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Review 2: "Safety, Immunogenicity and Antibody Persistence of a Bivalent Beta-Containing Booster Vaccine"

While this study presents important data for new-generation COVID-19 vaccines, uncertainty about the study design and reporting of outcomes suggests that the findings should be interpreted with caution.

Published onJul 19, 2022
Review 2: "Safety, Immunogenicity and Antibody Persistence of a Bivalent Beta-Containing Booster Vaccine"
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Safety, Immunogenicity and Antibody Persistence of a Bivalent Beta-Containing Booster Vaccine
Description

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants have caused multiple waves of infection globally. This phase 2/3 study evaluated the safety and immunogenicity of the bivalent vaccine candidate mRNA-1273.211 (equal mRNA amounts of ancestral SARS-CoV-2 and Beta variant spike proteins) as 50-µg (n=300) and 100-µg (n=595) first booster doses approximately 8.8-9.8 months after the mRNA-1273 primary series. The mRNA-1273.211 booster (50 and 100-µg) elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and the Beta variant than that after the second mRNA‑1273 dose. Antibody responses after the 50-µg mRNA-1273.211 booster dose were also higher than that after a 50-µg mRNA-1273 booster dose for the ancestral SARS-CoV-2, Beta, Omicron and Delta variants (28 days after the booster dose) and for the ancestral SARS-CoV-2, Beta and Omicron (180 days after the booster dose), and the immunogenicity objectives were met. The safety and reactogenicity profile of the mRNA-1273.211 booster (50-µg) was comparable to mRNA-1273 (50-µg). These results indicate that bivalent booster vaccines can induce potent and durable antibody responses providing a new tool in response to emerging variants. Trial registration: https://www.clinicaltrials.gov NCT04927065

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

This preprint by Chalkias et al. reported the interim analysis of the safety and immunogenicity of a bivalent COVID-19 vaccine containing mRNA that encodes for the spike protein of the original SARS-CoV-2 Wuhan strain and the beta variant (mRNA-1273.211), when given as a booster dose. The study involves 896 participants aged ≥18 years in the United States, who had received the mRNA-1273 primary series (i.e. 2 doses) at least 6 months prior, and who were allocated to receive either a 50 µg or 100 µg of mRNA-1273.211 booster. Immunological data from two previous cohorts involving 2-dose primary series of 100 µg of mRNA-1273 (N=584) and individuals who received 50 µg mRNA-1273 booster (N=171) were included as comparator groups in this study.

The main claims of the manuscript are that 50 µg or 100 µg of mRNA-1273.211 (bivalent) as a booster elicited strong neutralizing antibodies against the original SARS-CoV-2 Wuhan strain as well as the SARS-CoV-2 variants including Beta, Delta and Omicron. These antibody concentrations were superior to the antibody concentrations induced by the 50 µg mRNA-1273 (monovalent containing Wuhan strain) and persists for at least 6 months. Similar reactogenicity were observed between 50 µg of mRNA-1273.211 and mRNA-1273, while higher reactogenicity were observed for 100 µg of mRNA-1273.211 compared to either 50 µg of mRNA-1273.211 and mRNA-1273. While the conclusions appear to be supported by the data, issues around the study design and reporting of outcomes suggests that such findings should be interpreted with caution.

This study presents important data for new-generation COVID-19 vaccines. This is the major strength given the emphasis is now on how these new vaccine candidates might protect against new variants/subvariant. Although results here are for the beta-containing bivalent vaccine, the larger study includes omicron-containing candidates which are likely to be of more interest currently.

A limitation was the non-randomized nature of the study and that historical data were used as controls for the 2-dose primary series results and as an external comparator for bivalent and monovalent groups. The main claims of the manuscript could be improved by further explanation for the primary immunogenicity outcomes based on comparison with post-primary series as opposed to direct comparison of booster doses of mRNA-1273.211 and mRNA-1273. The authors also report efficacy data, but this analysis was not included in the methods and probably not powered for the study, and so the interpretation of the data is unclear. Some explanation of the rationale of using 100 µg mRNA-1273.211 where reactogenicity is known to be higher with increased dosing would be helpful. For the binding antibody analysis, there is no data for Delta/Omicron which makes it difficult to compare to other similar studies.

Overall, further discussion around the implications and relevance of the study findings in the context of the Omicron variant being the dominant circulating variant globally, and that the Wuhan- and Omicron-containing vaccines are under evaluation would help strengthen the paper.



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