RR:C19 Evidence Scale rating by reviewer:
The strength of the evidence in the current study is strong specifically that the main study claims are very well-justified by the data and analytic methods used.
The current study uses systems serology to describe the humoral responses to the three available vaccines in the United States against SARS-CoV-2 in an immunologically unbiased fashion in pregnant woman and concordant cord blood samples. This approach is highly effective and reveals the nuances of humoral immunity by providing a extensive profiling of the antibody response over a broad repertoire of humoral immune responses, and importantly provides functional data over a comprehensive range of antibody functions. This adds strength and importance to the study, not only to help clinicians understand how to vaccinate pregnant woman but also scientists trying to determine the nuances of the humoral immune response to COVID19 vaccines. The importance of this methodology is highlighted in the results of the study, not only allowing the authors to identify detailed differences in the immune responses between the vaccines, but importantly between maternal and fetal enrichment, which is vital for understanding placental transfer of humoral immune response specific to SARS-CoV-2 but also generally.
While the study is strong there are some limitations that are important to consider. This is not a randomized trial and therefore the vaccine platforms were not uniformly represented, however the differences were not statistically significant, and the baseline demographics were equivalent in the groups except for ethnicity. This makes the findings in the study unbiased for the characteristics measured. It should be noted that the chosen characteristics are important for birth outcomes, COVID-19 outcomes and potentially for immunogenicity to vaccines.
As mentioned, race and ethnicity are not well represented and therefore the generalizability of the results is not well supported. In addition, the distribution of insurance favored those with private insurance which is a marker for socioeconomic status and thus the diversity for this demographic was missing. These are important considerations.
Lastly, the number of women who were vaccinated in the first trimester was very small, thus leaving room for further evaluation of the findings pertaining to this timing of vaccination. This is particularly important in view of the conclusion that immunization should be adminsitered early in pregnancy. However, even in the context of this limitation, the findings are consistent with what is known about the immune system in pregnancy and the transfer of antibodies transplacentally. In addition, the authors provide comprehensive discussion on this point.
The first set of findings concentrate on comparisons of humoral immunity in pregnant woman, with findings that are consistent with what has been published regarding the differences between the mRNA and the adenovirus-vectored vaccine (Ad26.COV2.S) but advance the science in providing an understanding of why there may be a titer difference between the platforms. Now that booster doses are recommended for those receiving all three authorized vaccines these differences for the Ad26.COV2.S may become less evident and therefore less relevant given that Click here to access/download;Review;Rapid review.docx 2 does of the mRNA vaccines showed relatively equivalent responses. This will require further study. The authors do provide an evidence-based recommendation regarding boosters suggesting initial early priming doses with a late pregnancy booster dose, which is based to some degree in the results of the current study. The discussion on these points is well considered.
A very important caveat for all data comparing humoral immunity is that no protective titer against COVID has been established thus even the lowest titers and function measured may provide protection and higher titers do not necessarily provide better protection, Nonetheless the latter are expected to remain protective for longer. Modelling suggests that neutralizing assays may be predictive and thus the FcR-binding capacity used in this study may serve as a correlate however this association is yet to be tested.
Conclusions stating that mRNA-1273 vaccine shows functional advantages over BNT162b2 vaccine need further discussion given that the only differences observed were in IgG2 subclasses and the relevance of this subclass for viral immunity may not be important in the context of protection against COVID-19.
The evaluation of the immunogenicity of the vaccines by trimester is sound and important, except with the limitation of the relatively low number of woman who were vaccinated in the first trimester making some evaluations impossible and calling into question any conclusion in this cohort. However, the findings are consistent for all the evaluations measured which provides some consistency and validity to the results. The results highlighting the transplacental transfer of humoral immunity are important, with the results largely consistent with what is known, thus adding validity, but enhancing knowledge by showing enrichment of specific humoral immunity.
In summary, this is an elegant study that provides important confirmatory data and new insights into SARS-CoV-2 antibody responses during pregnancy and advances the knowledge in maternal-fetal vaccinology. While some limitations are highlighted above the overall strength of results and validity of the conclusions is high.