Review 2: "SARS-CoV-2 Correlates of Protection from Infection Against Variants of Concern"

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: In the context of natural immunity and immune evasion by SARS-CoV-2 variants, it is essential to identify the protective factors induced by natural infection and/or vaccination against SARS-CoV-2 variants. Of particular importance is the need for further study on the efficacy of serum neutralizing antibodies (nAbs) in preventing infection acquisition. This is an epidemiological study that utilizes unique serological and epidemiological data from the SARS-CoV-2, influenza, and respiratory syncytial virus community burden, transmission dynamics, and viral interaction in South Africa (PHIRST-C) cohort for conducting mediation analysis. In comparison with the Delta wave subgroup, the Omicron wave subgroup conducted further investigation into the impact of immune evasion on protection via neutralizing antibodies. It was observed that the overall protection conferred by anti-Omicron BA.1 subtype neutralizing antibodies against Omicron BA.1/2 wave infection was lower than that provided by anti-D614G neutralizing antibodies against previous exposure to SARS-CoV-2 during the Delta infection wave. The study also revealed that the likelihood of transmitting SARS-CoV-2 to other family members in cases of Omicron reinfections did not differ from that in initial infections, and that natural infection-induced immune protection against SARS-CoV-2 could not be fully accounted for by serum neutralizing antibodies. In general, this study has passed ethical review, taking into account the complexity of the COVID-19 research background. It has adopted reasonable cohorts and described the existing limitations, providing important reference opinions for this field. This study provides data support for understanding and predicting immune protection against SARS-CoV-2.

Major concerns:

1. Although this study was well-designed and had defined inclusion criteria for the population, the main research sites only included one rural and one urban location in two provinces of South Africa. Considering the different epidemiological characteristics and population features across regions, it may be difficult to generalize these findings to other countries. This limitation was not mentioned in the discussion section, but should be thoroughly discussed in the manuscript as potential biases that could affect the reliability of the conclusions.

2. This study employed mathematical modeling analysis and considered confounding factors. However, in real-life situations, it may still be challenging to fully account for all factors when applying mathematical models and selecting parameters. These limitations can be addressed by discussing them explicitly within the limitations section.

3. There are several limitations in this study, which have been explained. However, whether the factor of incomplete antigen strain matching can be avoided by increasing relevant experiments to provide stronger support for the research remains uncertain.

Minor points:

1. This study analyzed the incidence of different types of populations, and further detailed explanations or tables can be made regarding the infection situation in Table 1. For example, during the delta wave, there were 229 infections among unvaccinated individuals and 44 infections among participants who had previously been infected.

2. Table 1 also involves the HIV infection status of the population, which can be further analyzed and discussed.

3. Since some of the surveyed population had experienced previous infections, it is recommended to consider using "infection or reinfection" for specific descriptions, such as the infection situation among participants during Delta wave at line 133.