Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients
Mehul S Suthar, Matthew G Zimmerman, Robert C Kauffman, Grace Mantus, Susanne L Linderman, William H Hudson, Abigail Vanderheiden, Lindsay Nyhoff, Carl W Davis, Oluwaseyi Adekunle, Maurizio Affer, Melanie Sherman, Stacian Reynolds, Hans P Verkerke, David N Alter, Jeannette Guarner, Janetta Bryksin, Michael C Horwath, Connie M Arthur, Natia Saakadze, Geoffrey H Smith, Srilatha Edupuganti, Erin M Scherer, Kieffer Hellmeister, Andrew Cheng, Juliet A Morales, Andrew S Neish, Sean R Stowell, Filipp Frank, Eric Ortlund, Evan J Anderson, Vineet D Menachery, Nadine Rouphael, Aneesh K Mehta, David S Stephens, Rafi Ahmed, John D Roback, Jens Wrammert, Mehul S Suthar, Matthew G Zimmerman, Robert C Kauffman, Grace Mantus, Susanne L Linderman, William H Hudson, Abigail Vanderheiden, Lindsay Nyhoff, Carl W Davis, Oluwaseyi Adekunle, Maurizio Affer, Melanie Sherman, Stacian Reynolds, Hans P Verkerke, David N Alter, Jeannette Guarner, Janetta Bryksin, Michael C Horwath, Connie M Arthur, Natia Saakadze, Geoffrey H Smith, Srilatha Edupuganti, Erin M Scherer, Kieffer Hellmeister, Andrew Cheng, Juliet A Morales, Andrew S Neish, Sean R Stowell, Filipp Frank, Eric Ortlund, Evan J Anderson, Vineet D Menachery, Nadine Rouphael, Aneesh K Mehta, David S Stephens, Rafi Ahmed, John D Roback, Jens Wrammert
Abstract
SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
Keywords: COVID-19; SARS-CoV-2; coronavirus; humoral immune response; neutralizing antibody; protective immunity; receptor-binding protein; serology test; spike protein.
Conflict of interest statement
The authors declare no competing interests.
© 2020 The Author(s).
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References
- Bolles M., Donaldson E., Baric R. SARS-CoV and emergent coronaviruses: viral determinants of interspecies transmission. Curr. Opin. Virol. 2011;1:624–634.
- Deming D., Sheahan T., Heise M., Yount B., Davis N., Sims A., Suthar M., Harkema J., Whitmore A., Pickles R. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 2006;3:e525.
- Buchholz U.J., Bukreyev A., Yang L., Lamirande E.W., Murphy B.R., Subbarao K., Collins P.L. Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity. Proc. Natl. Acad. Sci. USA. 2004;101:9804–9809.
- Bosch B.J., van der Zee R., de Haan C.A., Rottier P.J. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J. Virol. 2003;77:8801–8811.
- Hoffmann M., Kleine-Weber H., Schroeder S., Kruger N., Herrler T., Erichsen S., Schiergens T.S., Herrler G., Wu N.H., Nitsche A. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181:271–280.
- Wang Q., Zhang Y., Wu L., Niu S., Song C., Zhang Z., Lu G., Qiao C., Hu Y., Yuen K.Y. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020;181:894–904.
- Tortorici M.A., Veesler D. Structural insights into coronavirus entry. Adv. Virus Res. 2019;105:93–116.
- Li F., Li W., Farzan M., Harrison S.C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005;309:1864–1868.
- Lu G., Hu Y., Wang Q., Qi J., Gao F., Li Y., Zhang Y., Zhang W., Yuan Y., Bao J. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013;500:227–231.
- Walls A.C., Park Y.J., Tortorici M.A., Wall A., McGuire A.T., Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181:281–292.
- ter Meulen J., van den Brink E.N., Poon L.L., Marissen W.E., Leung C.S., Cox F., Cheung C.Y., Bakker A.Q., Bogaards J.A., van Deventer E. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 2006;3:e237.
- Harcourt J., Tamin A., Lu X., Kamili S., Sakthivel S.K., Murray J., Queen K., Tao Y., Paden C.R., Zhang J. Severe Acute Respiratory Syndrome Coronavirus 2 from Patient with Coronavirus Disease, United States. Emerg. Infect. Dis. 2020;26:1266–1273.
- Rockx B., Corti D., Donaldson E., Sheahan T., Stadler K., Lanzavecchia A., Baric R. Structural basis for potent cross-neutralizing human monoclonal antibody protection against lethal human and zoonotic severe acute respiratory syndrome coronavirus challenge. J. Virol. 2008;82:3220–3235.
- Lee Y.L., Liao C.H., Liu P.Y., Cheng C.Y., Chung M.Y., Liu C.E., Chang S.Y., Hsueh P.R. Dynamics of anti-SARS-Cov-2 IgM and IgG antibodies among COVID-19 patients. J. Infect. 2020 doi: 10.1016/j.jinf.2020.04.019. Published online April 23, 2020.
- Okba N.M.A., Müller M.A., Li W., Wang C., GeurtsvanKessel C.H., Corman V.M., Lamers M.M., Sikkema R.S., de Bruin E., Chandler F.D. Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease 2019 Patients. Emerg. Infect. Dis. 2020;26:9.
- Bloch E.M., Shoham S., Casadevall A., Sachais B.S., Shaz B., Winters J.L., van Buskirk C., Grossman B.J., Joyner M., Henderson J.P. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J. Clin. Invest. 2020;130:2757–2765.
- Shen C., Wang Z., Zhao F., Yang Y., Li J., Yuan J., Wang F., Li D., Yang M., Xing L. Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. JAMA. 2020;323:1582–1589.
- Liu W., Fontanet A., Zhang P.H., Zhan L., Xin Z.T., Baril L., Tang F., Lv H., Cao W.C. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J. Infect. Dis. 2006;193:792–795.
- Amanat F., Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020;52:583–589.
- Smith K., Garman L., Wrammert J., Zheng N.Y., Capra J.D., Ahmed R., Wilson P.C. Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat. Protoc. 2009;4:372–384.
- Wrapp D., Wang N., Corbett K.S., Goldsmith J.A., Hsieh C.L., Abiona O., Graham B.S., McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367:1260–1263.
Source: PubMed