Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals
Davide F Robbiani, Christian Gaebler, Frauke Muecksch, Julio C C Lorenzi, Zijun Wang, Alice Cho, Marianna Agudelo, Christopher O Barnes, Anna Gazumyan, Shlomo Finkin, Thomas Hagglof, Thiago Y Oliveira, Charlotte Viant, Arlene Hurley, Hans-Heinrich Hoffmann, Katrina G Millard, Rhonda G Kost, Melissa Cipolla, Kristie Gordon, Filippo Bianchini, Spencer T Chen, Victor Ramos, Roshni Patel, Juan Dizon, Irina Shimeliovich, Pilar Mendoza, Harald Hartweger, Lilian Nogueira, Maggi Pack, Jill Horowitz, Fabian Schmidt, Yiska Weisblum, Eleftherios Michailidis, Alison W Ashbrook, Eric Waltari, John E Pak, Kathryn E Huey-Tubman, Nicholas Koranda, Pauline R Hoffman, Anthony P West Jr, Charles M Rice, Theodora Hatziioannou, Pamela J Bjorkman, Paul D Bieniasz, Marina Caskey, Michel C Nussenzweig, Davide F Robbiani, Christian Gaebler, Frauke Muecksch, Julio C C Lorenzi, Zijun Wang, Alice Cho, Marianna Agudelo, Christopher O Barnes, Anna Gazumyan, Shlomo Finkin, Thomas Hagglof, Thiago Y Oliveira, Charlotte Viant, Arlene Hurley, Hans-Heinrich Hoffmann, Katrina G Millard, Rhonda G Kost, Melissa Cipolla, Kristie Gordon, Filippo Bianchini, Spencer T Chen, Victor Ramos, Roshni Patel, Juan Dizon, Irina Shimeliovich, Pilar Mendoza, Harald Hartweger, Lilian Nogueira, Maggi Pack, Jill Horowitz, Fabian Schmidt, Yiska Weisblum, Eleftherios Michailidis, Alison W Ashbrook, Eric Waltari, John E Pak, Kathryn E Huey-Tubman, Nicholas Koranda, Pauline R Hoffman, Anthony P West Jr, Charles M Rice, Theodora Hatziioannou, Pamela J Bjorkman, Paul D Bieniasz, Marina Caskey, Michel C Nussenzweig
Abstract
During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21-5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
Conflict of interest statement
Declaration of conflict: In connection with this work The Rockefeller University has filed a provisional patent application on which D.F.R. and M.C.N. are inventors.
Figures
References
- Graham R. L., Donaldson E. F. & Baric R. S. A decade after SARS: strategies for controlling emerging coronaviruses. Nat Rev Microbiol 11, 836–848, doi:10.1038/nrmicro3143 (2013).
- Gralinski L. E. & Baric R. S. Molecular pathology of emerging coronavirus infections. J Pathol 235, 185–195, doi:10.1002/path.4454 (2015).
- Hoffmann M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 271–280 e278, doi:10.1016/j.cell.2020.02.052 (2020).
- Walls A. C. et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181, 281–292 e286, doi:10.1016/j.cell.2020.02.058 (2020).
- Jiang S., Hillyer C. & Du L. Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses. Trends Immunol, doi:10.1016/j.it.2020.03.007 (2020).
- Scheid J. F. et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458, 636–640, doi:10.1038/nature07930 (2009).
- Tiller T. et al. Autoreactivity in human IgG+ memory B cells. Immunity 26, 205–213, doi:10.1016/j.immuni.2007.01.009 (2007).
- Murugan R. et al. Clonal selection drives protective memory B cell responses in controlled human malaria infection. Sci Immunol 3, doi:10.1126/sciimmunol.aap8029 (2018).
- Briney B., Inderbitzin A., Joyce C. & Burton D. R. Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature 566, 393–397, doi:10.1038/s41586-019-0879-y (2019).
- ter Meulen J. et al. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med 3, e237, doi:10.1371/journal.pmed.0030237 (2006).
- Yuan M. et al. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633, doi:10.1126/science.abb7269 (2020).
- Walls A. C. et al. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell 176, 1026–1039 e1015, doi:10.1016/j.cell.2018.12.028 (2019).
- Pinto D. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature, doi:10.1038/s41586-020-2349-y (2020).
