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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 Cho, Alice and Jankovic, Mila and Schaefer-Babajew, Dennis and Oliveira, Thiago Y. and Cipolla, Melissa and Viant, Charlotte and Barnes, Christopher O. and Bram, Yaron and Breton, Gaëlle and Hägglöf, Thomas and Mendoza, Pilar 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 Martinez-Delgado, Gustavo and Yee, Jim and Patel, Roshni and Dizon, Juan and Unson-O’Brien, Cecille and Shimeliovich, Irina and Robbiani, Davide F. and Zhao, Zhen and Gazumyan, Anna and Schwartz, Robert E. and Hatziioannou, Theodora and Bjorkman, Pamela J. and Mehandru, Saurabh and Bieniasz, Paul D. and Caskey, Marina and Nussenzweig, Michel C. (2021) Evolution of antibody immunity to SARS-CoV-2. Nature, 591 (7851). pp. 639-644. ISSN 0028-0836. PMCID PMC8221082; PMC7654855. doi:10.1038/s41586-021-03207-w.

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[img] Image (JPEG) (Extended Data Fig. 3: Persistent longitudinal changes in the phenotypic landscape of B cells in individuals recovered from COVID-19) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 10: SARS-CoV-2 antigen and RNA is detectable in different intestinal segments in several individuals convalescent from COVID-19) - Supplemental Material
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection 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 with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. 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:Article
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URLURL TypeDescription ReadCube access Paper ItemCode article CentralArticle CentralDiscussion Paper
Gaebler, Christian0000-0001-7295-8128
Wang, Zijun0000-0002-2095-2151
Finkin, Shlomo0000-0003-4474-2658
Schaefer-Babajew, Dennis0000-0002-5380-2950
Oliveira, Thiago Y.0000-0002-2654-0879
Cipolla, Melissa0000-0001-8156-2512
Barnes, Christopher O.0000-0003-2754-5951
Hurley, Arlene0000-0003-0575-0233
Turroja, Martina0000-0001-9640-0559
Millard, Katrina G.0000-0003-2247-3178
Ramos, Victor0000-0001-8572-1621
Weisblum, Yiska0000-0002-9249-1745
Robbiani, Davide F.0000-0001-7379-3484
Gazumyan, Anna0000-0002-5976-9717
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:© 2021 Nature Publishing Group. Received 03 November 2020; Accepted 06 January 2021; Published 18 January 2021. We thank all study participants who devoted time to our research; B. Coller and S. Schlesinger, the Rockefeller University Hospital Clinical Research Support Office and nursing staff; M. Okawa Frank and R. B. Darnell for SARS-CoV-2 saliva PCR testing; C. M. Rice and all members of the M.C.N. laboratory for helpful discussions; M. Jankovic for laboratory support; and J. Vielmetter and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance. 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 grant EC 101003650 (D.F.R.); R37-AI64003 to P.D.B.; R01AI78788 to T. Hatziioannou; NCI R01CA234614, NIAID 2R01AI107301, NIDDK R01DK121072 and 1RO3DK117252 to R.E.S., NIH NIDDK R01 DK123749 01S1 to S.M. C.O.B. is supported by the HHMI Hanna Gray and Burroughs Wellcome PDEP fellowships. R.E.S. is an Irma Hirschl Trust Research Award Scholar. M.T. is supported by the Digestive Disease Research Foundation (DDRF). 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 programme, 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: Data are provided in Supplementary Tables 1–8. The raw sequencing data and computer scripts associated with Fig. 2 have been deposited at This study also uses data from a DRYAD accession linked to ref. 57 (, the Protein Data Bank (accession codes 6VYB and 6NB6) and ref. 53. Code availability: Computer code to process the antibody sequences is available at GitHub ( Author Contributions: C.G., P.D.B., P.J.B., T. Hatziioannou, S.M. and M.C.N. conceived, designed and analysed the experiments. D.F.R., M. Caskey and C.G. designed clinical protocols. Z.W., J.C.C.L., F.M., S.F., M. Tokuyama, A.C., M.J., D.S.-B., F.S., Y.W., T. Hägglöf, P.M., G.B., C.V., C.O.B., K.G., D.J., J.Y., G.M.-D., Y.B., R.E.S. 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., R.P, J.D. and C.U.-O. processed clinical samples. T.Y.O. and V.R. performed bioinformatic analysis. C.G, P.D.B., P.J.B., T. Hatziioannou, S.M. 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). R.E.S. is on the scientific advisory board of Miromatrix Inc and is a consultant and speaker for Alnylam Inc. S.M. has served as a consultant for Takeda Pharmaceuticals, Morphic and Glaxo Smith Kline. Z.Z. received seed instruments and sponsored travel from ET Healthcare. Peer review information: Nature thanks Michael Laue, Stanley Perlman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Group:Richard N. Merkin Institute for Translational Research, COVID-19
Funding AgencyGrant Number
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
NIHP50 AI150464-13
George Mason UniversityUNSPECIFIED
European ATAC ConsortiumEC 101003650
NIHR01 DK123749 01S1
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Irma Hirschl Trust Research AwardUNSPECIFIED
Digestive Disease Research FoundationUNSPECIFIED
Robert S. Wennett Postdoctoral FellowshipUNSPECIFIED
NIHUL1 TR001866
Shapiro-Silverberg Fund for the Advancement of Translational ResearchUNSPECIFIED
Subject Keywords:Antimicrobial responses; Humoral immunity; SARS-CoV-2
Issue or Number:7851
PubMed Central ID:PMC8221082; PMC7654855
Record Number:CaltechAUTHORS:20201105-121857214
Persistent URL:
Official Citation:Gaebler, C., Wang, Z., Lorenzi, J.C.C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021).
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:30 Aug 2021 22:48

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