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Cited by 204SARS-CoV-2 and COVID-19 ResearchImmune responses and vaccinationsvaccines and immunoinformatics approaches

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S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit

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Nguyen-Contant, Phuong, Embong, A. Karim, Kanagaiah, Preshetha, Chaves, Francisco A., Yang, Hongmei, Branche, Angela R., Topham, David J., Sangster, Mark Y.·2020·mBio
DOI 10.1128/mbio.01991-20PMC PMC7520599

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Abstract

The recent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key issues are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and postinfection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study results also suggest that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.

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FIG 1 Serum IgG levels against SARS-CoV-2 and non-SARS-CoV-2 proteins in non-SARS-CoV-2-exposed and COVID-19 convalescent subjects. Sera were collected from (i) 21 healthy donors sampled from 2011 to 2014 (HD), (ii) 20 SARS-CoV-2-negative health care workers sampled in 2020 (HCW), and (iii) 26 COVID-19 convalescent subjects sampled 4 to 9 weeks after symptom onset (Conv). (A) Serum IgG concentrations measured by ELISA against the SARS-CoV-2 spike (S), receptor binding domain (RBD), S2 subunit, and nucleocapsid (N). Columns represent individual HD and convalescent subjects in order of ascending titers against S. The assigned cutoff for positivity is shown by the horizontal gray bar. (B) Proportions of serum IgG against SARS-CoV-2 RBD, S2, and N for individual convalescent subjects. (C) Serum IgG concentrations against the S protein of the HCoV OC43 in Conv, HD, and HCW subjects. (D to F) Serum IgG concentrations against the S protein of HCoV 229E (D), influenza virus H1 hemagglutinin (E), and TTd (F) in Conv and HD subjects. (G) Correlation between serum IgG concentrations against the S2 subunit of SARS-CoV-2 and the S protein of the HCoV OC43. Significance (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant) for comparisons of serum IgG concentrations between subject groups was determined by the Wilcoxon rank sum test. Correlations were tested by Spearman correlation analysis with corresponding robust regression models.
FIG 1 Serum IgG levels against SARS-CoV-2 and non-SARS-CoV-2 proteins in non-SARS-CoV-2-exposed and COVID-19 convalescent subjects. Sera were collected from (i) 21 healthy donors sampled from 2011 to 2014 (HD), (ii) 20 SARS-CoV-2-negative health care workers sampled in 2020 (HCW), and (iii) 26 COVID-19 convalescent subjects sampled 4 to 9 weeks after symptom onset (Conv). (A) Serum IgG concentrations measured by ELISA against the SARS-CoV-2 spike (S), receptor binding domain (RBD), S2 subunit, and nucleocapsid (N). Columns represent individual HD and convalescent subjects in order of ascending titers against S. The assigned cutoff for positivity is shown by the horizontal gray bar. (B) Proportions of serum IgG against SARS-CoV-2 RBD, S2, and N for individual convalescent subjects. (C) Serum IgG concentrations against the S protein of the HCoV OC43 in Conv, HD, and HCW subjects. (D to F) Serum IgG concentrations against the S protein of HCoV 229E (D), influenza virus H1 hemagglutinin (E), and TTd (F) in Conv and HD subjects. (G) Correlation between serum IgG concentrations against the S2 subunit of SARS-CoV-2 and the S protein of the HCoV OC43. Significance (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant) for comparisons of serum IgG concentrations between subject groups was determined by the Wilcoxon rank sum test. Correlations were tested by Spearman correlation analysis with corresponding robust regression models.CC BY · PubMed Central
FIG 2 Analysis of IgG memory B cells (MBCs) reactive to SARS-CoV-2 and non-SARS-CoV-2 proteins in non-SARS-CoV-2-exposed and COVID-19 convalescent subjects. PBMCs for MBC analysis were collected from (i) 21 healthy donors sampled from 2011 to 2014 (HD) and (ii) 26 COVID-19 convalescent subjects sampled 4 to 9 weeks after symptom onset (Conv). PBMCs were stimulated in vitro to induce MBC differentiation into Ab-secreting cells. Antigen-specific quantitation of MBC-derived Ab (IgG)-secreting cells (MASCs) by ELISpot assay or of MBC-derived polyclonal (IgG) Abs (MPAbs) by ELISA provided a measure of the abundance of specific IgG MBCs. (A) IgG MBCs reactive to the SARS-CoV-2 spike (S), receptor binding domain (RBD), and nucleocapsid (N) in convalescent subjects. The assigned cutoff for positivity is shown by the horizontal gray bar. (B) IgG MBCs reactive to the influenza virus H1 hemagglutinin and TTd in convalescent subjects. (C) Proportions of IgG MBCs reactive to the SARS-CoV-2 RBD, S2, and N for individual convalescent subjects. A bar representing the mean value for the HD cohort is included for comparison. In all HD samples, MPAb IgG levels against RBD, S2, and N were below the cutoff for assay positivity. (D) Comparison of serum IgG concentrations (upper panels) and numbers of IgG MBCs (lower panels) reactive to the SARS-CoV-2 S (left-hand side) and N (right-hand side) proteins. Serum IgG was measured by ELISA; IgG MBC numbers were based on ELISA of MPAbs. Dilution curves are shown for individual convalescent subjects; curves for 4 subjects are shown in different colors to identify particular response patterns. (E to H) IgG MBCs reactive to the S proteins of HCoVs OC43 (E) and 229E (F), the H1 hemagglutinin (G), and TTd (H) in convalescent and HD subjects. Significance (*, P < 0.05; ns, not significant) for comparisons of IgG MBC numbers between subject groups was determined by the Wilcoxon rank sum test.
FIG 2 Analysis of IgG memory B cells (MBCs) reactive to SARS-CoV-2 and non-SARS-CoV-2 proteins in non-SARS-CoV-2-exposed and COVID-19 convalescent subjects. PBMCs for MBC analysis were collected from (i) 21 healthy donors sampled from 2011 to 2014 (HD) and (ii) 26 COVID-19 convalescent subjects sampled 4 to 9 weeks after symptom onset (Conv). PBMCs were stimulated in vitro to induce MBC differentiation into Ab-secreting cells. Antigen-specific quantitation of MBC-derived Ab (IgG)-secreting cells (MASCs) by ELISpot assay or of MBC-derived polyclonal (IgG) Abs (MPAbs) by ELISA provided a measure of the abundance of specific IgG MBCs. (A) IgG MBCs reactive to the SARS-CoV-2 spike (S), receptor binding domain (RBD), and nucleocapsid (N) in convalescent subjects. The assigned cutoff for positivity is shown by the horizontal gray bar. (B) IgG MBCs reactive to the influenza virus H1 hemagglutinin and TTd in convalescent subjects. (C) Proportions of IgG MBCs reactive to the SARS-CoV-2 RBD, S2, and N for individual convalescent subjects. A bar representing the mean value for the HD cohort is included for comparison. In all HD samples, MPAb IgG levels against RBD, S2, and N were below the cutoff for assay positivity. (D) Comparison of serum IgG concentrations (upper panels) and numbers of IgG MBCs (lower panels) reactive to the SARS-CoV-2 S (left-hand side) and N (right-hand side) proteins. Serum IgG was measured by ELISA; IgG MBC numbers were based on ELISA of MPAbs. Dilution curves are shown for individual convalescent subjects; curves for 4 subjects are shown in different colors to identify particular response patterns. (E to H) IgG MBCs reactive to the S proteins of HCoVs OC43 (E) and 229E (F), the H1 hemagglutinin (G), and TTd (H) in convalescent and HD subjects. Significance (*, P < 0.05; ns, not significant) for comparisons of IgG MBC numbers between subject groups was determined by the Wilcoxon rank sum test.CC BY · PubMed Central

