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Review 2: "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 2: "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:

  • 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.



This manuscript is of great interest to the COVID-19 vaccine community due to the current concerns about the efficacy of the COVID-19 vaccine schemes in protecting against SARS-CoV-2 Omicron BA.2 infection and preventing against severe disease. Although there have been other papers in the literature approaching this subject, this study may raise interest in the clinical and scientific community as it includes data on CoronaVac, a whole SARS-CoV-2-inactivated vaccine administered to over 2 billion people worldwide. The manuscript is not well written. It is hard to follow, and some sentences are not framed correctly. The analyses of humoral and cellular immune responses presented in this manuscript are not limited in scope. Still, some issues may impact drawing their conclusions from their data. Firstly, the authors claimed that “BA.2 infections were confirmed by governmental reverse transcriptase-polymerase chain reaction (RT-PCR) or lateral flow-based rapid antigen test (RAT) during the study period” (lines 83-85). However, it is not possible to confirm infection by BA.2 by these methods. Secondly, as the days between 3rd vaccine dose and blood collection vary among the vaccinee groups and the individuals within a vaccinee group (especially for the blood collection at earlier days post-3rd dose vaccination) (Table S2), presenting the data on B and T responses grouped as 0–4 weeks may not be appropriate. There is also an issue with correlating data about immune responses and infection rates and days of hospitalization rates: how were these rates distributed among vaccinee subgroups selected for immune response evaluation?

In summary, although the data shown are quite interesting, the manuscript requires a major revision. Altogether the issues described above render the manuscripts to be lacking impact.

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