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Review 1: "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 1: "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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

Any study on the subject is welcome, as it would add to the understanding of the generation and longevity of the immune responses against SARS-CoV-2 by vaccines of various types, and also against its different variants getting identified over time due to its continuous mutation. In that sense, this study definitely adds information that could help to introduce newer generations of the vaccine which include antigenic variants to improve the range of virus variants covered for a broader and more-sustained protection.

The data presented adds to the prior published information on the higher GMTs obtained through booster shots of Covid-19 vaccine, and their possible improved persistence to support the claims of “no serious disease or hospitalization (unless the person has any severe co-morbidities or immune-compromised)” for anyone who has completed the primary series and especially with any booster. The data is clear on the safety parameters, that no additional type/numbers are noted in terms of LAEs and SAEs with the trial (mRNA-1273.211) as against the original (mRNA-1273) vaccines used in the study; this supports their primary safety objective of the study. The data on GMTs and SRRs shown with the mRNA-1273.211 (trial) vaccine as against the original mRNA-1273 version support the claims made by the authors on the of immunogenicity elicited by the trial vaccine as against the comparator at same dose levels, and higher boosting with higher dose; this indicates that the study’s immunogenicity objectives of showing non-inferiority and/or superiority in responses against native (original) SARS-CoV-2 stain vs. its Beta variant are met. This evidence is strengthened by the dose response shown with data on 50µg dose vs. 100µg dose, and also by the neutralizing and binding antibody titer data shown against different variants of SARS-CoV-2 as response to the original (mRNA-1273) and trial (mRNA-1273.211) vaccines. The upcoming data from the follow-up testing on 180-day samples from the study participants could help to add information on the persistency of the bi/multivalent vaccine (booster) approach.

However, there are a few limitations other than those mentioned by the authors themselves which, if they had been taken care during the study-design stage, could have provided additional information to better understand the immunogenicity and/or safety profiles of the trial vaccines in terms of range, levels and longevity of responses against the different variants of the SARS-CoV-2. These are:

a. More even distribution of the test groups, though non-randomized, in terms of numbers (100µg booster dose group with the trial vaccine having 2X numbers as against the 50µg group in the study).

b. Inclusion of an additional “trial vaccine containing `only’ the mRNA sequence against the Beta-variant’s spike protein instead of the `bivalent’ one used”, as the majority of the variants circulating now being not the original one but more of Omicron type/subtypes; it only could have entailed a slightly higher number of study participants.

c. Inclusion of vaccines from the COVE trial who got the lower (50µg) dose primary series, as against only the higher (100µg) dose primary series vaccines for booster/follow-up data collection.

In addition, I am not sure why antibody profiles/titers against different sets of virus variants were shown for neutralizing vis-à-vis binding antibody titers; I believe that titers of these two ab. types against the same virus variant sets could also have given better comparability information.

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