di SARS-CoV-2 questo sia mutato e si tratti quindi di un ceppo B.1.1.7, il più comune nel Regno Unito nel periodo dello studio.

COMMENTO : Questo corposo studio osservazionale inglese evidenzia con accurata indagine epidemiologica la maggiore pericolosità della cosiddetta « variante inglese », in termini di ammissione in terapia intensiva e mortalità a 28 giorni rispetto alla variante « wild » originaria.

Tuttavia non si dimostrano differenze nella percentuale di mortalità in terapia intensiva dopo l’ammissione. Ribadita per l’ennesima volta attenzione all’esposizione alle varianti.

Carreño JM,e t al.

Evidence for retained spike-binding and neutralizing activity against emerging SARS-CoV-2 variants in serum of COVID-19 mRNA vaccine recipients

EBioMedicine.

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00419-9/fulltext

CONTENUTO : L’emergenza di varianti di SARS-CoV-2 è un argomento preoccupante a causa del loro potenziale di sfuggire parzialmente alla risposta anticorpale post vaccino. In questo studio, condotto nell’ambito dello studio osservazionale longitudinale PARIS, sono stati analizzati campioni sierici di 30 pazienti sottoposti a vaccinazione con 2 dosi di vaccino ad mRNA (15 Pfizer/BioNTech e 15 Moderna) per valutare gli anticorpi neutralizzanti nei confronti di varianti virali emergenti. È emersa una lieve riduzione della risposta neutralizzante contro le varianti Iota e Delta, più marcata nel caso di una sottovariante di Lambda, seguita da Beta e Alfa. Tali dati suggeriscono che i vaccini ad mRNA contro SARS-CoV-2 possono rimanere efficaci nei confronti di queste varianti e che gli anticorpi contro la proteina S mantengono probabilmente specificità anche di fronte all’evoluzione della diversità virale.

COMMENTO : I dati si questo lavoro confermano che i vaccini ad mRNA Pfizer/BioNTech o Moderna, dopo la somministrazione delle due dosi sono protettivi, anche se con una lieve riduzione, anche verso le varianti SARS-CoV-2. Pertanto, dal momento che gli stessi vaccini sembrano mantenere una memoria che decade man mano soprattutto dopo 6-8 mesi, la somministrazione della terza dose è quanto mai necessaria a livello di tutte le età, per irrobustire la risposta contro le varianti e per indurre una memoria più a lungo termine. 

Taylor C.A., et al.

Severity of Disease Among Adults Hospitalized with Laboratory-Confirmed COVID-19 Before and During the Period of SARS-CoV-2 B.1.617.2 (Delta) Predominance — COVID-NET, 14 States, January–August 2021

MMWR, https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7043e1-H.pdf

CONTENUTO : Studio del CDC sul confronto tra il periodo pre-variante Delta e post variante Delta in termini di ospedalizzazioni/severità della malattia.

COMMENTO :La variante Delta ha la trasmissibilità della varicella ed è la variante prevalente nel mondo.In questo articolo sono stati valutato dati da 14 stati per confrontare  il periodo pre e post Delta sul rapporto ospedalizzazioni vs severità di malattia.

Gli autori non trovano un aumento della ospedalizzazione con malattia severa durante la trsmissione pandemica della variante Delta.

Gli autori trovano che la proporzione di ospedalizzazione di soggetti non vaccinati tra i 18 e 49 anni aumenta nel periodo di trasmissione della variante Delta.

Abu-Raddad LJ, et al.

Severity, criticality, and fatality of the SARS-CoV-2 Beta variant

Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab909/6398699

CONTENUTO: Studio caso controllo condotto in Qatar, paese che ha assistito, a inizio 2021, alla compresenza di variante Alpha e variante Beta. In questo lavoro, la variante Alpha è risultata il 48% più contagiosa delle varianti “wild type” ma, sorprendentemente, la variante Beta è risultata associata ad un rischio aggiuntivo del 24% di contrarre una malattia severa, del 49% di essere ricoverati in terapia intensiva e del 57% di morire.

COMMENTO: Lo studio, che compara l’impatto clinico della variante Beta rispetto alla variante Alfa, evidenzia come caratteristiche fenotipiche di espressività, la maggiore severità della variante Beta in termini di malattia grave, di ricovero in terapia intensiva e di letalità. Viene sottolineata l’importanza di valutare queste caratteristiche cliniche, oltre che la trasmissibilità, nella caratterizzazione delle VOC.

Harder T. et al.

Effectiveness of COVID-19 vaccines against SARSCoV-2 infection with the Delta (B.1.617.2) variant: second interim results of a living systematic review and meta-analysis, 1 January to 25 August 2021

Eurosurveillance, https://www.eurosurveillance.org/docserver/fulltext/eurosurveillance/26/41/eurosurv-26-41-2.pdf?expires=1634748943&id=id&accname=guest&checksum=482288F5FBD5BBCA720A19FA33DC25B8

CONTENUTO : Seconda analisi ad interim dei risultati sults di una revisione sistematica e metanalisi di 17 studi aventi come end-point l’efficacia vaccinale e la durata della protezione (1 gennaio 2021, 25 agosto 2021), in particolare dei vaccini approvati in ambito europeo con un focus sulla protezione nei confronti dell’infezione dovuta alla variante Delta, maggiormente rappresentata nel periodo oggetto di studio. L’efficacia vaccinale aggregata nei confronti di quest’ultima variante è risultata essere del 63.1% (95% (CI) : 40.9–76.9) contro l’infezione asintomatica, 75.7% (95% CI: 69.3–80.8) contro l’infezione sintomatica e del 90.9% (95% CI: 84.5–94.7) nei confronti dell’ospedalizzazione. Comparati ai dati riguardanti la variante Alpha, l’efficacia vaccinale contro l’infezione moderata è ridotta del 10–20%, mentre è totalmente invariata nei confronti dell’infezione severa da SARS-CoV2.

COMMENTO : Si tratta di una rassegna con metanalisi degli studi fatti per valutare effettività della vaccinazione con i correnti vaccini, in particolare i due vaccini ad mRNA, contro l’infezione e la malattia causata dalla variante delta. La rassegna è stata eseguita esegiuta dai colleghi del Robert Koch Institure (Berlino). Nonostantela marcata eterogeneità degli asset studiati ed i piuttosto ampi intervalli di credibilità statistica, gli Autori concludono che nell’insieme la protezione vaccinale contro la malattia severa è tanto alta contro delta quanto lo è contro alfa, mentre la protezione contro l’infezione da delta è notevolmente bassa. Gli studi con esame della durata della protezione sono solo due e non contribuiscono significativamente alla tematica della caduta di immunità nel tempo.

Vöhringer, H. S. et al.

Genomic reconstruction of the SARS-CoV-2 epidemic in England

Nature, https://www.nature.com/articles/s41586-021-04069-y_reference.pdf

CONTENUTO: Questo lavoro descrive l’andamento epidemiologico delle varianti di SARS-CoV-2 in Inghilterra. Il fatto che la variante Delta abbia preso piede in aprile/maggio, quando i casi dovuti alla variante Alfa stavano diminuendo ha fortemente mascherato la reale portata dell’impatto della variante virale Delta. Ciò sottolinea la necessità di una sorveglianza genomica efficace per elaborare strategie di controllo tempestive.

