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Vaccination boosts naturally enhanced neutralizing breadth to SARS-CoV-2 one year after infection

Wang, Zijun and Muecksch, Frauke and Schaefer-Babajew, Dennis and Finkin, Shlomo and Viant, Charlotte and Gaebler, Christian and Barnes, Christopher O. and Cipolla, Melissa and Ramos, Victor and Oliveira, Thiago Y. and Cho, Alice and Schmidt, Fabian and da Silva, Justin and Bednarski, Eva and Daga, Mridushi and Turroja, Martina and Millard, Katrina G. and Jankovic, Mila and Gazumyan, Anna and Bieniasz, Paul D. and Caskey, Marina and Hatziioannou, Theodora and Nussenzweig, Michel C. (2021) Vaccination boosts naturally enhanced neutralizing breadth to SARS-CoV-2 one year after infection. Nature Publishing Group . (In Press)

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Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naive individuals. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants. Should memory responses evolve in a similar manner in vaccinated individuals, additional appropriately timed boosting with available vaccines could cover most circulating variants of concern.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemCode
Wang, Zijun0000-0002-2095-2151
Muecksch, Frauke0000-0002-0132-5101
Schaefer-Babajew, Dennis0000-0002-5380-2950
Finkin, Shlomo0000-0003-4474-2658
Gaebler, Christian0000-0001-7295-8128
Barnes, Christopher O.0000-0003-2754-5951
Cipolla, Melissa0000-0001-8156-2512
Ramos, Victor0000-0001-8572-1621
Oliveira, Thiago Y.0000-0002-2654-0879
Turroja, Martina0000-0001-9640-0559
Millard, Katrina G.0000-0003-2247-3178
Gazumyan, Anna0000-0002-5976-9717
Bieniasz, Paul D.0000-0002-2368-3719
Caskey, Marina0000-0003-1727-8693
Hatziioannou, Theodora0000-0002-7889-0766
Nussenzweig, Michel C.0000-0003-0592-8564
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted May 9, 2021. We thank all study participants who devoted time to our research; The Rockefeller University Hospital nursing staff and Clinical Research Support Office and nursing staff. Mayu Okawa Frank, Marissa Bergh, and Robert B. Darnell for SARS-CoV-2 saliva PCR testing. Charles M. Rice, Pamela J. Bjorkman and all members of the M.C.N. laboratory for helpful discussions and Maša Jankovic for laboratory support. This work was supported by NIH grant P01-AI138398-S1 (M.C.N.) and 2U19AI111825 (M.C.N.). R37-AI64003 to P.D.B.; R01AI78788 to T.H.; We thank Dr. Jost Vielmetter and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance. C.O.B. is supported by the HHMI Hanna Gray and Burroughs Wellcome PDEP fellowships. C.G. was supported by the Robert S. Wennett Post-Doctoral Fellowship, in part by the National Center for Advancing Translational Sciences (National Institutes of Health Clinical and Translational Science Award program, grant UL1 TR001866), and by the Shapiro-Silverberg Fund for the Advancement of Translational Research. P.D.B. and M.C.N. are Howard Hughes Medical Institute Investigators. Code availability statement: Computer code to process the antibody sequences is available at GitHub ( Data presentation: Figures arranged in Adobe Illustrator 2020. Author Contributions: P.D.B., T.H., and M.C.N. conceived, designed and analyzed the experiments. M. Caskey and C.G. designed clinical protocols. Z.W., F.M., D.S.B., S.F., C.V., J.D.S., E.B., C.O.B., F.S., A.C., and M.J. carried out experiments. A.G. and M. Cipolla produced antibodies. D.S.B., M.D., M.T., K.G.M., C.G. and M. Caskey recruited participants, executed clinical protocols and processed samples. T.Y.O. and V.R. performed bioinformatic analysis. Z.W., F.M, D.S.B., C.G. and M.C.N. wrote the manuscript with input from all co-authors. Competing Interest Statement: The Rockefeller University has filed a provisional patent application in connection with this work on which an inventor (US patent 63/021,387). The patent has been licensed by Rockefeller University to Bristol Meyers Squib.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Robert S. Wennett Postdoctoral FellowshipUNSPECIFIED
NIHUL1 TR001866
Shapiro-Silverberg Fund for the Advancement of Translational ResearchUNSPECIFIED
Record Number:CaltechAUTHORS:20210510-104403619
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Official Citation:Vaccination boosts naturally enhanced neutralizing breadth to SARS-CoV-2 one year after infection. Zijun Wang, Frauke Muecksch, Dennis Schaefer-Babajew, Shlomo Finkin, Charlotte Viant, Christian Gaebler, Christopher O Barnes, Melissa Cipolla, Victor Ramos, Thiago Y Oliveira, Alice Cho, Fabian Schmidt, Justin Da Silva, Eva Bednarski, Mridushi Daga, Martina Turroja, Katrina G Millard, Mila Jankovic, Anna Gazumyan, Paul D Bieniasz, Marina Caskey, Theodora Hatziioannou, Michel C Nussenzweig. bioRxiv 2021.05.07.443175; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109032
Deposited By: Tony Diaz
Deposited On:10 May 2021 17:54
Last Modified:02 Jun 2021 21:27

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