Peifang Sun et al.

Antibody Responses to the SARS-CoV-2 Ancestral Strain and Omicron Variants in Moderna mRNA-1273 Vaccinated Active-Duty US Navy Sailors and Marines

Academic.oup ; March 2023; doi.org/10.1093/infdis/jiad054

Abstract

Omicron and its subvariants have steadily gained greater capability of immune escape compared to other variants of concern, resulting in an increased incidence of reinfections even among vaccinated individuals. We evaluated the antibody response to Omicron BA.1, BA.2, and BA.4/5 in US military members vaccinated with the primary 2-dose series of Moderna mRNA-1273 in a cross-sectional study. While nearly all vaccinated participants had sustained spike (S) IgG and neutralizing antibodies (ND50) to the ancestral strain, only 7.7% participants had detectable ND50 to Omicron BA.1 at 8 months postvaccination. The neutralizing antibody response to BA.2 and BA.5 was similarly reduced. The reduced antibody neutralization of Omicron correlated with the decreased antibody binding to the receptor-binding domain. The participants’ seropositivity to the nuclear protein positively correlated with ND50. Our data emphasizes the need for continuous vigilance in monitoring for emerging variants and the need to identify potential alternative targets for vaccine design.

Freja Cordelia Møller Kirsebom et al.

Duration of protection of ancestral-strain monovalent vaccines and effectiveness of bivalent BA.1 boosters against COVID-19 hospitalisation in England: a test-negative case-control study

The Lancet, July 2023;  doi.org/10.1016/S1473-3099(23)00365-1

Abstract

Bivalent BA.1 booster vaccines were offered to adults aged 50 years or older and clinically vulnerable people as part of the 2022 autumn COVID-19 booster vaccination programme in England. Previously, all adults in England had been offered a primary course consisting of two doses of either ChAdOx1-S or monovalent mRNA vaccine and an mRNA monovalent booster vaccine. We aimed to estimate the long-term duration of protection provided by monovalent COVID-19 vaccines, and the incremental vaccine effectiveness of bivalent BA.1 boosters.

Methods

In this test-negative case-control study, cases of COVID-19 and controls aged 18 years or older were identified from national data for PCR tests done in hospital settings in England. Our analysis was restricted to people with acute respiratory infections coded in the primary diagnosis field. Data for vaccination status were extracted from the English national vaccine register and linked to COVID-19 testing data. Between June 13 and Dec 25, 2022, we estimated the vaccine effectiveness against hospitalisation of two or three or more doses of monovalent COVID-19 vaccines compared with being unvaccinated, stratified by age (18–64 years vs ≥65 years). Between Sept 5, 2022, and Feb 5, 2023, we estimated the incremental vaccine effectiveness (ie, in addition to the protection from earlier vaccines) of receiving a bivalent BA.1 booster vaccine in addition to at least two doses of a monovalent vaccine (when the last dose was at least 6 months ago) among people aged 50 years or older. Analyses were adjusted for week of test, gender, age, COVID-19 risk group, residing in a care home, being a health or social care worker, Index of Multiple Deprivation quintile, ethnicity, and recent COVID-19 positivity.

Findings

Our analysis of monovalent COVID-19 vaccines included 19 841 cases and 43 410 controls. Absolute vaccine effectiveness against hospitalisation among people who had received at least three doses plateaued from 6 months after the last dose at around 50% in those aged 65 years or older and at around 30% in those aged 18–64 years. Our analyses of the effectiveness of bivalent BA.1 boosters included data for 9954 cases and 39 108 controls aged 50 years or older. Incremental vaccine effectiveness peaked at 53·0% (95% CI 47·9–57·5) 2–4 weeks after administration, before waning to 35·9% (31·4–40·1) after 10 or more weeks.

Interpretation

Our study provides evidence that monovalent COVID-19 vaccines offer moderate long-term protection against hospitalisation in people aged 65 years or older and that the bivalent BA.1 booster vaccines were effective in preventing hospitalisation among people aged 50 years or older at a time when omicron lineages were circulating in England

Prof Jing-Xin Li et al.

Safety, immunogenicity and protection of heterologous boost with an aerosolised Ad5-nCoV after two-dose inactivated COVID-19 vaccines in adults: a multicentre, open-label phase 3 trial

The Lancet, June 2023; doi.org/10.1016/S1473-3099(23)00350-X

Abstract

Aerosolised Ad5-nCoV is one of the first licensed mucosal respiratory vaccine against SARS-CoV-2 in the world; however, the safety profile of this vaccine has not been reported in a large population yet.