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Metadata

Authors
Nguyen-Contant, P., Embong, A. K., Kanagaiah, P., Chaves, F. A., Yang, H., Branche, A. R., Topham, D. J., & Sangster, M. Y.
Affiliations
  • David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
  • University of Rochester Medicine (US)
Corresponding author
Sangster, Mark Y.
ORCID
Venue
mBio
Publisher
American Society for Microbiology
Published
2020-10-27
Volume
11
Issue
5
ISSN
  • 2150-7511 (ISSN-L)
  • 2161-2129
DOI
10.1128/mbio.01991-20
PMC
PMC7520599
OpenAlex
W3087903445
Cited by
204
References
35
Citations by year
2026: 3 · 2025: 13 · 2024: 16 · 2023: 29 · 2022: 60 · 2021: 75 · 2020: 8
FWCI
5.64
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
HHS | NIH | National Institute of Allergy and Infectious Diseases (HHSN272201400005C)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
SARS-CoV-2, COVID-19 pandemic, S protein, S2 subunit, receptor binding domain, memory B cells, IgG, antibody response, pre-existing immunity, reinfection, cross-reactive antibodies, coronavirus
MeSH terms
Betacoronavirus, COVID-19, SARS-CoV-2, Coronavirus Nucleocapsid Proteins, Adult, Antibodies, Viral, B-Lymphocytes, Convalescence, Cross Reactions, Female, Humans, Immunoglobulin G, Immunologic Memory, Male, Middle Aged, Phosphoproteins, Pneumonia, Viral, Coronavirus Infections, Nucleocapsid Proteins, Protein Subunits, Protein Interaction Domains and Motifs, Pandemics, Healthy Volunteers, Spike Glycoprotein, Coronavirus

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