COMMENTO : Questo articolo punta i riflettori sull’importanza oggettiva del consorzio inglese nato a marzo del 2020 per una sorveglianza genomica sequenziando random il 10% di tutti i tamponi covid positivi. Quindi si sottolinea la necessità di una sorveglianza epidemiologico molecolare che possa spiegare l’andamento evolutivo ed epidemiologico delle varianti.

Robilotti E.V., et al.

Clinical and Genomic Characterization of SARS CoV-2 infections in mRNA Vaccinated Health Care Personnel in New York City

Clin Infect Dis, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab886/6396142

CONTENUTO: Uno studio retrospettivo su >13000 operatori sanitari ha mostrato che l'efficacia dei vaccini a mRNA contro l’infezione da SARS-CoV-2 è stata del 94% durante i primi 5 mesi di follow-up, con una riduzione al 75% durante il successivo periodo di dominanza Delta. Non ci sono state variazioni dell’efficacia in termini di ospedalizzazioni.

COMMENTO : Articolo interessante che descrive uno studio retrospettivo su operatori sanitari in due periodi differenti caratterizzati da dominanza prima del virus Alfa (pre Delta) e poi dal virus Delta. Importante come gli autori descrivono  come in una coorte di 13658  operatori sanitari con il 90% vaccinati con almeno una dose, l’efficacia vaccinale  diminuisca dal 94.5% nel periodo pre Delta, al 75.6% nel periodo di circolazione prevalente del virus Delta. Durante tutto il periodo di studio si era poi evidenziata una forte protezione contro l’ospedalizzazione indipendentemente dalla fase pre Delta e Delta.

Nanduri S., et al.

Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant - National Healthcare Safety Network, March 1-August 1, 2021

MMWR, https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7034e3-H.pdf

CONTENUTO E COMMENTO: Questo lavoro è stato accostato al precedente poichè affronta lo stesso tema dalla prospettiva dell’altra popolazione sottoposta a vaccinazione con vaccini a mRNA : i residenti delle RSA in cui l’epidemiologia dell’infezione si è nuovamente modificata.

Due dosi di vaccini mRNA erano efficaci per il 74,7% contro l’infezione da SARS-CoV-2 tra i residenti nelle case di cura all'inizio del programma di vaccinazione (marzo-maggio 2021). Da giugno a luglio 2021, quando la variante Delta è diventata predominante, l’efficacia è scesa significativamente (53,1%).

Tartof S. Y. et al.

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2821%2902183-8

CONTENUTO : Studio retrospettivo, condotto negli Stati Uniti dal 14 dicembre 2020 all’8 agosto 2021, su una popolazione di 3.436.957 persone di età >12 aa (52.4% F, 47.6% M) appartenenti al consorzio di cure integrate Kaiser Permanente Southern California, al fine di determinare l’efficacia del vaccino BNT162b2 contro l’infezione da SARS-CoV-2 e il tasso di ospedalizzazione COVID-19 relato fino a 6 mesi dal termine del ciclo vaccinale in un ampio sistema di assistenza sanitaria negli Stati Uniti. Nella popolazione con ciclo vaccinale completo si è riscontrata una efficacia nel prevenire l’infezione da SARS-CoV-2 del 73% e una prevenzione dell’ospedalizzazione del 90%. Si è evidenziata inoltre una riduzione dell’efficacia nei confronti dell’infezione nel corso dei 6 mesi oggetto di studio, passando dall’88% nel primo mese al 47% dopo 5 mesi. Dato aggiuntivo è quello riguardante la protezione nei confronti della variante delta di SARS-CoV-2, pari al 93% il primo mese dopo la conclusione del ciclo vaccinale, fino ad arrivare ad un 53% dopo 5 mesi (vs 97% al primo mese e 67% a 5 mesi per le restanti varianti). Tali conclusioni sembrano suggerire che una dose booster dello stesso vaccino potrebbe essere efficace nei confronti della predominante variante delta, la cui diffusione sarebbe da imputare ad un calo dell’immunità specifica nel tempo piuttosto che ai meccanismi del virus di aggirare la protezione vaccinale.

COMMENTO : Conferma autorevolmente quanto già girava in letteratura, cioè è la perdità di immunità non la presenza di variante delta di per sè a far diminuire di effettività la vaccinazione anti-COVID-19. Dà quindi un razionale solido alla terza dose. Dimostra anche che fino almeno ai 6 mesi, la protezione contro l’ospedalizzazione e la malattia

Tao K. et al.

Nature Review Genetics

The biological and clinical significance of emerging SARS-CoV-2 variants

Nature Review Genetics,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447121/pdf/41576_2021_Article_408.pdf

CONTENUTO: Questa review aggiornata passa in rassegna le quattro varianti di SARS-CoV-2 (Alpha, Beta, Gamma e Delta) emerse negli ultimi mesi, associate ad una maggiore trasmissibilità, aumento del rischio di reinfezione e/o riduzione dell'efficacia del vaccino.

COMMENTO : un buon aritcolo sulla circolazione delle varianti in Africa e della necessità di studiarle anche dal punto di vista epidemiologico e di laboratorio.

Lopez Bernal

Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant

NEJM, July 2021; DOI: 10.1056/NEJMoa2108891

COMMENTO:

BACKGROUND

The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.

METHODS

We used a test-negative case–control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status.

RESULTS

Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant.

CONCLUSIONS

Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations.

Vasireddy D et al

Review of COVID-19 Variants and COVID-19 Vaccine Efficacy: What the Clinician Should Know?

J Clin Med Res, June 2021; DOI: 10.14740/jocmr4518 

COMMENTO: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta coronavirus that belongs to the Coronaviridae family. SARS-CoV-2 is an enveloped spherical-shaped virus. The ribonucleic acid (RNA) is oriented in a 5'-3'direction which makes it a positive sense RNA virus, and the RNA can be read directly as a messenger RNA. The nonstructural protein 14 (nsp14) has proofreading activity which allows the rate of mutations to stay low. A change in the genetic sequence is called a mutation. Genomes that differ from each other in genetic sequence are called variants. Variants are the result of mutations but differ from each other by one or more mutations. When a phenotypic difference is demonstrated among the variants, they are called strains. Viruses constantly change in two different ways, antigenic drift and antigenic shift. SARS-CoV-2 genome is also prone to various mutations that led to antigenic drift resulting in escape from immune recognition. The Center of Disease Control and Prevention (CDC) updates the variant strains in the different classes. The classes are variant of interest, variant of concern and variant of high consequence. The current variants included in the variant of interest by the USA are: B.1.526, B.1.525, and P.2; and those included in the variant of concern by the USA are B.1.1.7, P.1, B.1.351, B.1.427, and B.1.429. The double and triple mutant variants first reported in India have resulted in a massive increase in the number of cases. Emerging variants not only result in increased transmissibility, morbidity and mortality, but also have the ability to evade detection by existing or currently available diagnostic tests, which can potentially delay the diagnosis and treatment, exhibit decreased susceptibility to treatment including antivirals, monoclonal antibodies and convalescent plasma, possess the ability to cause reinfection in previously infected and recovered individuals, and vaccine breakthrough cases in fully vaccinated individuals. Hence, continuation of precautionary measures, genomic surveillance and vaccination plays an important role in the prevention of spread, early identification of variants, prevention of mutations and viral replication, respectively.