Methods

This multicentre, open-label phase 3 trial, done in 15 centres in six provinces (Jiangsu, Hunan, Anhui, Chongqing, Yunnan, Shandong) in China, aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV in healthy adults (members of the general population with no acute febrile disorders, infectious disease, serious cardiovascular diseases, serious chronic diseases or progressive diseases that cannot be controlled) at least 18 years old, who had received two doses of inactivated COVID-19 vaccine as their primary regimen. This study contained a non-randomly assigned safety cohort and a centrally randomly assigned (1:1) immunogenicity subcohort. The patients in the immunogenicity subcohort received aerosolised Ad5-nCov (aerosolised Ad5-nCoV group) or inactivated vaccine (inactivated COVID-19 group) The primary endpoints were the incidence of adverse reactions within 28 days following the booster vaccination with aerosolised Ad5-nCoV in the safety population (collected through a daily record of any solicited or unsolicited adverse events filled by each participant) and the geometric mean titre of neutralising antibodies at day 28 after the booster dose in the immunogenicity subcohort (measured with a pseudovirus neutralisation test). This study was registered with ClinicalTrials.gov, NCT05204589.

Findings

Between Jan 22, 2022, and March 12, 2022, we recruited 11 410 participants who were screened for eligibility, of whom 10 267 (99·8%) participants (5738 [55·9%] men, 4529 [44·1%] women; median age 53 years [18–92]) received the study drugs: 9847 (95·9%) participants in the open-label cohort to receive aerosolised Ad5-nCoV, and 420 (4·1%) in the immunogenicity subcohort (212 in the aerosolised Ad5-nCoV group and 208 in the inactivated vaccine group). Adverse reactions were reported by 1299 (13%) of 10 059 participants within 28 days after receiving the booster vaccination with aerosolised Ad5-nCoV, but most of the adverse reactions reported were mild to moderate in severity. Participants in the aerosolised Ad5-nCoV group had a significantly higher level of the neutralising antibodies against omicron BA.4/5 (GMT 107·7 [95% CI 88·8–130·7]) than did those in the inactivated vaccine group (17·2 [16·3–18·2]) at day 28.

Interpretation

The heterologous booster regimen with aerosolised Ad5-nCoV is safe and highly immunogenic, boosting both systemic and mucosal immunity against omicron subvariants.

Ivan T Lee et al.

Omicron BA.1-containing mRNA-1273 boosters compared with the original COVID-19 vaccine in the UK: a randomised, observer-blind, active-controlled trial

The Lancet, June 2023 ; doi.org/10.1016/S1473-3099(23)00295-5

Abstract

The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial.

Methods

In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 μg omicron BA.1 monovalent or bivalent vaccines or 50 μg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing.

Findings

Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6–4·7]) and mRNA-1273 (4·1 [3·5–4·7]), and for the omicron BA.1 bivalent (5·5 [4·8–6·2]) and mRNA-1273 (5·4 [4·8–6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45−1·95) and 1·53 (1·41−1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9–3169·9]) versus mRNA-1273 (2911·3 [2750·9–3081·0]) and lower for the monovalent (2699·7 [2431·3–2997·7] vs 3020·6 [2776·5–3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96–1·15) and 0·82 (95% CI 0·74–0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events.

Interpretation

Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emergent.

Joel N Blankson

Bivalent COVID-19 Vaccines: Can the Original Antigenic Sin Be Forgiven?

Academic.oup, April 2023; doi.org/10.1093/infdis/jiad073

Abstract

On 31 August 2022, the United States (US) Food and Drug Administration authorized bivalent formulations of the Moderna and Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccines [1]. These modified vaccines contain messenger RNA (mRNA) encoding for both the ancestral WA1/2020 and the Omicron BA.4/BA.5 spike proteins. The hope was that they would provide immunity to the BA.5 virus, which differs from WA1/2020 by >30 mutations in the spike protein and was the predominant variant in circulation at the time. Unfortunately, studies have shown that the levels of neutralizing antibodies to the BA.5 variant were not significantly higher in patients who received the bivalent vaccine than those who received the monovalent vaccine with WA1/2020 mRNA [2, 3]. In other words, vaccination with BA.5 spike protein did not lead to an appreciably better antibody response. The reason for this disappointing result has not yet been determined, but antigenic imprinting, also known as the “original antigenic sin,” has been invoked as a potential cause for these results.

