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Evolution of Antibody Immunity to SARS-CoV-2

Gaebler, Christian and Wang, Zijun and Lorenzi, Julio C. C. and Muecksch, Frauke and Finkin, Shlomo and Tokuyama, Minami and Ladinsky, Mark and Cho, Alice and Jankovic, Mila and Schaefer-Babajew, Dennis and Oliveira, Thiago Y. and Cipolla, Melissa and Viant, Charlotte and Barnes, Christopher O. and Hurley, Arlene and Turroja, Martina and Gordon, Kristie and Millard, Katrina G. and Ramos, Victor and Schmidt, Fabian and Weisblum, Yiska and Jha, Divya and Tankelevich, Michael and Yee, Jim and Shimeliovich, Irina and Robbiani, Davide F. and Zhao, Zhen and Gazumyan, Anna and Hatziioannou, Theodora and Bjorkman, Pamela J. and Mehandru, Saurabh and Bieniasz, Paul D. and Caskey, Marina and Nussenzweig, Michel C. (2020) Evolution of Antibody Immunity to SARS-CoV-2. . (Unpublished)

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SARS-CoV-2 has infected 47 million individuals and is responsible for over 1.2 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 3 months after COVID-19 onset, using immunofluorescence, electron tomography or polymerase chain reaction, revealed persistence of SARS-CoV-2 in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemData article ItemCode
Gaebler, Christian0000-0001-7295-8128
Finkin, Shlomo0000-0003-4474-2658
Ladinsky, Mark0000-0002-1036-3513
Barnes, Christopher O.0000-0003-2754-5951
Hurley, Arlene0000-0003-0575-0233
Weisblum, Yiska0000-0002-9249-1745
Robbiani, Davide F.0000-0001-7379-3484
Hatziioannou, Theodora0000-0002-7889-0766
Bjorkman, Pamela J.0000-0002-2277-3990
Bieniasz, Paul D.0000-0002-2368-3719
Caskey, Marina0000-0003-1727-8693
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 November 5, 2020. We thank all study participants who devoted time to our research; Drs. Barry Coller and Sarah Schlesinger, the Rockefeller University Hospital Clinical Research Support Office and nursing staff. Mayu Okawa Frank and Robert B. Darnell for SARS-CoV-2 saliva PCR testing. Charles M. Rice 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 P.J.B.) and 2U19AI111825 (M.C.N.).; the Caltech Merkin Institute for Translational Research and P50 AI150464-13 (P.J.B.), George Mason University Fast Grant (D.F.R. and P.J.B.) and the European ATAC consortium EC 101003650 (D.F.R.); 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. Electron microscopy was performed in the Caltech Beckman Institute Resource Center for Transmission Electron Microscopy. 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. Data availability statement: Data are provided in SI Tables 1-7. The raw sequencing data associated with Figure 2 has been deposited at Github ( This study also uses data from “A Public Database of Memory and Naive B-Cell Receptor Sequences” (, PDB (6VYB and 6NB6) and from “High frequency of shared clonotypes in human B cell receptor repertoires” ( Code availability statement: Computer code to process the antibody sequences is available at GitHub ( Author Contributions: C.G., P.D.B., P.J.B., T.H., S.B. and M.C.N. conceived, designed and analyzed the experiments. D.F.R., M.Caskey. and C.G. designed clinical protocols. Z.W., J.C.C.L., F.M., S.F., M.T., M.L., A.C., M.J., D.S.B., F.S., Y.W., C.V., C.O.B., K.G., D.J., J.Y. and Z.Z. carried out experiments. A.G. and M.Cipolla produced antibodies. A.H., D.S.B., M.Turroja, K.G.M., M.Tankelevich, C.G. and M.Caskey recruited participants and executed clinical protocols. I.S. processed clinical samples. T.Y.O. performed bioinformatic analysis. C.G, P.D.B., P.J.B., T.H., S.B. and M.C.N. wrote the manuscript with input from all co-authors. Competing interests: The Rockefeller University has filed a provisional patent application in connection with this work on which D.F.R. and M.C.N. are inventors (US patent 63/021,387).
Group:Richard N. Merkin Institute for Translational Research
Funding AgencyGrant Number
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
NIHP50 AI150464-13
George Mason UniversityUNSPECIFIED
European ATAC ConsortiumEC 101003650
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:20201105-121857214
Persistent URL:
Official Citation:Evolution of Antibody Immunity to SARS-CoV-2. Christian Gaebler, Zijun Wang, Julio C. C. Lorenzi, Frauke Muecksch, Shlomo Finkin, Minami Tokuyama, Mark Ladinsky, Alice Cho, Mila Jankovic, Dennis Schaefer-Babajew, Thiago Y. Oliveira, Melissa Cipolla, Charlotte Viant, Christopher O. Barnes, Arlene Hurley, Martina Turroja, Kristie Gordon, Katrina G. Millard, Victor Ramos, Fabian Schmidt, Yiska Weisblum, Divya Jha, Michael Tankelevich, Jim Yee, Irina Shimeliovich, Davide F. Robbiani, Zhen Zhao, Anna Gazumyan, Theodora Hatziioannou, Pamela J. Bjorkman, Saurabh Mehandru, Paul D. Bieniasz, Marina Caskey, Michel C. Nussenzweig. bioRxiv 2020.11.03.367391; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106451
Deposited By: Tony Diaz
Deposited On:05 Nov 2020 20:42
Last Modified:05 Nov 2020 20:42

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