The receptor binding domain of SARS-CoV-2 spike is the key target of neutralizing antibody in human polyclonal sera
Abstract
Natural infection of SARS-CoV-2 in humans leads to the development of a strong neutralizing antibody response, however the immunodominant targets of the polyclonal neutralizing antibody response are still unknown. Here, we functionally define the role SARS-CoV-2 spike plays as a target of the human neutralizing antibody response. In this study, we identify the spike protein subunits that contain antigenic determinants and examine the neutralization capacity of polyclonal sera from a cohort of patients that tested qRT-PCR-positive for SARS-CoV-2. Using an ELISA format, we assessed binding of human sera to spike subunit 1 (S1), spike subunit 2 (S2) and the receptor binding domain (RBD) of spike. To functionally identify the key target of neutralizing antibody, we depleted sera of subunit-specific antibodies to determine the contribution of these individual subunits to the antigen-specific neutralizing antibody response. We show that epitopes within RBD are the target of a majority of the neutralizing antibodies in the human polyclonal antibody response . These data provide critical information for vaccine development and development of sensitive and specific serological testing.
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Most serum nAb responses elicited during natural infection are directed at the RBD.
“Most serum nAb responses elicited during natural infection are directed at the RBD (21, 23, 30, 31).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [31]
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Emerging SARS-CoV-2 Variants of Concern (VOCs): An Impending Global Crisis
Thye, A. Y.-K., Law, J. W., Pusparajah, P., Letchumanan, V., Chan, K., & Lee, L. (2021) · Biomedicines · doi:10.3390/biomedicines9101303 · Cited by 116 · see citing works
“Several studies showed that RBD-binding antibodies account for most of the plasma neutralizing activity of most convalescent human plasma and sera [147,155].”
BackgroundConcerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination
Cobey, S. E., Larremore, D. B., Grad, Y. H., & Lipsitch, M. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00544-9 · Cited by 118 · see citing works
“…antibodies to the spike protein are likely a major component of protection after either kind of exposure (Addetia et al. 2020; Zost et al. 2020; Steffen et al. 2020), and genetic variants that escape polyclonal sera after natural infection have already been identified (Weisblum et al. 2020;…”
BackgroundWang, W. B., Liang, Y., Jin, Y. Q., Zhang, J., Su, J. G., & Li, Q. M. (2021) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2021.108035 · Cited by 80 · see citing works
“In addition, many studies have indicated that the S protein, especially the RBD, contains the major neutralizing epitopes, and the RBD-targeting antibodies immunodominantly contribute to the neutralizing activity of the convalescent sera from SARSCoV-2 infected patients[21-23].”
Focosi, D., Maggi, F., Mazzetti, P., & Pistello, M. (2020) · Reviews in Medical Virology · doi:10.1002/rmv.2170 · Cited by 57 · see citing works
“the target of a majority of the nAb in the human polyclonal antibody response.(8) Barnes et al.”
BackgroundAhmad, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.742167 · Cited by 46 · see citing works
Farrell, A. G., Dadonaite, B., Greaney, A. J., Eguia, R. T., Loes, A. N., Franko, N., Logue, J. K., Carreño, J. M., Abbad, A., Chu, H. Y., et al. (2022) · Viruses · doi:10.3390/v14092061 · Cited by 33 · see citing works
Sariol, C. A., Pantoja, P., Serrano-Collazo, C., Rosa-Arocho, T., Armina-Rodríguez, A., Cruz, L. A., Stone, E. T., Arana, T., Climent, C., Latoni, G., et al. (2021) · Viruses · doi:10.3390/v13101972 · Cited by 31 · see citing works
“Using previous experience from our group [28,38], those experiments are underway using a larger number of well characterized individuals.”
MethodSelf-citationHassert, M., Geerling, E., Stone, E. T., Steffen, T. L., Feldman, M. S., Dickson, A. M., Class, J., Richner, J. M., Brien, J. D., & Pinto, A. K. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1009163 · Cited by 32 · see citing works
Self-citationTharmalingam, T., Han, X., Wozniak, A., & Saward, L. L. (2021) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2021.1886560 · Cited by 27 · see citing works
Virtanen, J. M. E., Uusitalo, R., Korhonen, E. M., Aaltonen, K., Smura, T., Kuivanen, S. H., Pakkanen, S. H., Mero, S., Patjas, A., Riekkinen, M., et al. (2021) · Viruses · doi:10.3390/v13060996 · Cited by 24 · see citing works
State of the Art in Epitope Mapping and Opportunities in COVID-19
Hamed, S. M., Sakr, M. M., El-Housseiny, G. S., Wasfi, R., & Aboshanab, K. M. (2023) · Future Science OA · doi:10.2144/fsoa-2022-0048 · Cited by 15 · see citing works
“Several reports mentioned that RBD-binding antibodies constitute the majority of the neutralizing activity observed in plasma of convalescent patients [66,67].”
BackgroundKumar, N., Kaushik, R., Zhang, K. Y. J., Uversky, V. N., Sahu, U., Sood, R., & Bhatia, S. (2023) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.26467 · Cited by 15 · see citing works
“43 These NAbs targeting the RBD or NTD of the spike protein offer protections by inhibiting the attachment of SARS-CoV-2 spike protein to ACE2 receptor on the target cells.”
BackgroundVaccine Candidate Against COVID-19 Based on Structurally Modified Plant Virus as an Adjuvant
Kovalenko, A. O., Ryabchevskaya, E. M., Evtushenko, E. A., Manukhova, T. I., Kondakova, O. A., Pa, I., Arkhipenko, M. V., Gushchin, V. А., Nikitin, N. A., & Karpova, O. V. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.845316 · Cited by 13 · see citing works
Liang, Y., Zhang, J., Yuan, R. Y., Wang, M. Y., He, P., Su, J. G., Han, Z. B., Jin, Y. Q., Hou, J. W., Zhang, H., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.18.448958 · Cited by 7 · see citing works
Jana, I. D., Kanjo, K., Roy, S., Bhasin, M., Bhattacharya, S., Banerjee, I., Jana, S., Chatterjee, A., Chakraborty, A., Chakraborty, S. K., et al. (2025) · Journal of Virology · doi:10.1128/jvi.00051-25 · Cited by 1 · see citing works
McKechnie, J. L., Fiala, B., Wolf, C., Ellis, D., Holtzman, D. A., & Feldhaus, A. L. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.29.518404 · Cited by 1 · see citing works
McCann, N. R., & Castellino, F. (2026) · Bioscience Reports · doi:10.1042/bsr20260440
- Authors
- Steffen, T. L., Stone, E. T., Hassert, M., Geerling, E., Grimberg, B. T., Espino, A. M., Pantoja, P., Climent, C., Hoft, D. F., George, S. L., Sariol, C. A., Pinto, A. K., & Brien, J. D.
- Affiliations
- Saint Louis University (US)
- Case Western Reserve University (US)
- University of Puerto Rico, Medical Sciences Campus (PR)
- Saint Louis University (ES)
- Corresponding author
- Pinto, Amelia K.
- Brien, James D.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-08-22
- OpenAlex
- W3080825851
- Cited by
- 25
- References
- 60
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2022: 3 · 2021: 13 · 2020: 5
- Type
- posted content
- Language
- en
- Open access
- closed
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Keywords
- SARS-CoV-2, spike protein, receptor binding domain, neutralizing antibodies, antigenic determinants, S1 subunit, S2 subunit, natural infection, vaccine development, serological testing
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