To fully explain this tenant of immunotheology, one has to review some basic principles. While there are some notable exceptions [4], the process of extensive gene segment recombination leads to the production of diverse T- and B-cell receptors that should be capable of recognizing almost any conceivable pathogen we will ever encounter. The drawback is that there are very few cells with any given receptor and so when we first see a pathogen, naive cells with receptors specific for the pathogen's antigens have to proliferate extensively before we can mount an effective primary adaptive immune response. Some of these naive cells will become memory cells that circulate at higher levels so that if the same antigen is encountered again, a faster, more effective secondary adaptive immune response will occur.

The original antigenic sin occurs when we encounter antigens on a pathogen that is similar to one we have previously encountered [5, 6]. It is thought that rather than initiating a primary immune response where rare naive lymphocytes that have high-affinity receptors for the new antigens proliferate, a secondary response occurs where memory cells with receptors that are cross-reactive for both the original and new antigens are stimulated. This could potentially be advantageous if the targeted epitopes of the 2 pathogens are identical or very similar because then the 2 epitopes will be equally recognized. However, in many cases, because the cross-reactive memory cells were primed to respond to the antigen on the first pathogen, the cross-reactive receptors will have a higher affinity for the first pathogen, leading to a suboptimal response to the newer pathogen….

Simon Dedroogh et al

Impact of timing and combination of different BNT162b2 and ChAdOx1-S COVID-19 basic and booster vaccinations on humoral immunogenicity and reactogenicity in adults

Nature, June 2023; doi.org/10.1038/s41598-023-34961-8

Abstract

In this single-center observational study with 1,206 participants, we prospectively evaluated SARS-CoV-2-antibodies (anti-S RBD) and vaccine-related adverse drug reactions (ADR) after basic and booster immunization with BNT162b2- and ChAdOx1-S-vaccines in four vaccination protocols: Homologous BNT162b2-schedule with second vaccination at either three or six weeks, homologous ChAdOx1-S-vaccination or heterologous ChAdOx1-S/BNT162b2-schedule, each at 12 weeks. All participants received a BNT162b2 booster. Blood samples for anti-S RBD analysis were obtained multiple times over a period of four weeks to six months after basic vaccination, immediately before, and up to three months after booster vaccination. After basic vaccination, the homologous ChAdOx1-S-group showed the lowest anti-S RBD levels over six months, while the heterologous BNT162b2-ChAdOx1-S-group demonstrated the highest anti-S levels, but failed to reach level of significance compared with the homologous BNT162b2-groups. Antibody levels were higher after an extended vaccination interval with BNT162b2. A BNT162b2 booster increased anti-S-levels 11- to 91-fold in all groups, with the homologous ChAdOx1-S-cohort demonstrated the highest increase in antibody levels. No severe or serious ADR were observed. The findings suggest that a heterologous vaccination schedule or prolonged vaccination interval induces robust humoral immunogenicity with good tolerability. Extending the time to boost-immunization is key to both improving antibody induction and reducing ADR rate.

Meghan K Herring et al

Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses Get access Arrow

CID, May 2023, doi.org/10.1093/cid/ciac976

Abstract

Data on antibody kinetics are limited among individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From a cohort of healthcare personnel and other frontline workers in 6 US states, we assessed antibody waning after messenger RNA (mRNA) dose 2 and response to dose 3 according to SARS-CoV-2 infection history.

Methods

Participants submitted sera every 3 months, after SARS-CoV-2 infection, and after each mRNA vaccine dose. Sera were tested for antibodies and reported as area under the serial dilution curve (AUC). Changes in AUC values over time were compared using a linear mixed model.

Results

Analysis included 388 participants who received dose 3 by November 2021. There were 3 comparison groups: vaccine only with no known prior SARS-CoV-2 infection (n = 224); infection prior to dose 1 (n = 123); and infection after dose 2 and before dose 3 (n = 41). The interval from dose 2 and dose 3 was approximately 8 months. After dose 3, antibody levels rose 2.5-fold (95% confidence interval [CI] = 2.2–3.0) in group 2 and 2.9-fold (95% CI = 2.6–3.3) in group 1. Those infected within 90 days before dose 3 (and median 233 days [interquartile range, 213–246] after dose 2) did not increase significantly after dose 3.

Conclusions

A third dose of mRNA vaccine typically elicited a robust humoral immune response among those with primary vaccination regardless of SARS-CoV-2 infection >3 months prior to boosting. Those with infection <3 months prior to boosting did not have a significant increase in antibody concentrations in response to a booster.

Joel N Blankson

Bivalent COVID-19 Vaccines: Can the Original Antigenic Sin Be Forgiven?

