Age-Associated Seroprevalence of Coronavirus Antibodies: Population-Based Serosurveys in 2013 and 2020, British Columbia, Canada

Abstract

Background: Older adults have been disproportionately affected during the SARS-CoV-2 pandemic, including higher risk of severe disease and long-COVID. Prior exposure to endemic human coronaviruses (HCoV) may modulate the response to SARS-CoV-2 infection and contribute to age-related observations. We hypothesized that cross-reactive antibodies to SARS-CoV-2 are associated with antibodies to HCoV and that both increase with age.

Methods: To assess SARS-CoV-2 unexposed individuals, we drew upon archived anonymized residual sero-surveys conducted in British Columbia (BC), Canada, including before SARS-CoV-2 emergence (May, 2013) and before widespread community circulation in BC (May, 2020). Fifty sera, sex-balanced per ten-year age band, were sought among individuals ≤10 to ≥80 years old, supplemented as indicated by sera from March and September 2020. Sera were tested on the Meso Scale Diagnostics (MSD) electrochemiluminescent multiplex immunoassay to quantify IgG antibody against the Spike proteins of HCoV, including alpha (HCoV-229E, HCoV-NL63) and beta (HCoV-HKU1, HCoV-OC43) viruses, and the 2003 epidemic beta coronavirus, SARS-CoV-1. Cross-reactive antibodies to Spike, Nucleocapsid, and the Receptor Binding Domain (RBD) of SARS-CoV-2 were similarly measured, with SARS-CoV-2 sero-positivity overall defined by positivity on ≥2 targets.

Results: Samples included 407 sera from 2013, of which 17 were children ≤10 years. The 2020 samples included 488 sera, of which 88 were children ≤10 years. Anti-Spike antibodies to all four endemic HCoV were acquired by 10 years of age. There were 20/407 (5%) sera in 2013 and 8/488 (2%) in 2020 that were considered sero-positive for SARS-CoV-2 based on MSD testing. Of note, antibody to the single SARS-CoV-2 RBD target was detected in 329/407 (81%) of 2013 sera and 91/488 (19%) of 2020 sera. Among the SARS-CoV-2 overall sero-negative population, age was correlated with anti-HCoV antibody levels and these, notably 229E and HKU1, were correlated with cross-reactive anti-SARS-CoV-2 RBD titres. SARS-CoV-2 overall sero-positive individuals showed higher titres to HCoV more generally.

Conclusion: Most people have an HCoV priming exposure by 10 years of age and IgG levels are stable thereafter. Anti-HCoV antibodies can cross-react with SARS-CoV-2 epitopes. These immunological interactions warrant further investigation with respect to their implications for COVID-19 clinical outcomes.

Keywords: COVID-19; COVID-19 severity; SARS-CoV-2; antibodies; cross-reactive antibodies; endemic coronavirus; humoral immune response.

Figure 1

Geometric mean IgG antibody titres against HCoV-229E, HCoV-HKU1, HCoV-NL63, and HCoV-OC43 spike in SARS-CoV-2 sero-negative populations (N = 887) by chronological age. SARS-CoV-2 sero-negative populations include all 2013 individuals (N = 407) and SARS-CoV-2 sero-negative individuals from 2020 (N = 480). Red dots indicate the geometric mean antibody titres for each HCoV among all individuals of that age (in years), with the black solid line connecting geometric means. Red bars represent upper and lower standard deviations. Black dashed lines describe the positivity cutoff for each antigen target.

Figure 2

HCoV-229E, HCoV-HKU1, HCoV-NL63, and HCoV-OC43 spike IgG antibody levels between sexes and seasons (2013 and 2020) by chronological age among SARS-CoV-2 sero-negative persons (N = 887). (A, B) describe the HCoV antibody levels between male and female sexes by (A) age category and (B) chronological age. (C, D) describe the HCoV antibody levels between 2013 and 2020 seasons by (C) age category and (D) chronological age. In (A, C), age categories are stratified according to children (≤10 years old), pre-teens to adults (11-69 years old), and the elderly (≥70 years old). Black dashed lines describe the positivity cutoff for each antigen target. Wilcoxon rank sum test was used to compare antibody levels between (A) sexes and (C) seasons. Spearman’s rank correlation was used to describe the relationship between antibody level and age in (B, D), and Spearman’s correlation coefficient rho (R) and corresponding P-values (P) are reported. ns, not significant, * = p < 0.05, ** = p < 0.01 **** = p < 0.0001.

