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Review 1: "Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles"

Published onMar 25, 2022
Review 1: "Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles"
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key-enterThis Pub is a Review of
Subtle immunological differences in mRNA-1273 and BNT162b2 COVID-19 vaccine induced Fc-functional profiles

AbstractThe successful development of several COVID-19 vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants, able to evade vaccine induced neutralizing antibodies, real world vaccine efficacy has begun to show differences across the mRNA platforms, suggesting that subtle variation in immune responses induced by the BNT162b2 and mRNA1273 vaccines may provide differential protection. Given our emerging appreciation for the importance of additional antibody functions, beyond neutralization, here we profiled the postboost binding and functional capacity of the humoral response induced by the BNT162b2 and mRNA-1273 in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to WT SARS-CoV-2 and VOCs. However, differences emerged across epitopespecific responses, with higher RBD- and NTD-specific IgA, as well as functional antibodies (ADNP and ADNK) in mRNA-1273 vaccine recipients. Additionally, RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector function induced across the mRNA vaccines, providing novel insights into potential differences in protective immunity generated across these vaccines in the setting of newly emerging VOCs.

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.



In my opinion, this manuscript provides reliable results that are well justified by the data and analytic methods used. The data was clearly and accurately presented and shows that overall, both BNT162b2 and mRNA1273 mRNA-based vaccines induce similar immunological responses, which differ very subtlely. BNT162b2 induces more IgM titer and IgG1 levels across all VOCs and mRNA1273 induces much more IgA and functional ADNP & ADNK, as referenced in the title of the manuscript. However, although at the present time the immunological differences found herein are insufficient to explain the observed differences in the protective immunity generated across these vaccines when facing new emerging VOCs, it would not be improbable that such differences really played a relevant role. However, it is necessary to recall that this work was done with samples collected in the peak of immunity generated by both vaccines and did not take into account how these discrete differences in antibody isotypes and antibody functionality vary as antibody titers decline over time in response to vaccines. Although in this work the responses induced by mRNA vaccines and those induced by the natural infection were compared the data obtained cannot be considered relevant or representative of each one because the number of samples included in this comparison was very few.

The observation of higher functional ADNP and ADNK in individuals that received the mRNA1273 vaccine than in those that received the BNT162b2 vaccine is interesting but the potential beneficial or prejudicial implications of these observations require more studies. In Ebola, for example (, the high levels of IgG1 specific for GP were detected in individuals that survive the infection, whereas those that developed ADCP or ADNK had less odds of developing the most common sequelae to the virus. It is unknown whether in the COVID-19 context the differences in functionality of antibodies detected herein for mRNA1273 vaccine could be interpreted as a good signal or could actually be irrelevant.

Based on my understanding, the scope of the study is basically descriptive and not focused on addressing whether the differences found are going to contribute to differences in efficacy across vaccines over time, which will require long-term follow-up studies. From this perspective, I consider that the manuscript is acceptable for publication. However, I would strongly encourage the authors to expand and improve the discussion comparing their results with those obtained by other authors in the context of diseases such as Ebola, malaria, influenza, etc. in which the Fc-effector function has been extensively scrutinized.

An ethical committee approved the work and although it included individuals of different races, sexes, and ethnicities, the differences found were not associated with any of these factors.



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