Academic.oup, April 2023; doi.org/10.1093/infdis/jiad073

Abstract

On 31 August 2022, the United States (US) Food and Drug Administration authorized bivalent formulations of the Moderna and Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccines [1]. These modified vaccines contain messenger RNA (mRNA) encoding for both the ancestral WA1/2020 and the Omicron BA.4/BA.5 spike proteins. The hope was that they would provide immunity to the BA.5 virus, which differs from WA1/2020 by >30 mutations in the spike protein and was the predominant variant in circulation at the time. Unfortunately, studies have shown that the levels of neutralizing antibodies to the BA.5 variant were not significantly higher in patients who received the bivalent vaccine than those who received the monovalent vaccine with WA1/2020 mRNA [2, 3]. In other words, vaccination with BA.5 spike protein did not lead to an appreciably better antibody response. The reason for this disappointing result has not yet been determined, but antigenic imprinting, also known as the “original antigenic sin,” has been invoked as a potential cause for these results.

To fully explain this tenant of immunotheology, one has to review some basic principles. While there are some notable exceptions [4], the process of extensive gene segment recombination leads to the production of diverse T- and B-cell receptors that should be capable of recognizing almost any conceivable pathogen we will ever encounter. The drawback is that there are very few cells with any given receptor and so when we first see a pathogen, naive cells with receptors specific for the pathogen's antigens have to proliferate extensively before we can mount an effective primary adaptive immune response. Some of these naive cells will become memory cells that circulate at higher levels so that if the same antigen is encountered again, a faster, more effective secondary adaptive immune response will occur.

Unfortunately, by the time 2 bivalent booster shots are given to a significant part of the population—an unlikely prospect given the limited uptake of the bivalent vaccine and the vaccine weariness of the US population—the variant in question will probably no longer be the dominant variant in circulation. The question then becomes should we periodically modify the bivalent vaccines to target the spike protein from the most prevalent circulating variant, or can we just rely on a monovalent vaccine to expand preexisting memory cells with cross-reactive receptors?

It is likely that we have low frequencies of naive B and T cells with high-affinity receptors specific for every SARS-CoV-2 variant that will emerge. So, if we continue to vaccinate with different spike proteins and generate more cells with cross-reactive receptors, will we be able to prime the rare naive cells with the high-affinity receptors we want, or will we just amplify cells with less effective cross-reactive receptors that are circulating at much higher levels? The good news is that if new variants escape to a point where there is little cross-recognition by preexisting memory B and T cells, then it should be possible to prime an effective primary immune response against the emerging spike protein. This phenomenon is routinely seen in untreated human immunodeficiency virus infection where there is a much higher degree of virologic escape [10]. At this point, hopefully the original antigenic sin will be forgiven

JiaWei et al.

Protection against SARS-CoV-2 Omicron BA.4/5 variant following booster vaccination or breakthrough infection in the UK

Nature, May 2023; doi.org/10.1038/s41467-023-38275-1

Abstract

Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.

Georgia Deliyannis et al.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine

Lancet, May 2023; doi.org/10.1016/j.ebiom.2023.104574

Abstract

The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines.

Methods

We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine.

Findings

Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The ‘beta variant’ RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5.

Interpretation

These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial.

Alexandra F Dalton et al.

Relationships Between Social Vulnerability and Coronavirus Disease 2019 Vaccination Coverage and Vaccine Effectiveness

CID, January 2023; doi.org/10.1093/cid/ciad003

Abstract

Coronavirus disease 2019 (COVID-19) vaccination coverage remains lower in communities with higher social vulnerability. Factors such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure risk and access to healthcare are often correlated with social vulnerability and may therefore contribute to a relationship between vulnerability and observed vaccine effectiveness (VE). Understanding whether these factors impact VE could contribute to our understanding of real-world VE.

Methods

We used electronic health record data from 7 health systems to assess vaccination coverage among patients with medically attended COVID-19-like illness. We then used a test-negative design to assess VE for 2- and 3-dose messenger RNA (mRNA) adult (≥18 years) vaccine recipients across Social Vulnerability Index (SVI) quartiles. SVI rankings were determined by geocoding patient addresses to census tracts; rankings were grouped into quartiles for analysis.

Results

In July 2021, primary series vaccination coverage was higher in the least vulnerable quartile than in the most vulnerable quartile (56% vs 36%, respectively). In February 2022, booster dose coverage among persons who had completed a primary series was higher in the least vulnerable quartile than in the most vulnerable quartile (43% vs 30%). VE among 2-dose and 3-dose recipients during the Delta and Omicron BA.1 periods of predominance was similar across SVI quartiles.