Bates TA et al

Age-Dependent Neutralization of SARS-CoV-2 and P.1 Variant by Vaccine Immune Serum Samples

JAMA, July 2021; DOI: 10.1001/jama.2021.11656

COMMENTO: Vaccination with 2 doses of the BNT162b2 vaccine (Pfizer-BioNTech) reportedly provides 95% protection from COVID-19.1 However, patient age is known to contribute to the risk of COVID-19 incidence and severity.2 We examined the relationship between age and neutralizing antibody titers against the early SARS-CoV-2 USA-WA1/2020 strain and the P.1 variant of concern after 2 doses of the BNT162b2 vaccine.

Lopez Bernal J et al

Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant

NEJM, July 2021;  DOI: 10.1056/NEJMoa2108891

COMMENTO: BACKGROUND

The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.

METHODS

We used a test-negative case–control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status.

RESULTS

Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant.

CONCLUSIONS

Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations.

Lazarevic I et al

Immune Evasion of SARS-CoV-2 Emerging Variants: What Have We Learnt So Far?

Viruses, June 2021;  DOI: 10.3390/v13071192

COMMENTO:  Despite the slow evolutionary rate of SARS-CoV-2 relative to other RNA viruses, its massive and rapid transmission during the COVID-19 pandemic has enabled it to acquire significant genetic diversity since it first entered the human population. This led to the emergence of numerous variants, some of them recently being labeled “variants of concern” (VOC), due to their potential impact on transmission, morbidity/mortality, and the evasion of neutralization by antibodies elicited by infection, vaccination, or therapeutic application. The potential to evade neutralization is the result of diversity of the target epitopes generated by the accumulation of mutations in the spike protein. While three globally recognized VOCs (Alpha or B.1.1.7, Beta or B.1.351, and Gamma or P.1) remain sensitive to neutralization albeit at reduced levels by the sera of convalescent individuals and recipients of several anti-COVID19 vaccines, the effect of spike variability is much more evident on the neutralization capacity of monoclonal antibodies. The newly recognized VOC Delta or lineage B.1.617.2, as well as locally accepted VOCs (Epsilon or B.1.427/29-US and B1.1.7 with the E484K-UK) are indicating the necessity of close monitoring of new variants on a global level. The VOCs characteristics, their mutational patterns, and the role mutations play in immune evasion are summarized in this review.

Gan HH et al

Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface can Identify High-Affinity Variants Asso-ciated with Increased Transmissibility

JMB, July 2021; DOI: 10.1016/j.jmb.2021.167051

COMMENTO: The COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the func- tional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike pro-

tein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 inter- face and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are tructurally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation

in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S477N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S477N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional

modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.

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: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine rollout has coincided with the spread of variants of concern. We investigated whether 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 messenger RNA vaccine BNT162b2 in health care 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 the spike protein, and neutralizing antibodies effective against variants 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.

Krause P et al

SARS-CoV-2 Variants and Vaccines

NEJM, June 2021 ; DOI: 10.1056/NEJMsr2105280

COMMENTO: Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

Pascarella S et al

SARS-CoV-2 B.1.617 Indian variants: are electrostatic potential changes responsible for a higher transmission rate?

BioRXiv, june 2021, doi.org/10.1101/2021.06.08.445535

COMMENTO : Lineage B.1.617+, also known as G/452R.V3, is a recently described SARS-CoV-2 variant under investigation (VUI) firstly identified in October 2020 in India. As of May 2021, three sublineages labelled as B.1.617.1, B.1.617.2 and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R and P681R. Here we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the Receptor Binding Domain (RBD) of the spike protein. Enhanced RBD-EP is particularly noticeable in the B.1.617.2 sublineage, which shows multiple replacements of neutral or negatively-charged amino acids with positively-charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+RBD and the negatively-charged ACE2 thus conferring a potential increase in the virus transmission.

Sheikh A et al

SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness

The Lancet, June 2021; doi.org/10.1016/S0140-6736(21)01358-1

COMMENTO: In summary, we show that the Delta VOC in Scotland was found mainly in younger, more affluent groups. Risk of COVID-19 hospital admission was approximately doubled in those with the Delta VOC when compared to the Alpha VOC, with risk of admission particularly increased in those with five or more relevant comorbidities. Both the Oxford–AstraZeneca and Pfizer–BioNTech COVID-19 vaccines were effective in reducing the risk of SARS-CoV-2 infection and COVID-19 hospitalisation in people with the Delta VOC, but these effects on infection appeared to be diminished when compared to those with the Alpha VOC. We had insufficient numbers of hospital admissions to compare between vaccines in this respect. The Oxford–AstraZeneca vaccine appeared less effective than the Pfizer–BioNTech vaccine in preventing SARS-CoV-2 infection in those with the Delta VOC. Given the observational nature of these data, estimates of vaccine effectiveness need to be interpreted with caution.

Nyberg T et al

Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis

BMJ, June 2021; doi.org/10.1136/bmj.n1412 

COMMENTO: Objective To evaluate the relation between diagnosis of covid-19 with SARS-CoV-2 variant B.1.1.7 (also known as variant of concern 202012/01) and the risk of hospital admission compared with diagnosis with wild-type SARS-CoV-2 variants.

Design Retrospective cohort analysis.

Setting Community based SARS-CoV-2 testing in England, individually linked with hospital admission data.

Participants 839 278 patients with laboratory confirmed covid-19, of whom 36 233 had been admitted to hospital within 14 days, tested between 23 November 2020 and 31 January 2021 and analysed at a laboratory with an available TaqPath assay that enables assessment of S-gene target failure (SGTF), a proxy test for the B.1.1.7 variant. Patient data were stratified by age, sex, ethnicity, deprivation, region of residence, and date of positive test.

Main outcome measures Hospital admission between one and 14 days after the first positive SARS-CoV-2 test.

Results 27 710 (4.7%) of 592 409 patients with SGTF variants and 8523 (3.5%) of 246 869 patients without SGTF variants had been admitted to hospital within one to 14 days. The stratum adjusted hazard ratio of hospital admission was 1.52 (95% confidence interval 1.47 to 1.57) for patients with covid-19 infected with SGTF variants, compared with those infected with non-SGTF variants. The effect was modified by age (P<0.001), with hazard ratios of 0.93-1.21 in patients younger than 20 years with versus without SGTF variants, 1.29 in those aged 20-29, and 1.45-1.65 in those aged ≥30 years. The adjusted absolute risk of hospital admission within 14 days was 4.7% (95% confidence interval 4.6% to 4.7%) for patients with SGTF variants and 3.5% (3.4% to 3.5%) for those with non-SGTF variants.

Conclusions The results suggest that the risk of hospital admission is higher for people infected with the B.1.1.7 variant compared with wild-type SARS-CoV-2, likely reflecting a more severe disease. The higher severity may be specific to adults older than 30 years.

Shen X et al

Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351

NEJM, June 2021; DOI: 10.1056/NEJMc2103740

COMMENTO: The neutralizing activity of all serum samples was tested against the B.1.429 variant and a variant of concern that first emerged in South Africa (B.1.351, also called 20H/501Y.V2). We compared this neutralizing activity to the activity the serum samples exhibited against the prototypical D614G variant. As compared with the D614G variant, we found that B.1.429 was approximately 2 to 3 times less sensitive to neutralization by convalescent serum and by serum samples obtained from vaccinated persons, whereas B.1.351 was approximately 9 to 14 times less sensitive to neutralization.

