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. 2022 Oct 18;41(3):111496.
doi: 10.1016/j.celrep.2022.111496.

SARS-CoV-2 infections elicit higher levels of original antigenic sin antibodies compared with SARS-CoV-2 mRNA vaccinations

Elizabeth M Anderson  1 , Shuk Hang Li  1 , Moses Awofolaju  1 , Theresa Eilola  1 , Eileen Goodwin  1 , Marcus J Bolton  1 , Sigrid Gouma  1 , Tomaz B Manzoni  1 , Philip Hicks  1 , Rishi R Goel  2 , Mark M Painter  2 , Sokratis A Apostolidis  3 , Divij Mathew  2 , Debora Dunbar  4 , Danielle Fiore  5 , Amanda Brock  6 , JoEllen Weaver  6 , John S Millar  7 , Stephanie DerOhannessian  8 ; UPenn COVID Processing Unit; Allison R Greenplate  9 , Ian Frank  4 , Daniel J Rader  8 , E John Wherry  10 , Paul Bates  1 , Scott E Hensley  11
Affiliations

SARS-CoV-2 infections elicit higher levels of original antigenic sin antibodies compared with SARS-CoV-2 mRNA vaccinations

Elizabeth M Anderson et al. Cell Rep. .

Abstract

It is important to determine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and SARS-CoV-2 mRNA vaccinations elicit different types of antibodies. Here, we characterize the magnitude and specificity of SARS-CoV-2 spike-reactive antibodies from 10 acutely infected health care workers with no prior SARS-CoV-2 exposure history and 23 participants who received SARS-CoV-2 mRNA vaccines. We found that infection and primary mRNA vaccination elicit S1- and S2-reactive antibodies, while secondary vaccination boosts mostly S1 antibodies. Using absorption assays, we found that SARS-CoV-2 infections elicit a large proportion of original antigenic sin-like antibodies that bind efficiently to the spike of common seasonal human coronaviruses but poorly to the spike of SARS-CoV-2. In converse, vaccination modestly boosts antibodies reactive to the spike of common seasonal human coronaviruses, and these antibodies cross-react more efficiently to the spike of SARS-CoV-2. Our data indicate that SARS-CoV-2 infections and mRNA vaccinations elicit fundamentally different antibody responses.

Keywords: CP: Immunology; SARS-CoV-2; antibodies; coronavirus; mRNA vaccines; original antigenic sin.

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Conflict of interest statement

Declaration of interests E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Elstar, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S.E.H. has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this report.

Figures

None
Graphical abstract
Figure 1
Figure 1
Specificity of SARS-CoV-2 antibodies induced after SARS-CoV-2 infection versus vaccination (A and B) ELISAs were completed to quantify levels of serum antibodies binding to the SARS-CoV-2 full-length spike (FL-S) protein, the S1 domain (S1) of S, and the S2 domain (S2) of S after SARS-CoV-2 infection (A) and mRNA vaccination (B). (C–E) We calculated fold change in antibody titers before and after seroconversion and pre-/post-prime and boost doses of a SARS-CoV-2 mRNA vaccine. (F and G) SARS-CoV-2 pseudotype neutralization assays were completed with sera samples from SARS-CoV-2-infected individuals (F) and SARS-CoV-2 mRNA-vaccinated participants (G). (H) Fold change in neutralization titers was calculated before and after seroconversion and pre-/post-prime and boost doses of a SARS-CoV-2 mRNA vaccine. For (A), (B), (F), and (G), we completed paired t tests or one-way ANOVA of log2-transformed titers; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05. For (C)–(E) and (H), we completed one-way ANOVA of titer fold changes; ∗∗∗∗p < 0.0001, ∗∗p < 0.01 ∗p < 0.05. Data are representative of two independent experiments. Neutralizing antibody titers of SARS-CoV-2 mRNA vaccinated participants have been previously reported in Goel et al. (2021a).
Figure 2
Figure 2
Antibodies to the FL-S of other betacoronaviruses are boosted upon SARS-CoV-2 infection and after vaccination to a lesser extent (A and B) ELISAs were completed to quantify levels of serum antibodies binding to the FL-S protein of other betacoronaviruses (OC43, HKU1, SARS-CoV) and alphacoronavirus (229E) after SARS-CoV-2 infection (A) and mRNA vaccination (B). Paired t tests or one-way ANOVA of log2 transformed antibody titers; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05. Data are representative of two independent experiments. (C) We calculated fold change in antibody titers against spike before and after seroconversion and pre-/post-prime and boost doses of a SARS-CoV-2 mRNA vaccine. One-way ANOVA of antibody fold change; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01.
Figure 3
Figure 3
Antibodies reactive to the S2 domain of seasonal betacoronaviruses are boosted upon SARS-CoV-2 infection and after vaccination to a lesser extent (A and B) ELISAs were completed to determine the levels of S1- and S2-specific antibodies against spike of OC43, HKU1, and SARS-CoV after SARS-CoV-2 infection (A) or SARS-CoV-2 mRNA vaccination (B). Paired t tests or one-way ANOVA of log2-transformed antibody titers; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05. Data are representative of two independent experiments. (C and D) Fold change of S1- and S2-specific antibodies was calculated before and after seroconversion and pre-/post-prime and boost mRNA vaccines. One-way ANOVA of antibody fold change; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01.
Figure 4
Figure 4
Seasonal coronavirus spike antibodies boosted by SARS-CoV-2 infection do not bind effectively to the SARS-CoV-2 spike Sera samples from 10 SARS-CoV-2-infected health care workers and 10 SARS-CoV-2 mRNA-vaccinated participants were absorbed with SARS-CoV-2, OC43, HKU1, and 229E spike-coupled beads or mock-treated beads prior to antibody quantification by ELISA. We determined reciprocal antibody titers in samples before and after infection and pre-/post-the first dose of an mRNA vaccine for SARS-CoV-2, OC43, HKU1, 229E, and an unrelated antigen, influenza hemagglutinin H1.
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