Conclusions

COVID-19 vaccination coverage varied substantially by SVI. Differences in VE estimates by SVI were minimal across groups after adjusting for baseline patient factors. However, lower vaccination coverage among more socially vulnerable groups means that the burden of illness is still disproportionately borne by the most socially vulnerable populations.

Dan-Yu Lin et al.

Durability of Bivalent Boosters against Omicron Subvariants

NEJM, May 2023; DOI: 10.1056/NEJMc2302462

Abstract

On September 1, 2022, the Moderna and Pfizer–BioNTech bivalent vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containing equal amounts of spike messenger RNA from the ancestral and omicron BA.4–BA.5 subvariants replaced their monovalent counterparts as booster doses for persons who are 12 years of age or older in the United States. We previously reported surveillance data from North Carolina on the effectiveness of these two bivalent boosters against coronavirus disease 2019 (Covid-19) during the first 3 months after deployment (September 1 to December 8, 2022); the BA.4–BA.5 subvariants were predominant during the first 2.5 months of this period.1 Here, we present two additional months of data that were obtained during a period when the omicron BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants had become predominant to show the durability of protection conferred by these two bivalent boosters against a wider range of clinical outcomes than were included in our previous report.

The data sources and study design have been described previously,1-3 and updated information is provided in the Methods section of the Supplementary Appendix, available with the full text of this letter at NEJM.org. The current study used data regarding booster doses and clinical outcomes from September 1, 2022, to February 10, 2023, for all North Carolina residents who were 12 years of age or older. During this period, a total of 6,306,311 residents were eligible to receive bivalent boosters; of these residents, 1,279,802 received the injections. A total of 19,462 of the 154,581 SARS-CoV-2 infections, 253 of the 2208 Covid-19–related hospitalizations, and 79 of the 867 Covid-19–related deaths occurred after receipt of the bivalent booster (Table S1 in the Supplementary Appendix).

We considered four outcome measures: infection, severe infection resulting in hospitalization, severe infection resulting in hospitalization or death, and severe infection resulting in death. We fit the Cox regression model with a time-varying hazard ratio for severe infection and fit the proportional-rates model with a time-varying rate ratio for recurrent infection for each additional booster dose that was received (i.e., first booster vs. primary vaccination, second booster vs. first booster, or third booster vs. second booster); all measures were adjusted for the baseline characteristics shown in Table S1. We estimated the booster effectiveness on a particular day as 1 minus the hazard ratio or rate ratio on that day multiplied by 100%.

Effectiveness of Bivalent Boosters According to the Interval since Administration.

The estimation results are shown in the left column of Figure 1 and in Table S2. Effectiveness against severe infection resulting in hospitalization or death reached a level of 67.4% (95% confidence interval [CI], 46.2 to 80.2) after 2 weeks and decreased to 47.5% (95% CI, 32.6 to 59.2) after 4 weeks, to 44.3% (95% CI, 35.7 to 51.7) after 10 weeks, and to 38.4% (95% CI, 13.4 to 56.1) after 20 weeks. Effectiveness against severe infection resulting in hospitalization was slightly lower, and effectiveness against infection was much lower. The effectiveness against severe infection resulting in death was the highest despite uncertainty because of the small number of events.

We also analyzed the data separately for participants who received bivalent boosters before November 1, 2022 (when the BA.4–BA.5 subvariants were predominant) and after November 1, 2022 (when the BQ.1–BQ.1.1 subvariants were more prevalent and then were gradually replaced by the XBB–XBB.1.5 subvariants). The results are shown in the right column of Figure 1 and in Tables S3 and S4. The effectiveness was broadly similar between the two booster cohorts.

Finally, we performed subgroup analyses according to the participant’s age and previous infection status and according to the manufacturers of the bivalent vaccine and the previous vaccine. Effectiveness against infection was higher for the Moderna bivalent vaccine than for the Pfizer–BioNTech bivalent vaccine and higher among previously infected participants than among those with no previous infection .

The two types of bivalent boosters were associated with an additional reduction in the incidence of omicron infection among participants who had previously been vaccinated or boosted. Although the two bivalent vaccines were designed to target the BA.4–BA.5 subvariants, they were also associated with a lower risk of infection or severe infection with the BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants. The effectiveness was higher against hospitalization and death than against infection and waned gradually from its peak over time.

Francesco Menegale et al

Evaluation of Waning of SARS-CoV-2 Vaccine–Induced Immunity

A Systematic Review and Meta-analysis

JAMA, May 2023; doi:10.1001/jamanetworkopen.2023.10650

Abstract

Importance Estimates of the rate of waning of vaccine effectiveness (VE) against COVID-19 are key to assess population levels of protection and future needs for booster doses to face the resurgence of epidemic waves.