Yuan M et al

Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Science, May 2021 ; DOI: 10.1126/science.abh1139

COMMENTO : Neutralizing antibodies (nAbs) elicited against the receptor-binding site (RBS) of the spike protein of wild-type SARS-CoV-2 are generally less effective against recent variants of concern. RBS residues E484, K417 and N501 are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on ACE2 binding and K417N and E484K mutations on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternate binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.

Istituto Superiore di Sanità

Prevalenza e distribuzione delle varianti del virus SARS-CoV-2 di interesse per la sanità pubblica in Italia

https://www.iss.it/news/-/asset_publisher/gJ3hFqMQsykM/content/id/5746202

COMMENTO: La variante del virus SARS-CoV-2 prevalentemente circolante in Italia è la variante VOC-202012/01 (cosiddetta variante UK) - lignaggio B.1.1.7, caratterizzata da una elevata trasmissibilità.

Il lignaggio P.1 (cosiddetta variante brasiliana) ha una diffusione maggiore in alcune Regioni italiane.

La prevalenza di altre varianti del virus SARS-CoV-2 di interesse per la sanità pubblica è <1% nel nostro paese, ad eccezione della cosiddetta variante nigeriana (1,17%).

È necessario continuare a monitorare con grande attenzione la circolazione delle varianti del virus SARS-CoV-2 ed in particolare la presenza di mutazioni riconducibili ad una maggiore trasmissibilità e/o associate ad un potenziale immune escape.

Colson P et al

Spreading of a new SARS-CoV-2 N501Y spike variant in a new lineage

Clinical Microbiology and Infection, May 2021; doi.org/10.1016/j.cmi.2021.05.006

COMMENTO : Objectives : Our surveillance of the SARS-CoV-2 genomicepidemiologyled us to detectseveral variants sincesummer 2020. We report the recent spread of a new SARS-CoV-2 spike 501Y variant.

Methods : SARS-CoV-2 sequencesobtainedfromhumannasopharyngealsamples by Illumina next-generation sequencing were analyzed using Nextclade and an in-house Python script and comparedusingBLASTn to the GISAID database. Phylogeny was performed using the IQ-TREE software.

Results : We identified that SARS-CoV-2 genomes from four patients diagnosed in our institute harbored a new set of amino acid substitutions including L18F;L452R;N501Y;A653V;H655Y;D796Y;G1219V±Q677H. These spike N501Y genomes are the first of Nextstrain clade 19B. Weobtained partial spike genesequences of thisgenotype for an additional 43 patients. All patients infectedwiththisgenotypewerediagnosedsincemid-January 2021. Wedetected 42 othergenomes of thisgenotype in GISAID, which were obtained from samples collected in December 2020 in four cases and in 2021 in 38 cases. The 89 sequences obtained in our institute or other laboratories originated from the Comoros archipelago, Western European countries (mostlymetropolitan France), Turkey and Nigeria.

Conclusion : These findings warrant further studies to investigate the spread, epidemiological and clinical features, and sensitivity to immune responses of this variant.

Clark SA et al

SARS-CoV-2 evolution in an immunecompromised host reveals shared neutralization escape mechanisms

Cell, May 2021; doi.org/10.1016/j.cell.2021.03.027

COMMENTO : Many individuals mountn early identical antibody responses to SARS-CoV-2. To gain insight into how the viral spike (S) protein receptor-binding domain (RBD) might evolve in response to common antibody responses, we studied mutations occurring during virus evolution in a persistently infected immuno compromised individual. We use antibodyFab/RBD structures to predict, and pseudo types to confirm, that mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies we isolated from a healthy COVID-19 convalescent donor. Resistance extends to the polyclonal serum immunoglobulins of four out of four healthy convalescent donors we tested and to monoclonal antibodies in clinical use. Wefurther show that affinity maturation is unimportant for wild-type virus neutralization but iscritical to neutralization breadth. Because the mutations we studied for eshadowed emerging variants that are now circulating across the globe, our results have implications to the long-termefficacy of S-directed counter measures.

Chodick G et al

The effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world data

CID, May 2021; doi.org/10.1093/cid/ciab438

COMMENTO : Background : COVID-19 mRNA vaccines were shown to be highly efficacious in preventing the disease in randomized controlled trials; nonetheless, evidence on the real-world effectiveness of this vaccine is limited. Study objective was to evaluate the effectivenessof BNT162b2 vaccine in preventing SARS-CoV-2 infection and COVID-19-related hospitalization and mortality.

Methods : This historical cohort studyincluded members of a large health provider in Israel that were vaccinated with at least one dose of BNT162b2. The primary outcome was incidence rate of a SARS-CoV-2 infection confirmed with rt-PCR, between 7 to 27 days after second dose (protection-period), as compared to days 1 to 7 after the first dose, where no protection by the vaccine is assumed (reference-period).

Results : Data of 1,178,597 individuals vaccinated with BNT162b2 were analyzed (mean age 47.7 years [SD=18.1], 48.4% males) of whom 872,454 (74.0%) reached the protection period. Overall, 4514 infections occurred during the reference period compared to 728 during the protection period, yielding a weighted mean daily incidence of 54.8 per 100,000 (95%CI: 26.1-115.0 per 100,000) and 5.4 per 100,000 (95%CI: 3.5-8.4 per 100,000), respectively. The vaccine effectiveness in preventing infection was 90% (95%CI:79%- 95%) and 94% (95%CI:88%-97%) against COVID-19. Among immune suppressed patients, vaccine effectiveness against infection was 71% (95%CI:37%-87%). The adjusted hazard ratios for hospitalization in those infected were 0.82 (95%CI:0.36-1.88), 0.45 (95%CI:0.23-0.90), and 0.56 (95%CI:0.36-0.89) in the age groups 16-44, 45-64 and 75 and above, respectively.

Conclusions : The effectiveness of the BNT162b2 vaccine is comparable to the one reported in the phase III clinical trial.

Bartolini B

The newly introduced SARS-CoV-2 variant A222V is rapidly spreading in Lazio region, Italy

medRXiv – preprint, November 2020; doi.org/10.1101/2020.11.28.20237016

COMMENTO : A new SARS-CoV-2 clade (GV) characterized by S substitution A222V, first reported from Spain in March, is rapidly spreading across Europe. To establish the A222V variant involvement in the infection rise in Italy, all GISAID sequences from Italy and those from our Laboratory (Lazio) in the period June-October were analysed. A222V, first recognized in August, represents 11.2% of sequences in thisperiod, reaching 100% of autochthonous sequences in October, supporting increased GV circulation in Italy.

Alpert T et al

Early introductions and transmission of SARS-CoV-2 variant B.1.1.7 in the United States

Cell, May 2021; doi.org/10.1016/j.cell.2021.03.061

COMMENTO : The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2,500 COVID-19 cases associated with this variant have been detected in the United States (US) since December 2020, but the extent of establishment is relatively unknown. Usingtravel, genomic, and diagnostic data, we highlight that the primary ports of entry for B.1.1.7 in the US were in New York, California, and Florida. Furthermore, we found evidence for manyindependent B.1.1.7 establishments starting in earlyDecember 2020, followed by interstate spread by the end of the month. Finally, weprojectthat B.1.1.7 willbe the dominant lineage in many states by mid- to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to beenhanced to better inform the public health response.

