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. 2021 Apr 1;184(7):1858-1864.e10.
doi: 10.1016/j.cell.2021.02.010. Epub 2021 Feb 9.

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection

Elizabeth M Anderson  1 , Eileen C Goodwin  1 , Anurag Verma  2 , Claudia P Arevalo  1 , Marcus J Bolton  1 , Madison E Weirick  1 , Sigrid Gouma  1 , Christopher M McAllister  1 , Shannon R Christensen  1 , JoEllen Weaver  2 , Philip Hicks  3 , Tomaz B Manzoni  1 , Oluwatosin Oniyide  4 , Holly Ramage  5 , Divij Mathew  6 , Amy E Baxter  6 , Derek A Oldridge  6 , Allison R Greenplate  6 , Jennifer E Wu  7 , Cécile Alanio  7 , Kurt D'Andrea  6 , Oliva Kuthuru  6 , Jeanette Dougherty  6 , Ajinkya Pattekar  6 , Justin Kim  6 , Nicholas Han  6 , Sokratis A Apostolidis  6 , Alex C Huang  6 , Laura A Vella  8 , Leticia Kuri-Cervantes  1 , M Betina Pampena  1 ; UPenn COVID Processing Unit; Michael R Betts  1 , E John Wherry  7 , Nuala J Meyer  4 , Sara Cherry  5 , Paul Bates  9 , Daniel J Rader  2 , Scott E Hensley  10
Affiliations

Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection

Elizabeth M Anderson et al. Cell. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.

Keywords: SARS-CoV-2; antibodies; coronavirus; pre-existing immunity.

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Conflict of interest statement

Declaration of interests A.C.H. is a consultant for Immunai. 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 (U.S. patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. D.J.R. is on scientific advisory boards for Alnylam, Metrea, Novartis, Pfizer, and Verve; is a consultant for and receives research support from Regeneron for work unrelated to this report; and is a founder of Vascular Strategies and Staten Biotechnologies. S.E.H. has received consultancy fee from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this report.