Objective To quantify the progressive waning of VE associated with the Delta and Omicron variants of SARS-CoV-2 by number of received doses.

Data Sources PubMed and Web of Science were searched from the databases’ inception to October 19, 2022, as well as reference lists of eligible articles. Preprints were included.

Study Selection Selected studies for this systematic review and meta-analysis were original articles reporting estimates of VE over time against laboratory-confirmed SARS-CoV-2 infection and symptomatic disease.

Data Extraction and Synthesis Estimates of VE at different time points from vaccination were retrieved from original studies. A secondary data analysis was performed to project VE at any time from last dose administration, improving the comparability across different studies and between the 2 considered variants. Pooled estimates were obtained from random-effects meta-analysis.

Main Outcomes and Measures Outcomes were VE against laboratory-confirmed Omicron or Delta infection and symptomatic disease and half-life and waning rate associated with vaccine-induced protection.

Results A total of 799 original articles and 149 reviews published in peer-reviewed journals and 35 preprints were identified. Of these, 40 studies were included in the analysis. Pooled estimates of VE of a primary vaccination cycle against laboratory-confirmed Omicron infection and symptomatic disease were both lower than 20% at 6 months from last dose administration. Booster doses restored VE to levels comparable to those acquired soon after the administration of the primary cycle. However, 9 months after booster administration, VE against Omicron was lower than 30% against laboratory-confirmed infection and symptomatic disease. The half-life of VE against symptomatic infection was estimated to be 87 days (95% CI, 67-129 days) for Omicron compared with 316 days (95% CI, 240-470 days) for Delta. Similar waning rates of VE were found for different age segments of the population.

Conclusions and Relevance These findings suggest that the effectiveness of COVID-19 vaccines against laboratory-confirmed Omicron or Delta infection and symptomatic disease rapidly wanes over time after the primary vaccination cycle and booster dose. These results can inform the design of appropriate targets and timing for future vaccination programs.

Caige Huang et al.

Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 omicron infection and related hospital admission among people with substance use disorder in Hong Kong: a matched case-control study

The Lancet, May 2023; doi.org/10.1016/S2215-0366(23)00111-6

Abstract

People with substance use disorder have a high risk of SARS-CoV-2 infection and subsequent poor outcomes. Few studies have evaluated COVID-19 vaccine effectiveness among people with substance use disorder. We aimed to estimate the vaccine effectiveness of BNT162b2 (Fosun-BioNTech) and CoronaVac (Sinovac) against SARS-CoV-2 omicron (B.1.1.529) infection and related hospital admission in this population.

Methods

We did a matched case-control study using electronic health databases in Hong Kong. Individuals diagnosed with substance use disorder between Jan 1, 2016, and Jan 1, 2022, were identified. People aged 18 years and older with SARS-CoV-2 infection from Jan 1 to May 31, 2022, and people with COVID-19-related hospital admission from Feb 16 to May 31, 2022, were included as cases and were matched by age, sex, and previous clinical history with controls from all individuals diagnosed with substance use disorder who attended the Hospital Authority health services: up to three controls for SARS-CoV-2 infection and up to ten controls for hospital admission. Conditional logistical regression was used to evaluate the association between vaccination status (ie, one, two, or three doses of BNT162b2 or CoronaVac) and the risk of SARS-CoV-2 infection and COVID-19-related hospital admission, adjusted for baseline comorbidities and medication use.

Findings

Among 57 674 individuals with substance use disorder, 9523 people with SARS-CoV-2 infections (mean age 61·00 years, SD 14·90; 8075 [84·8%] males and 1448 [15·2%] females) were identified and matched to 28 217 controls (mean age 60·99 years, 14·67; 24 006 [85·1%] males and 4211 [14·9%] females), and 843 people with COVID-19-related hospital admissions (mean age 70·48 years, SD 14·68; 754 [89·4%] males and 89 [10·6%] females) were identified and matched to 7459 controls (mean age 70·24 years, 13·87; 6837 [91·7%] males and 622 [8·3%] females). Data on ethnicity were not available. We observed significant vaccine effectiveness against SARS-CoV-2 infection for two-dose BNT162b2 vaccination (20·7%, 95% CI 14·0–27·0, p<0·0001) and three-dose vaccination (all BNT162b2 41·5%, 34·4–47·8, p<0·0001; all CoronaVac 13·6%, 5·4–21·0, p=0·0015; BNT162b2 booster after two-dose CoronaVac 31·3%, 19·8–41·1, p<0·0001), but not for one dose of either vaccine or two doses of CoronaVac.Significant vaccine effectiveness against COVID-19-related hospital admission was detected after one dose of BNT162b2 vaccination (35·7%, 3·8–57·1, p=0·032), two-dose vaccination (both BNT162b2 73·3%, 64·3 to 80·0, p<0·0001; both CoronaVac 59·9%, 50·2–67·7, p<0·0001), and three-dose vaccination (all BNT162b2 86·3%, 75·6–92·3, p<0·0001; all CoronaVac 73·5% 61·0–81·9, p<0·0001; BNT162b2 booster after two-dose CoronaVac 83·7%, 64·6–92·5, p<0·0001), but not after one dose of CoronaVac.