Liu Y et al

BNT162b2-Elicited Neutralization against New SARS-CoV-2 Spike Variants

NEJM, May 2021; DOI: 10.1056/NEJMc2106083             

COMMENTO : All the serum samples neutralized USA-WA1/2020 and the variant viruses at titers of 1:80 or higher. The geometric mean neutralizing titers against USA-WA1/2020, B.1.429-spike, B.1.526-spike, and B.1.1.7-spike+E484K viruses were 520, 394, 469, and 597, respectively (Figure 1 and Table S1). Thus, as compared with neutralization of USA-WA1/2020, neutralization of B.1.1.7-spike+E484K and B.1.526-spike viruses was approximately equivalent, and neutralization of B.1.429-spike was slightlylower, possibly reflecting  the influence of the L452R mutation, which appears to be under positive selective pressure.3 Our results suggest that, as compared with the previously reported neutralization of B.1.1.7-spike, the additional E484K mutation, which is also found in the B.1.351 and B.1.526 lineages, caused little compromise to neutralization.

Feder KA et al

Linked Clusters of SARS-CoV-2 Variant B.1.351 — Maryland, January–February 2021

Morbidity and Mortality Weekly Report,

https://www.cdc.gov/mmwr/volumes/70/wr/mm7017a5.htm#suggestedcitation

COMMENTO : What is already known about this topic?

In January 2021, a SARS-CoV-2 specimen from a Maryland resident was determined to be the B.1.351 variant, first identified in South Africa. The SARS-CoV-2 B.1.351 variant might elicit a reduced neutralizing antibody response.

What is added by this report?

Investigation identified two linked clusters of SARS-CoV-2 infection, comprising 17 total patients (two were hospitalized and one died) who did not report recent travel. Four patients’ specimens were sequenced; all were the B.1.351 variant.

What are the implications for public health practice?

These were the first identified clusters of B.1.351 in the United States with no link to travel. Completed contact investigations, expanded genetic sequencing, and universal prevention strategies, including vaccination, masking, and distance, might prevent the spread of SARS-CoV-2 variants of concern, including B.1.351.

Hacisuleyman E et al

Vaccine Breakthrough Infections with SARS-CoV-2 Variants

NEJM, April 2021 ; DOI: 10.1056/NEJMoa2105000

COMMENTO : Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of clinical concern. In a cohort of 417 persons who had received the second dose of BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine at least 2 weeks previously, we identified 2 women with vaccine breakthrough infection. Despite evidence of vaccine efficacy in both women, symptoms of coronavirus disease 2019 developed, and they tested positive for SARS-CoV-2 by polymerase-chain-reaction testing. Viral sequencing revealed variants of likely clinical importance, including E484K in 1 woman and three mutations (T95I, del142–144, and D614G) in both. These observations indicate a potential risk of illness after successful vaccination and subsequent infection with variant virus, and they provide support for continued efforts to prevent and diagnose infection and to characterize variants in vaccinated persons.

Faria NR et al

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Science, April 2021; DOI: 10.1126/science.abh2644

COMMENTO : Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7–2.4-fold more transmissible, and that previous (non-P.1) infection provides 54–79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

Betton M et al

Sera neutralizing activities against SARS-CoV-2 and multiple variants six month after hospitalization for COVID-19

Clinical Infectious Diseases, April 2021; doi.org/10.1093/cid/ciab308

COMMENTO : Background : Humoral response to SARS-CoV-2 occurs within the first weeks after COVID-19. Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution overtime after COVID-19 as well as efficiency against novel variants are however poorly characterized.

Methods : In this prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3- and 6-months post-infection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-Spike (S) and anti-Nucleocapsid (NP) IgG.

Findings : Levels of sero-neutralization and IgG rates against the ancestral strain decreased significantly over time. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect against SARS-CoV-2. IgG levels correlated with sero-neutralization and this correlation was stronger for anti-S than for anti-NP antibodies. The level of sero-neutralization quantified at 6 months correlated with markers of initial severity, notably admission in intensive care units and the need for mechanical invasive ventilation. In addition, sera collected at 6 months were tested against multiple SARS-CoV-2 variants and showed efficient neutralizing effects against D614G, B.1.1.7 and P.1 variants but a significantly weaker activity against B.1.351 variant.

Interpretation : Decrease of IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Our results indicate a sustained humoral response against the ancestral strain and the D614G, B.1.1.7 and P.1 variants for at least 6 months in patients previously hospitalized for COVID-19. A weaker protection was however observed for the B.1.351 variant.

Frampton D et al

Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study

The Lancet, April 2021; doi.org/10.1016/S1473-3099(21)00170-5

COMMENTO : Background : Emergence of variants with specific mutations in key epitopes in the spike protein of SARS-CoV-2 raises concerns pertinent to mass vaccination campaigns and use of monoclonal antibodies. We aimed to describe the emergence of the B.1.1.7 variant of concern (VOC), including virological characteristics and clinical severity in contemporaneous patients with and without the variant.

Methods : In this cohort study, samples positive for SARS-CoV-2 on PCR that were collected from Nov 9, 2020, for patients acutely admitted to one of two hospitals on or before Dec 20, 2020, in London, UK, were sequenced and analysed for the presence of VOC-defining mutations. We fitted Poisson regression models to investigate the association between B.1.1.7 infection and severe disease (defined as point 6 or higher on the WHO ordinal scale within 14 days of symptoms or positive test) and death within 28 days of a positive test and did supplementary genomic analyses in a cohort of chronically shedding patients and in a cohort of remdesivir-treated patients. Viral load was compared by proxy, using PCR cycle threshold values and sequencing read depths.

Findings : Of 496 patients with samples positive for SARS-CoV-2 on PCR and who met inclusion criteria, 341 had samples that could be sequenced. 198 (58%) of 341 had B.1.1.7 infection and 143 (42%) had non-B.1.1.7 infection. We found no evidence of an association between severe disease and death and lineage (B.1.1.7 vs non-B.1.1.7) in unadjusted analyses (prevalence ratio [PR] 0·97 [95% CI 0·72–1·31]), or in analyses adjusted for hospital, sex, age, comorbidities, and ethnicity (adjusted PR 1·02 [0·76–1·38]). We detected no B.1.1.7 VOC-defining mutations in 123 chronically shedding immunocompromised patients or in 32 remdesivir-treated patients. Viral load by proxy was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold value (mean 28·8 [SD 4·7] vs 32·0 [4·8]; p=0·0085) and genomic read depth (1280 [1004] vs 831 [682]; p=0·0011).

Interpretation : Emerging evidence exists of increased transmissibility of B.1.1.7, and we found increased virus load by proxy for B.1.1.7 in our data. We did not identify an association of the variant with severe disease in this hospitalised cohort.

