Review 1: "mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants"

Rino Rappuoli

doi:doi:10.1162/2e3983f5.cc94515d

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

by Zijun Wang, Fabian Schmidt, Yiska Weisblum, Frauke Muecksch, Christopher O. Barnes, Shlomo Finkin, Dennis Schaefer-Babajew, Melissa Cipolla, Christian Gaebler, Jenna A. Lieberman, Thiago Y. Oliveira, Zhi Yang, Morgan E. Abernathy, Kathryn E. Huey-Tubman, Arlene Hurley, Martina Turroja, Kamille A. West, Kristie Gordon, Katrina G. Millard, Victor Ramos, Justin Da Silva, Jianliang Xu, Robert A. Colbert, Roshni Patel, Juan Dizon, Cecille Unson-O’Brien, Irina Shimeliovich, Anna Gazumyan, Marina Caskey, Pamela J. Bjorkman, Rafael Casellas, Theodora Hatziioannou, Paul D. Bieniasz, and Michel C. Nussenzweig

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dx.doi.org

Description

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3–6. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers3,5,6. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The manuscript by Wang et al describes a number of experiments that provide an early view of how the emerging SARS-CoV-2 variants of concern may affect the neutralizing potency of vaccines and monoclonal antibodies. Briefly, they take sera from 20 people vaccinated with Moderna or Pfizer vaccines and they show that both induce antibodies that are equivalent to those found in convalescents 1.3 months after infections. Then they tested the sera pseudotypes containing the major mutations present in the variants of concern and found that mutations K417N, E484K, and N501Y affect the recognition by most of the sera.

Similarly, observations are found using a panel of monoclonal antibodies. Interestingly, the monoclonal antibodies have the same mutations when incubated in vitro with replicating pseudoviruses.

I find the study well done, very timely, and consistent with the information coming from other groups.

The data can inform policymakers on how to manage the COVID-19 pandemic and the design of vaccines and monoclonal antibodies to control emerging variants