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Review 1: "Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron-BA.2"

This preprint investigates the efficacy of 2/3 dose regimes of vaccines against Omicron BA.2 infection. Reviewers overall find this study informative, but highlight technical issues, and stylistic issues of results, that impact the conclusions drawn from the presented data.

Published onJun 08, 2022
Review 1: "Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron-BA.2"
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key-enterThis Pub is a Review of
Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron-BA.2

SummaryThe ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the world model city of universal masking, has resulted in a major public health crisis. In this study, we investigate public servants who had been vaccinated with two dose (82.7%) or three dose (14%) of either CoronaVac (CorV) or BNT162b2 (BNT). During the BA.2 outbreak, 29.3% vaccinees were infected. Three-dose vaccination provided protection with lower incidence rates of breakthrough infections (2×BNT 49.2% vs 3×BNT 16.6%, p<0.0001; 2×CorV 48.6% vs 3×CoV 20.6%, p=0.003). The third heterologous vaccination showed the lowest incidence (2×CorV+1×BNT 6.3%). Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested, the third dose vaccination-activated spike-specific memory B and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Our results have implications to timely boost vaccination and immune responses likely required for vaccine-mediated protection against Omicron BA.2 pandemic.

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.



The evidence and arguments presented are strong and support the advancement of COVID-19 understanding. The manuscript also provides important information about different booster schemes against omicron and comparison with other viral variants; however, it requires several improvements. Understanding this mechanism is crucial in developing health policies associated with the pandemic and suggesting the steps to follow in terms of population immunization.

The manuscript requires improvements to be ready for publication, specifically in the writing of the results and discussion, since this makes it difficult to read. Regarding some references, it is necessary to cite the original references of where they originate, especially from the methods, such as the determination of neutralizing antibodies initially published by Beltran-Pavez et al. 2021. It is necessary to simplify; for example, when ages and doses are compared, it can be said that for the two doses, the age was significantly lower than the 3rd dose in all cases; refer to the table. Also, the nomenclature can be simplified since the comparison of the boosters is made with respect to the complete schemes with a single type of vaccine. Similarly, a large amount of information and how it is presented in results makes it difficult to understand it globally, which is why it is suggested to include a summary table, that includes the different parameters analyzed. The analysis of the Correlogram of clinical characteristics and immune responses among patients does not contribute much to the work and complicates the vision of parameters that may be interesting. In this case, it is better to show and perform analysis regarding also data that may be of interest and shows a correlation indicating that there are cases in which it does not occur. Since the absence of correlation in several aspects has been previously concluded, it is difficult to understand why this type of analysis is incorporated in the work. The discussion section should include comparisons with literature, including similar vaccination schedules (for instance, Coronavac in Chile and Brazil), different vaccination schedules, and comparisons with respect to similar booster schemes. You should at least compare epidemiology and baseline data (for instance, 10.3389/fimmu.2021.766278) from other reports. If there are no data regarding the immune response associated with the booster, it is necessary to compare using epidemiological data. The description of the results in the discussion section should be deleted.

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