- Zhu Z. et al. Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies. Proc Natl Acad Sci U S A 104, 12123–12128, doi:10.1073/pnas.0701000104 (2007).
- Salazar G., Zhang N., Fu T. M. & An Z. Antibody therapies for the prevention and treatment of viral infections. NPJ Vaccines 2, 19, doi:10.1038/s41541-017-0019-3 (2017).
- Bournazos S. & Ravetch J. V. Anti-retroviral antibody FcgammaR-mediated effector functions. Immunol Rev 275, 285–295, doi:10.1111/imr.12482 (2017).
- Feinberg M. B. & Ahmed R. Advancing dengue vaccine development. Science 358, 865–866, doi:10.1126/science.aaq0215 (2017).
- Iwasaki A. & Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nat Rev Immunol, doi:10.1038/s41577-020-0321-6 (2020).
- Van Rompay K. K. A. et al. A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques. Proc Natl Acad Sci U S A 117, 7981–7989, doi:10.1073/pnas.2000414117 (2020).
- Plotkin S. A. Correlates of protection induced by vaccination. Clin Vaccine Immunol 17, 1055–1065, doi:10.1128/CVI.00131-10 (2010).
- Scheid J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637, doi:10.1126/science.1207227 (2011).
- Robbiani D. F. et al. Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico. Cell 169, 597–609 e511, doi:10.1016/j.cell.2017.04.024 (2017).
- Ehrhardt S. A. et al. Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV. Nat Med 25, 1589–1600, doi:10.1038/s41591-019-0602-4 (2019).
- Pappas L. et al. Rapid development of broadly influenza neutralizing antibodies through redundant mutations. Nature 516, 418–422, doi:10.1038/nature13764 (2014).
- Kane M. et al. Identification of Interferon-Stimulated Genes with Antiretroviral Activity. Cell Host Microbe 20, 392–405, doi:10.1016/j.chom.2016.08.005 (2016).
- Adachi A. et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol 59, 284–291 (1986).
- Wang Z. et al. Isolation of single HIV-1 Envelope specific B cells and antibody cloning from immunized rhesus macaques. J Immunol Methods 478, 112734, doi:10.1016/j.jim.2019.112734 (2020).
- Tiller T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329, 112–124, doi:10.1016/j.jim.2007.09.017 (2008).
- von Boehmer L. et al. Sequencing and cloning of antigen-specific antibodies from mouse memory B cells. Nat Protoc 11, 1908–1923, doi:10.1038/nprot.2016.102 (2016).
- Klein F. et al. Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants. J Exp Med 211, 2361–2372, doi:10.1084/jem.20141050 (2014).
- Schoofs T. et al. Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope. Immunity 50, 1513–1529 e1519, doi:10.1016/j.immuni.2019.04.014 (2019).
- Ye J., Ma N., Madden T. L. & Ostell J. M. IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res 41, W34–40, doi:10.1093/nar/gkt382 (2013).
- Gupta N. T. et al. Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics 31, 3356–3358, doi:10.1093/bioinformatics/btv359 (2015).
- Rubelt F. et al. Onset of immune senescence defined by unbiased pyrosequencing of human immunoglobulin mRNA repertoires. PLoS One 7, e49774, doi:10.1371/journal.pone.0049774 (2012).
- Kyte J. & Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol 157, 105–132, doi:10.1016/0022-2836(82)90515-0 (1982).
- Guy H. R. Amino acid side-chain partition energies and distribution of residues in soluble proteins. Biophys J 47, 61–70, doi:10.1016/S0006-3495(85)83877-7 (1985).
- DeWitt W. S. et al. A Public Database of Memory and Naive B-Cell Receptor Sequences. PLoS One 11, e0160853, doi:10.1371/journal.pone.0160853 (2016).
- Mastronarde D. N. Automated electron microscope tomography using robust prediction of specimen movements. J Struct Biol 152, 36–51, doi:10.1016/j.jsb.2005.07.007 (2005).
- Punjani A., Rubinstein J. L., Fleet D. J. & Brubaker M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods 14, 290–296, doi:10.1038/nmeth.4169 (2017).
- Goddard T. D., Huang C. C. & Ferrin T. E. Visualizing density maps with UCSF Chimera. J Struct Biol 157, 281–287, doi:10.1016/j.jsb.2006.06.010 (2007).
Source: PubMed