Ong SWX et al

Lack of detail in population-level data impedes analysis of SARS-CoV-2 variants of concern and clinical outcomes

The Lancet, April 2021; doi.org/10.1016/S1473-3099(21)00201-2

COMMENTO : Genetic drift and selection pressures (in particular with passive antibody treatments and vaccination) will continue to engender changes in SARS-CoV-2 and might result in the emergence of variants of high consequence—variants that are more virulent, escape from host immunity, or are resistant to treatment. Active, timely, and broad-based genomic surveillance is crucial for their early detection. But careful epidemiologic and clinical assessment, coupled with a healthy scepticism, is important when assessing claims of the effect of these variants.

Lustig Y et al

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

NEJM, April 2021; DOI: 10.1056/NEJMc2104036

COMMENTO: Samples obtained at the first time point had neutralizing activity against the original virus and the B.1.1.7 and P.1 variants, with geometric mean titers of 456, 256, and 71, respectively, but had little or no neutralizing activity against the B.1.351 variant, with a geometric mean titer of 8. At the second time point, geometric mean titers were 81, 40, 36, and 7 for the original virus and the B.1.1.7, P.1, and B.1.351 variants, respectively. Of note, at the third time point, geometric mean titers were 9195, 8192, 2896, and 1625 for the original virus and the B.1.1.7, P.1, and B.1.351 variants, respectively — that is, the titers after vaccination were 114, 203, 81, and 228 times as high as the titers immediately before vaccination (Figure 1 and Table S2).

Shen X et al

Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351

NEJM, April 2021; DOI: 10.1056/NEJMc2103740

COMMENTO: The neutralizing activity of all serum samples was tested against the B.1.429 variant and a variant of concernthat first emerged in South Africa (B.1.351, alsocalled 20H/501Y.V2). We compared this neutralizing activity to the activity the serum samples exhibited against the prototypical D614G variant. As comparedwith the D614G variant, wefoundthat B.1.429 was approximately 2 to 3 times less sensitive to neutralization by convalescent serum and by serum samples obtained from vaccinated persons, where as B.1.351 was approximately 9 to 14 times less sensitive to neutralization.

Cele S et al

Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma

Nature, March 2021; doi.org/10.1038/s41586-021-03471-w

COMMENTO : SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations and may reduce the efficacy of current vaccines targeting the spike glycoprotein. Here, using a live virus neutralization assay (LVNA), we compared neutralization of a non-VOC variant versus the 501Y.V2 variant using plasma collected from adults hospitalized with COVID-19 from two South African infection waves, with the second wave dominated by 501Y.V2 infections. Sequencing demonstrated that infections in first wave plasma donors were with viruses harbouring none of the 501Y.V2-defining mutations, except for one with the E484K mutation in the receptor binding domain. 501Y.V2 virus was effectively neutralized by plasma from second wave infections and first wave virus was effectively neutralized by first wave plasma. In cross-neutralization, 501Y.V2 virus was poorly neutralized by first wave plasma, with a 15.1-fold drop relative to 501Y.V2 neutralization by second wave plasma across participants. In contrast, second wave plasma cross-neutralization of first wave virus was more effective, showing only a 2.3-fold decline relative to first wave plasma neutralization of first wave virus. While we only tested one plasma elicited by E484K alone, this potently neutralized both variants. The observed effective neutralization of first wave virus by 501Y.V2 infection elicited plasma provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.

Ufficio Stampa Istituto Superiore di Sanità                                                                                           

Comunicato Stampa N° 20/2021 Covid-19: in Italia la ‘variante inglese’ all’86,7% Il 4,0% dei casi con quella ‘brasiliana’

https://www.iss.it/web/guest/primo-piano/-/asset_publisher/3f4alMwzN1Z7/content/id/5672623

COMMENTO : In Italia al 18 marzo scorso la prevalenza della cosiddetta ‘variante inglese’ del virus Sars-CoV-2 era del 86,7%, con valori oscillanti tra le singole regioni tra il 63,3% e il 100%. Per quella ‘brasiliana’ la prevalenza era del 4,0% (0%-32,0%), mentre le altre monitorate sono sotto lo 0,5%. La stima viene dalla nuova indagine rapida condotta dall’Iss e dal Ministero della Salute insieme ai laboratori regionali e alla Fondazione Bruno Kessler, che fa seguito a quelle diffuse nelle scorse settimane da cui era emersa una maggior trasmissibilità per la variante ‘inglese’ del 37%.

Emary KRW et al

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial

The Lancet, March 2021, doi.org/10.1016/S0140-6736(21)00628-0

COMMENTO : Background : A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant.

Methods : Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 − relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

Findings : Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18–55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2–11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6–84·5) for B.1.1.7 and 81·5% (67·9–89·4) for non-B.1.1.7 lineages.

Interpretation : ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2.

Abdool Karim SS et al

New SARS-CoV-2 Variants — Clinical, Public Health, and Vaccine Implications

NEJM, March 2021; DOI: 10.1056/NEJMc2100362

COMMENTO : Across the world, there are multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). SARS-CoV-2 variants have been classified by the Centers for Disease Control and Prevention (CDC) as variants of interest, variants of concern, and variants of high consequence. Three new variants1 that have rapidly become dominant within their countries have aroused concerns: B.1.1.7 (also known as VOC-202012/01), 501Y.V2 (B.1.351), and P.1 (B.1.1.28.1).

Davies NG et al

Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7

Nature, March 2021 ; doi.org/10.1038/s41586-021-03426-1

COMMENTO : SARS-CoV-2 lineage B.1.1.7, a variant first detected in the UK in September 20201, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than preexisting variants, but have not identified whether it leads to any change in disease severity2. Here we analyse a dataset linking 2,245,263 positive SARS-CoV-2 community tests and 17,452 COVID-19 deaths in England from 1 September 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because of mutations in this lineage preventing PCR amplification of the spike gene target (S gene target failure, SGTF). Based on 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% CI 39–72%) higher after adjustment for age, sex, ethnicity, deprivation, care home residence, local authority of residence and test date. This corresponds to the absolute risk of death for a 55–69-year-old male increasing from 0.6% to 0.9% (95% CI 0.8–1.0%) within 28 days after a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate a 61% (42–82%) higher hazard of death associated with B.1.1.7. Our analysis suggests that B.1.1.7 is not only more transmissible than preexisting SARS-CoV-2 variants, but may also cause more severe illness.

Wu K et al

Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine

NEJM, March 2021; DOI: 10.1056/NEJMc2102179

COMMENTO: Protection conferred by the mRNA-1273 vaccine against the P.1, B.1.427/B.1.429, and B.1.351 variants remains to be determined. Our findings underscore the importance of continued viral surveillance and evaluation of vaccine efficacy against new variants and may help to facilitate the establishment of correlates of protection in both nonhuman primates and humans.

Tse H et al

Emergence of a Severe Acute Respiratory Syndrome Coronavirus 2 virus variant with novel genomic architecture in Hong Kong

Clinical Infectious Diseases, March 2021; doi: 10.1093/cid/ciab198

COMMENTO : Throughout the COVID-19 pandemic, divergent SARS-CoV-2 lineages have emerged continuously, mostly through the genomic accumulation of substitutions. We report the discovery of a SARS-CoV-2 variant with a novel genomic architecture characterized by absent ORF7a, ORF7b and ORF8, and a C-terminally modified ORF6 product resulting from partial 5'-UTR duplication and transposition.