Figures

None
Graphical abstract
Figure 1
Figure 1
Identification of pre-existing cross-reactive SARS-CoV-2 antibodies in human serum prior to the pandemic (A–C) ELISAs were completed to quantify levels of serum antibodies binding to the SARS-CoV-2 full-length S protein (A), the S-RBD (B), and the N protein (C). Dashed line denotes lower limit of detection (LOD = 50); dotted line represents a threshold set 2-fold above LOD (>100). We tested samples collected from 431 individuals in the summer of 2017, prior to the global pandemic. We also tested samples collected from 15 individuals after confirmed SARS-CoV-2 infections as well as from recovered adults. (D) The relationship between antibody titers in donors with detectable IgG against the S-RBD and/or full-length S is shown. (E) SARS-CoV-2 pseudotype neutralization assays were completed with pre-pandemic serum samples with (n = 14) and without (n = 29) cross-reactive SARS-CoV-2 antibodies, as well as serum samples from individuals after confirmed SARS-CoV-2 infections (n = 15); one-way ANOVA Tukey’s multiple comparisons of log2 transformed antibody titers ∗∗∗∗p < 0.0001; dotted line denotes lower LOD (=10). (F–H) ELISAs were completed to quantify levels of serum antibodies binding to the full-length S proteins from 229E, NL63, and OC43 with pre-pandemic serum samples with (n = 17) and without (n = 17) cross-reactive SARS-CoV-2 antibodies. Unpaired t tests of log2 transformed antibody titers ∗∗p < 0.002. Horizontal lines indicate geometric mean and error bars represent standard deviation. See also Figure S1, Figure S2, Figure S3, Figure S4, and S5.
Figure S1
Figure S1
There are no obvious age-related differences in pre-pandemic SARS-CoV-2 and hCoV reactive antibodies, related to Figure 1 ELISAs were completed to measure levels of serum antibodies binding to the SARS-CoV-2 full-length spike (S) protein (A), SARS-CoV-2 receptor binding domain (S-RBD) of S (B), SARS-CoV-2 nucleocapsid (N) protein (C), 229E S protein (D), NL63 S protein (E), and OC43 S protein (F). Serum samples collected from 431 individuals in the summer of 2017 were tested. Reciprocal titer from serially-diluted serum samples (A-C) and optical densities at 450nm wavelength (OD450) of 1:500 dilution of serum (D-F) are shown. Dashed line denotes lower limit of detection (LOD = 50), dotted line represents a threshold set 2-fold above LOD (> 100).
Figure S2
Figure S2
Comparison of ELISA data using unpurified and purified serum IgG antibodies, related to Figure 1 and 2 IgG was purified from sera samples from individuals without (A; n = 5) and with (B; n = 11) pre-pandemic cross-reactive antibodies. IgG was also purified from serum samples from individuals who had recovered from a confirmed SARS-CoV-2 infection (C; n = 5). ELISAs were completed to quantify levels of serum antibodies binding to SARS-CoV-2 full length S, S-RBD, and N protein with and without IgG magnetic bead purification. The dotted line represents a threshold set 2-fold above the limit of detection (> 100).
Figure S3
Figure S3
Correlation between N, S, and S-RBD antibody titers in pre-pandemic samples, related to Figure 1 Shown are the relationships between serum IgG antibody titers against the SARS-CoV-2 N protein and S-RBD (A) or full length S (B) from 431 individuals whose samples were collected prior to the pandemic in the summer of 2017. Dotted line represents a threshold set 2-fold above the limit of detection (> 100).
Figure S4
Figure S4
SARS-CoV-2 pseudotype neutralization curves, related to Figure 1 Raw neutralization curves for data from Figure 1E are shown, including samples from individuals who did not have pre-pandemic cross reactive SARS-CoV-2 antibodies (A), individuals who possessed pre-pandemic cross reactive SARS-CoV-2 antibodies (B), and individuals following confirmed SARS-CoV-2 infection (C). Mean and error bars are shown for each replicate; dotted line denotes the cut-off for foci reduction neutralization of 50% (FRNT50).
Figure S5
Figure S5
Pre-pandemic cross-reactive antibodies do not neutralize SARS-CoV-2 in bonafide BSL3-level neutralization assays, related to Figure 1 Neutralization assays with live SARS-CoV-2 were completed using 9 pre-pandemic samples with cross-reactive SARS-CoV-2 antibodies, 7 pre-pandemic samples without cross-reactive SARS-CoV-2 antibodies, and 5 samples from individuals who recovered from a PCR-confirmed SARS-CoV-2 infection. The pre-pandemic samples for these experiments were collected in 2019 and are different from those shown in Figure 1 (which were collected in 2017).
Figure 2
Figure 2
Pre-pandemic SARS-CoV-2 and OC43-reactive antibodies are not associated with protection from SARS-CoV-2 infection (A and B) We quantified antibody levels in pre-pandemic serum samples collected from individuals who later became SARS-CoV-2 infected (cases; n = 251) and those who did not become SARS-CoV-2 infected (controls; n = 251). ELISAs were completed to quantify levels of antibodies reactive to SARS-CoV-2 proteins (S, S-RBD, and N) and the OC43 S protein. Shown are data using samples collected from the entire cohort between August 2013 and March 2020 (A) and samples from a smaller subset of individuals collected between April 2019 and March 2020 (B). Antibody titers between cases and controls were not significantly different as determined by unpaired t tests of log2 transformed antibody titers. Dashed line denotes lower limit of detection (LOD = 50), dotted line represents a threshold set 2-fold above LOD (>100). See also Tables S1 and S2.
Figure 3
Figure 3
SARS-CoV-2 infections boost antibodies that react to OC43 S protein (A–D) We quantified antibody levels in serum collected from 27 individuals 0 and 7 days after hospitalization for COVID-19. ELISAs were completed to quantify levels of antibodies reactive to the S proteins of 229E, NL63, OC43, and SARS-CoV-2. IgG titers (A) and titer fold change (B) are shown. Levels of OC43 S-reactive antibodies (C) and fold change in OC43 S-reactive antibodies (D) were not associated with disease outcome. Paired t test of log2 transformed antibody titers, ∗∗∗∗p < 0.0001. One-way ANOVA Tukey’s multiple comparisons fold-change in antibody titers, ∗p < 0.04. Horizontal lines indicate the median and error bars show interquartile ranges. See also Figure S6.
Figure S6
Figure S6
Antibodies directed to the S2 region of OC43 spike are boosted during SARS-CoV-2 infection, related to Figure 3 We quantified antibody levels in serum collected from 27 individuals 0 and 7 days after hospitalization for COVID-19. ELISAs were completed to measure levels of serum antibodies binding to the OC43 full-length spike (FL) protein and the individual S1 and S2 subunits of the OC43 spike. (A) IgG titers and (B) titer fold change are shown. Paired t test of log2 transformed antibody titers, ∗∗∗∗p < 0.0001. One-way ANOVA Tukey’s multiple comparisons fold-change in antibody titers, * p < 0.02 ∗∗p < 0.005. Horizontal lines indicate the median and error bars show interquartile range.
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