Figure 3

Correlation matrix describing relationship among Age and HCoV-specific IgG antibodies in SARS-CoV-2 sero-negative persons (N = 887). (A) describes correlations within the entire SARS-CoV-2 sero-negative population, comprised of all 2013 individuals (N = 407) and SARS-CoV-2 sero-negative individuals from 2020 (N = 480), which are further stratified by age categories: (B) children (≤10 years old) (N = 587), (C) pre-teens to adults (11-69 years old) (N = 104), and (D) the elderly (≥70 years old) (N = 196). Darker colours represent stronger correlations. Spearman’s correlation coefficient is reported in each matrix (top numerical value). P-values are reported in italics.

Figure 4

Geometric mean IgG antibody titres against SARS-CoV-1 spike and SARS-CoV-2 nucleocapsid, S1 RBD, and spike in SARS-CoV-2 sero-negative populations (N = 887) by chronological age. SARS-CoV-2 sero-negative populations comprise of all 2013 individuals (N = 407) and SARS-CoV-2 sero-negative individuals from 2020 (N = 480). Red dots indicate the geometric mean antibody titres for each HCoV among all individuals of that age (in years), with the black solid line connecting geometric means. Red bars represent upper and lower standard deviations. Black dashed lines describe the manufacturer provided positivity cutoff for each antigen target. No cutoff is available for SARS-CoV-1 spike.

Figure 5

SARS-CoV-1 Spike and SARS-CoV-2 S1 RBD, nucleocapsid and spike IgG antibody levels between sexes and seasons by age among SARS-CoV-2 sero-negative persons (N=887). (A, B) describe the SARS-CoV-1 and SARS-CoV-2 cross-reactive antibody levels between male and female sexes by (A) age category and (B) chronological age. (C, D) describe the SARS-CoV-1 and SARS-CoV-2 cross-reactive antibody levels between 2013 and 2020 seasons by (C) age category and (D) chronological age. In (A-C), age categories are stratified according to children (≤10 years old), pre-teens to adults (11-69 years old), and the elderly (≥70 years old). Black dashed lines describe the positivity cutoff for SARS-CoV-2 targets. Wilcoxon rank sum test was used to compare antibody levels between (A) sexes and (C) seasons. Spearman’s rank correlation was used to describe the relationship between antibody level and age in (B, D), and Spearman’s correlation coefficient rho (R) and corresponding P-values (P) are reported. ns, not significant, * = p < 0.05, ** = p < 0.01, *** = p < 0.001 **** = p < 0.0001.

Figure 6

Relationship between age and HCoV-specific IgG antibodies with SARS-CoV-2 S1 RBD antibodies among SARS-CoV-2 overall sero-negative persons who are positive for SARS-CoV-2 S1 RBD antibodies. (A) describes all individuals from 2013 season who have SARS-CoV-2 S1 RBD antibodies above positivity cutoff (N = 329). (B) describes SARS-CoV-2 sero-negative individuals from 2020 who have SARS-CoV-2 S1 RBD above positivity cutoff (N = 87). (C) describes SARS-CoV-2 sero-positive individuals from 2020 who also have SARS-CoV-2 S1 RBD above positivity cutoff (N = 27). SARS-CoV-2 sero-positive individuals are from the serosurvey cohort (N = 8) and the known positive controls added (N = 27). Gray shaded area indicates 95% confidence intervals. Spearman correlations were used to describe the relationship between samples, and corresponding Spearman correlation coefficient (R) and p-values are reported.

Figure 7

Comparison of HCoV-specific and SARS-CoV-2 specific IgG antibody levels between SARS-CoV-2 sero-negative and sero-positive individuals. (A) describes the entire population from 2013 and 2020. All 2013 individuals were classified as sero-negative for SARS-CoV-2 status, regardless of whether they appeared SARS-CoV-2 sero-positive by MSD algorithm or not. (B) describes only the 2020 population stratified by age category: children (≤10 years old), pre-teens to adults (11-69 years old), and the elderly (≥70 years old). SARS-CoV-2 sero-positive individuals include children (N = 2), pre-teens to adults (N = 20), elderly (N = 5); similar to SARS-CoV-2 sero-negative individuals where the distribution by age category is children (N = 88), pre-teens to adults (N = 295), elderly (N = 97). Black dashed lines describe the positivity cutoff for each antigen target. ns, not significant, ** = p < 0.01, **** = p < 0.0001.