Tegally H et al

Emergence of a SARS-CoV-2 variant of concern with mutations in spike glycoprotein

Nature, March 2021; doi.org/10.1038/s41586-021-03402-9

COMMENTO : Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for signifcant virus evolution. Here, we describe a new SARS-CoV-2 lineage (501Y.V2) characterised by eight lineage-defning mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) that may have functional signifcance . This lineage was identifed in South Africa after the frst epidemic wave in a severely afected metropolitan area, Nelson Mandela Bay, located on the coast of the Eastern Cape Province. This lineage spread rapidly, becoming dominant in the Eastern Cape, Western Cape and KwaZulu-Natal Provinces within weeks. Whilst the full signifcance of the mutations is yet to be determined, the genomic data, showing the rapid expansion and displacement of other lineages in multiple regions, suggest that this lineage is associated with a selection advantage, most plausibly as a result of increased transmissibility or immune escape.

Nakamichi K et al

Hospitalization and mortality associated with SARS-CoV-2 viral clades in COVID-19

Scientific Reports, February 2021; doi.org/10.1038/s41598-021-82850-9

COMMENTO : The COVID-19 epidemic of 2019-20 is due to the novel coronavirus SARS-CoV-2. Following first case description in December, 2019 this virus has infected over 10 million individuals and resulted in at least 500,000 deaths world-wide. The virus is undergoing rapid mutation, with two major clades of sequence variants emerging. This study sought to determine whether SARS-CoV-2 sequence variants are associated with differing outcomes among COVID-19 patients in a single medical system. Whole genome SARS-CoV-2 RNA sequence was obtained from isolates collected from patients registered in the University of Washington Medicine health system between March 1 and April 15, 2020. Demographic and baseline clinical characteristics of patients and their outcome data including their hospitalization and death were collected. Statistical and machine learning models were applied to determine if viral genetic variants were associated with specific outcomes of hospitalization or death. Full length SARS-CoV-2 sequence was obtained 190 subjects with clinical outcome data. 35 (18.4%) were hospitalized and 14 (7.4%) died from complications of infection. A total of 289 single nucleotide variants were identified. Clustering methods demonstrated two major viral clades, which could be readily distinguished by 12 polymorphisms in 5 genes. A trend toward higher rates of hospitalization of patients with Clade 2 infections was observed (p = 0.06, Fisher's exact). Machine learning models utilizing patient demographics and co-morbidities achieved area-under-the-curve (AUC) values of 0.93 for predicting hospitalization. Addition of viral clade or sequence information did not significantly improve models for outcome prediction. In summary, SARS-CoV-2 shows substantial sequence diversity in a community-based sample. Two dominant clades of virus are in circulation. Among patients sufficiently ill to warrant testing for virus, no significant difference in outcomes of hospitalization or death could be discerned between clades in this sample. Major risk factors for hospitalization and death for either major clade of virus include patient age and comorbid conditions.

Nonaka CKV et al

Genomic Evidence of SARS-CoV-2 Reinfection Involving E484K Spike Mutation, Brazil

Emerging Infectious Diseases, February 2021; DOI: 10.3201/eid2705.210191

COMMENTO : Uncertainty remains about how long the protective immune responses against severe acute respiratory syndrome coronavirus 2 persists, and suspected reinfection in recovered patients has been reported. We describe a case of reinfection from distinct virus lineages in Brazil harboring the E484K mutation, a variant associated with escape from neutralizing antibodies.

Plante JA et al

The Variant Gambit: COVID’s Next Move

Cell Host and Microbe, March 2021 ; doi.org/10.1016/j.chom.2021.02.020

COMMENTO : Over a year after its emergence, COVID-19, the disease caused by SARS-CoV-2, continues to plague the world and dominate our daily lives. Even with the development of effective vaccines, this coronavirus pandemic continues to cause a fervor with the identification of major new variants hailing from the United Kingdom, South Africa, Brazil, and California. Coupled with worries over a distinct mink strain that has caused human infections and potential for further mutations, SARS-CoV-2 variants bring concerns for increased spread and escape from both vaccine and natural infection immunity. Here, we outline factors driving SARS-CoV-2 variant evolution, explore the potential impact of specific mutations, examine the risk of further mutations, and consider the experimental studies needed to understand the threat these variants pose.

Davies NG et al

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England

Science, March 2021 ; DOI: 10.1126/science.abg3055

COMMENTO: A novel SARS-CoV-2 variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in November 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modelling approaches, we estimate that this variant has a 43–90% (range of 95% credible intervals 38–130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalisations and deaths across England in 2021 will exceed those in 2020. Concerningly, VOC 202012/01 has spread globally and exhibits a similar transmission increase (59–74%) in Denmark, Switzerland, and the United States.

Li Q et al

No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants

Cell, February 2021; doi.org/10.1016/j.cell.2021.02.042

COMMENTO : The 501Y.V2 variants of SARS-CoV-2 containing multiple mutations in Spike are now dominant in South Africa and are rapidly spreading to other countries. Here, experiments with 18 pseudotyped viruses showed that the 501Y.V2 variants do not confer increased infectivity in multiple cell types except for murine ACE2-overexpressing cells, where a substantial increase in infectivity was observed. Notably, the susceptibility of the 501Y.V2 variants to 12 of 17 neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced for these variants. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of Spike. The enhanced infectivity in murine ACE2-overexpressing cells suggests the possibility of spillover of the 501Y.V2 variants to mice. Moreover, the neutralization resistance we detected for the 501Y.V2 variants suggests the potential for compromised efficacy of monoclonal antibodies and vaccines.

New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG)

NERVTAG: Update note on B.1.1.7 severity, 11 February 2021

https://www.gov.uk/government/publications/nervtag-update-note-on-b117-severity-11-february-2021 , February 2021

COMMENTO : On Thursday, 21st January, NERVTAG presentedevidence to SAGE of increaseddiseaseseverity in people infectedwith variant of concern (VOC) B.1.1.7 comparedto people infectedwith non-VOC virus variants. In that report itwasstatedthat ‘datawill accrue in comingweeks, at which time the analyses willbecome more definitive’.Herewe report updated and additional analyses, whichtogetherstrengthen theearlierfinding of increaseddiseaseseverity in people infectedwith VOC B.1.1.7compared to other virus variants […] Based on these analyses, itislikelythat infection with VOC B.1.1.7 isassociatedwith an increasedrisk of hospitalisation and deathcompared toinfection with non-VOC viruses.It shouldbenotedthat the absoluterisk of death per infection remainslow.

Maggi F et al

Imported SARS-COV-2 Variant P.1 Detected in Traveler Returning from Brazil to Italy

Emerging Infectious Diseases, February 2021; DOI: 10.3201/eid2704.210183

COMMENTO: We report an imported case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant P.1 detected in an asymptomatic traveler whoarrived in Italy on an indirect flight from Brazil. This case shows the risk for introduction of SARS-CoV-2 variants from indirect flights and the need for continued SARS-CoV-2 surveillance.