Interpretation

For both BNT162b2 and CoronaVac, two-dose or three-dose vaccination was protective against COVID-19-related hospital admission and the booster dose provided protection against SARS-CoV-2 infection among people with substance use disorder. Our findings confirm the importance of booster doses in this population during the period dominated by the omicron variant.

Anthony Ravussin et al.

Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study

The Lancet, May 2023; doi.org/10.1016/S2666-7568(23)00055-7

Abstract

Older age is associated with poorer outcomes to COVID-19 infection. The Norwegian Institute of Public Health established a longitudinal cohort of adults aged 65–80 years to study the effects of the COVID-19 pandemic. Here we describe the characteristics of the cohort in general, and specifically the immune responses at baseline and after primary and booster vaccination in a subset of longitudinal blood samples, and the epidemiological factors affecting these responses.

Methods

4551 participants were recruited, with humoral (n=299) and cellular (n=90) responses measured before vaccination and after two and three vaccine doses. Information on general health, infections, and vaccinations were obtained from questionnaires and national health registries.

Findings

Half of the participants had a chronic condition. 849 (18·7%) of 4551 were prefrail and 184 (4%) of 4551 were frail. 483 (10·6%) of 4551 had general activity limitations (scored with the Global Activity Limitation Index). After dose two, 295 (98·7%) of 299 participants were seropositive for anti-receptor binding domain IgG, and 210 (100%) of 210 participants after dose three. Spike-specific CD4 and CD8 T cell responses showed high heterogeneity after vaccination and responded to the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) variants of concern. Cellular responses to seasonal coronaviruses increased after SARS-CoV-2 vaccination. Heterologous prime boosting with mRNA vaccines was associated with the highest antibody (p=0·019) and CD4 T cell responses (p=0·003), and hypertension with lower antibody levels after three doses (p=0·04).

Interpretation

Most older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing.

Ngoc H Tan et al.

Immunogenicity of bivalent omicron (BA.1) booster vaccination after different priming regimens in health-care workers in the Netherlands (SWITCH ON): results from the direct boost group of an open-label, multicentre, randomised controlled trial

The Lancet, April 2023; doi.org/10.1016/S1473-3099(23)00140-8

Abstract

Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and omicron spike (S) protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We aimed to assess the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent omicron (BA.1) vaccines in individuals who were primed with adenovirus-based or mRNA-based vaccines encoding the ancestral spike protein.

missing blood sample at day 0 or day 28. This trial is registered with ClinicalTrials.gov, NCT05471440.

Interpretation

Booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 in adult healthcare workers resulted in a rapid recall of humoral and cellular immune responses independent of the priming regimen. Monitoring of SARS-CoV-2 immunity at the population level, and simultaneously antigenic drift at the virus level, remains crucial to assess the necessity and timing of COVID-19 variant-specific booster vaccinations.

Zhuoying Huang et al.

Effectiveness of inactivated COVID-19 vaccines among older adults in Shanghai: retrospective cohort study

Nature, April 2023; doi.org/10.1038/s41467-023-37673-9

Abstract

We conducted a matched retrospective cohort study of two cohorts to estimate inactivated vaccine effectiveness (VE) and its comparative effectiveness of booster dose among older people in Shanghai. Cohort 1 consisted of a vaccinated group (≥1 dose) and an unvaccinated group (3,317,475 pairs), and cohort 2 consisted of a booster vaccinated group and a fully vaccinated group (2,084,721 pairs). The Kaplan–Meier method and Cox regression models were used to estimate risk and hazard ratios (HRs) study outcomes. For cohort 1, the overall estimated VEs of ≥1 dose of inactivated vaccine against SARS-CoV-2 infection, severe/critical Covid-19, and Covid-19 related death were 24.7% (95%CI 23.7%−25.7%), 86.6% (83.1%−89.4%), and 93.2% (88.0%−96.1%), respectively. Subset analysis showed that the booster vaccination provided greatest protection. For cohort 2, compared with full vaccination, relative VEs of booster dose against corresponding outcome were 16.3% (14.4%−17.9%), 60.5% (37.8%−74.9%), and 81.7% (17.5%−95.9%). Here we show, although under the scenario of persistent dynamic zero-Covid policy and non-pharmaceutical interventions, promoting high uptake of the full vaccination series and booster dose among older adults is critically important. Timely vaccination with the booster dose provided effective protection against Covid-19 outcomes.