Kissler SM et al

Densely sampled viral trajectoriessuggest longer duration of acuteinfection with B.1.1.7 variantrelative to non-B.1.1.7 SARS-CoV-2

Harvard Library – preprint, February 2021; doi.org/10.1101/2021.02.16.21251535

COMMENTO: To test whether acute infection with B.1.1.7 isassociatedwithhigher or more sustainednasopharyngeal viral concentrations, weassessed longitudinal PCR tests performed in a cohort of 65 individualsinfectedwith SARS-CoV-2 undergoingdaily surveillance testing, includingseven in fectedwith B.1.1.7. For individualsinfectedwith B.1.1.7, the mean duration of the proliferation phase was 5.3 days (90% credibleinterval [2.7, 7.8]), the mean duration of the clearance phase was 8.0 days [6.1, 9.9], and the meanoverall duration of infection (proliferation plus clearance) was 13.3 days [10.1, 16.5]. These compare to a meanproliferation phase of 2.0 days [0.7, 3.3], a mean clearance phase of 6.2 days [5.1, 7.1], and a mean duration of infection of 8.2 days [6.5, 9.7] for non-B.1.1.7 virus. The peak viral concentration for B.1.1.7 was 19.0 Ct [15.8, 22.0] compared to 20.2 Ct [19.0, 21.4] for non-B.1.1.7. This converts to 8.5 log10 RNA copies/ml [7.6, 9.4] for B.1.1.7 and 8.2 log10 RNA copies/ml [7.8, 8.5] for non-B.1.1.7. These data offerevidencethat SARS-CoV-2 variant B.1.1.7 may cause longer infections withsimilarpeak viral concentration compared to non-B.1.1.7 SARS-CoV-2. This extended duration maycontribute to B.1.1.7 SARS CoV-2’s increasedtransmissibility.

Liu Y et al

Neutralizing Activity of BNT162b2-Elicited Serum — Preliminary Report

NEJM , February 2021; DOI: 10.1056/NEJMc2102017

COMMENTO : BNT162b2 is a nucleoside-modified RNA vaccine expressing the full-lengthprefusion spike glycoprotein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In a randomized, placebo-controlledclinical trial involvingapproximately 44,000 participants, immunizationconferred 95% efficacyagainst coronavirus disease 2019 (Covid-19).

Huang B et al

Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines

BioRXiv, February 2021; doi.org/10.1101/2021.02.01.429069

COMMENTO : Recently, the emerged and rapidlyspreading SARS-CoV-2 variant of concern (VOC) 501Y.V2 with 10 aminoacids in spike proteinwerefound to escape host immunityinduced by infection or vaccination. Global concerns have been raised for itspotential to affect vaccine efficacy. Here, weevaluated the neutralizationactivities of two vaccines developed in China against 501Y.V2. One islicensedinactivated vaccine BBIBP-CorV and the other one is recombinant dimericreceptor-binding domain (RBD) vaccine ZF2001. Encouragingly, both vaccines largelypreservedneutralizing titres, withslightlyreduction, against 501Y.V2 authentic virus compare to their titres againstboth original SARS-CoV-2 and the currentlycirculating D614G virus. These data indicatedthat 501Y.V2 variant will not escape the immunityinduced by vaccines targetingwhole virus or RBD.

Davies NG et al

Increased hazard of death in community-tested cases of SARS-CoV-2 Variant of Concern 202012/01

medRXiv – not peer reviewed, February 2021; DOI: 10.1101/2021.02.01.21250959

COMMENTO: VOC 202012/01, a SARS-CoV-2 variant first detected in the United Kingdom in September 2020, has spread to multiple countries worldwide. Several studies have established that this novel variant is more transmissible than preexisting variants of SARS-CoV-2, but have not identified whether the new variant leads to any change in disease severity. We analyse a large database of SARS-CoV-2 community test results and COVID-19 deaths for England, representing approximately 47% of all SARS-CoV-2 community tests and 7% of COVID-19 deaths in England from 1 September 2020 to 22 January 2021. Fortuitously, these SARS-CoV-2 tests can identify VOC 202012/01 because mutations in this lineage prevent PCR amplification of the spike gene target (S gene target failure, SGTF). We estimate that the hazard of death among SGTF cases is 30% (95% CI 9–56%) higher than among non-SGTF cases after adjustment for age, sex, ethnicity, deprivation level, care home residence, local authority of residence and date of test. In absolute terms, this increased hazard of death corresponds to the risk of death for a male aged 55–69 increasing from 0.56% to 0.73% (95% CI 0.60–0.86%) over the 28 days following a positive SARS-CoV-2 test in the community. Correcting for misclassification of SGTF, we estimate a 35% (12–64%) higher hazard of death associated with VOC 202012/01. Our analysis suggests that VOC 202012/01 is not only more transmissible than preexisting SARS-CoV-2 variants but may also cause more severe illness.

Mallapaty S et al

What’s the risk of dying from a fast-spreading COVID-19 variant?

Nature, Febraury 2021; DOI: 10.1038/d41586-021-00299-2

COMMENTO: The news is sobering, but complicated. Scientists have released the data behind a British government warning last week that the fast-spreading SARS-CoV-2 variant B.1.1.7 increases the risk of dying from COVID-19 compared with previous variants. But some scientists caution that the latest study — like the government warning — is preliminary and still does not indicate whether the variant is more deadly or is just spreading faster and so reaching greater numbers of vulnerable people.

Martin MA et al

Insights from SARS-CoV-2 sequences

Science, January 2021; DOI: 10.1126/science.abf3995

COMMENTO: As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe, so have efforts to sequence its RNA genome. More than 260,000 sequences are now available in public databases, about a year after the viral genome was first sequenced (1). These sequences and their associated metadata have allowed researchers to estimate the timing of SARS-CoV-2 spillover into humans, characterize the spread of the virus, and gauge virus adaptation to its new host. Such analyses rely on interpreting patterns of nucleotide changes that have occurred in the virus population over time and are brought into focus through the reconstruction of genealogical relationships between sampled viruses that are depicted in phylogenetic trees.

Zhang W et al

Emergence of a Novel SARS-CoV-2 Variant in Southern California

JAMA, January 2021 ; doi.org/10.1101/2021.01.18.21249786

COMMENTO: A spike in coronavirus disease 2019 (COVID-19) has occurred in Southern California since October 2020. Analysis of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in Southern California prior to October indicated most isolates originated from clade 20C that likely emerged from New York via Europe early in the pandemic. Since then, novel variants of SARS-CoV-2 including those seen in the UK (20I/501Y.V1/B.1.1.7), South Africa (20H/501Y.V2/B.1.351), and Brazil (P.1/20J/501Y.V3/B.1.1.248) have emerged with the concern of increased infectivity and virulence. Thus, we analyzed variants of SARS-CoV-2 in Southern California to establish whether one of these known strains or a novel variant had emerged.

McCarthy KR et al

Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

Science, Febrary 2021; DOI: 10.1126/science.abf6950

COMMENTO: Zoonotic pandemics, like that caused by SARS-CoV-2, can follow the spillover of animal viruses into highly susceptible human populations. Their descendants have adapted to the human host and evolved to evade immune pressure. Coronaviruses acquire substitutions more slowly than other RNA viruses, due to a proofreading polymerase. In the spike glycoprotein, we find recurrent deletions overcome this slow substitution rate. Deletion variants arise in diverse genetic and geographic backgrounds, transmit efficiently, and are present in novel lineages, including those of current global concern. They frequently occupy recurrent deletion regions (RDRs), which map to defined antibody epitopes. Deletions in RDRs confer resistance to neutralizing antibodies. By altering stretches of amino acids, deletions appear to accelerate SARS-CoV-2 antigenic evolution and may, more generally, drive adaptive evolution.

master logo