TomohiroTakano et al.

Heterologous SARS-CoV-2 spike protein booster elicits durable and broad antibody responses against the receptor-binding domain

Nature, March 2023; doi.org/10.1038/s41467-023-37128-1

Abstract

The immunogenicity of mRNA vaccines has not been well studied when compared to different vaccine modalities in the context of additional boosters. Here we show that longitudinal analysis reveals more sustained SARS-CoV-2 spike receptor-binding domain (RBD)-binding IgG titers with the breadth to antigenically distinct variants by the S-268019-b spike protein booster compared to the BNT162b2 mRNA homologous booster. The durability and breadth of RBD-angiotensin-converting enzyme 2 (ACE2) binding inhibitory antibodies are pronounced in the group without systemic adverse events (AEs) after the S-268019-b booster, leading to the elevated neutralizing activities against Omicron BA.1 and BA.5 variants in the stratified group. In contrast, BNT162b2 homologous booster elicited antibodies to spike N-terminal domain in proportion to the AE scores. High-dimensional immune profiling identifies early CD16+ natural killer cell dynamics with CCR3 upregulation, as one of the correlates for the distinct anti-RBD antibody responses by the S-268019-b booster. Our results illustrate the combinational effects of heterologous booster on the immune dynamics and the durability and breadth of recalled anti-RBD antibody responses against emerging virus variants.

VéroniqueBarateau et al.

Prior SARS-CoV-2 infection enhances and reshapes spike protein–specific memory induced by vaccination

Science, March 2023; doi/10.1126/scitranslmed.ade0550

Abstract

The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein–specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein–specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced TH1 polarization of their SARS-CoV-2 spike protein–specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein–specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein–specificmemory B cell pool that are compatible with enhanced functional protection at mucosal sites.

Anastasia Chatzilena et al.

Relative vaccine effectiveness (rVE) of mRNA COVID-19 1 boosters in the UK vaccination

programme, during the Spring-Summer (monovalent vaccine) and Autumn-Winter 2022

(bivalent vaccine) booster campaigns: a prospective test negative case-control study

MedRxiv, March 2023; doi.org/10.1101/2023.03.16.23287360

Abstract

Background Understanding the relative vaccine effectiveness (rVE) of new COVID-19 vaccine formulations against SARS-CoV-2 infection is an urgent public health priority. A precise comparison of the rVE of monovalent and bivalent boosters given during the 2022 Spring-Summer and Autumn-Winter campaigns, respectively, in a defined population has not been reported. We therefore assessed rVE against hospitalisation for the Spring-Summer (fourth vs third monovalent mRNA vaccine doses) and Autumn-Winter (fifth BA.1/ancestral bivalent vs fourth monovalent mRNA vaccine dose) boosters. Methods A prospective single-centre test-negative design case-control study of ≥75 year-olds hospitalised with COVID-19 or other acute respiratory disease. We conducted regression analyses controlling for age, gender, socioeconomic status, patient comorbidities, community SARS-CoV-2 prevalence, vaccine brand and time between baseline dose and hospitalisation. Results 682 controls and 182 cases were included in the Spring-Summer booster analysis; 572 controls and 152 cases for the Autumn-Winter booster analysis. A monovalent mRNA COVID-19 vaccine as fourth dose showed rVE 46∙9% (95% confidence interval [CI] 14∙4-67∙3) versus those not boosted. A bivalent mRNA COVID-19 vaccine as fifth dose had rVE 46∙4% (95%CI 17∙5-65), compared to a fourth monovalent mRNA COVID-19 vaccine dose. Interpretation Both fourth monovalent and fifth BA.1/ancestral mRNA bivalent COVID-19 vaccine doses demonstrated benefit as a booster in older adults. Bivalent mRNA boosters offer equivalent protection against hospitalisation with Omicron infection to monovalent mRNA boosters given earlier in the year. These findings support the current UK immunisation programme that advises the use of bivalent booster doses.

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