Boosting of cross-reactive antibodies to endemic coronaviruses by SARS-CoV-2 infection but not vaccination with stabilized spike

Abstract

Preexisting antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross-reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross-react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better-conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.

Distinct Antibody Responses to Endemic Coronaviruses Pre- and Post-SARS-CoV-2 Infection in Kenyan Infants and Mothers

“…Increased eHCoV antibody levels upon SARS-CoV-2 seroconversion have been observed in some cohorts [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ] but not others [ 28 , 29 ], and when detected, they have been hypothesized to reflect a boosting of pre-existing cross-reactive responses. We observed significant increases in betacoronavirus but not alphacoronavirus antibody levels (SARS-CoV-1 in the infants and mothers; HCoV-OC43 and HCoV-HKU1 in the mothers) upon SARS-CoV-2 seroconversion compared to the most recent seronegative sample, suggesting that there are cross-reactive antibodies to SARS-CoV-2, which may be more likely to be present in the context of more closely related eHCoVs.…”

“…Several explanations for this phenomenon have been hypothesized, including the influence of cross-reactive immune responses to endemic human coronaviruses (eHCoVs), also known as seasonal or common colds which cause human coronaviruses. Many studies have shown that eHCoV antibody levels are increased upon SARS-CoV-2 infection [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], which may indicate “boosted” pre-existing memory responses that are cross-reactive. It remains unclear whether such cross-reactive antibody responses could modulate SARS-CoV-2 infection risk.…”

Distinct antibody responses to endemic coronaviruses pre- and post-SARS-CoV-2 infection in Kenyan infants and mothers

“…Increased eHCoV antibody levels upon SARS-CoV-2 seroconversion have been observed in some cohorts [3][4][5][6][7][8][9][10], but not others [18,19], and, when detected, have been hypothesized to reflect boosting of pre-existing cross-reactive responses. We observed significant increases in betacoronavirus, but not alphacoronavirus, antibody levels (SARS-CoV-1 in infants and mothers; HCoV-OC43 and HCoV-HKU1 in mothers) upon SARS-CoV-2 seroconversion compared to the most recent seronegative sample, suggesting that there are cross-reactive antibodies to SARS-CoV-2, and they may be more likely to be present in the context of more closely related eHCoVs.…”

“…Several explanations for this phenomenon have been hypothesized, including the influence of cross-reactive immune responses to endemic human coronaviruses (eHCoVs), also known as seasonal or common-cold causing human coronaviruses. Many studies have shown that eHCoV antibody levels are increased upon SARS-CoV-2 infection [3][4][5][6][7][8][9][10][11], which may indicate "boosted" pre-existing memory responses that are cross-reactive.…”

Younger Children Develop Higher Effector Antibody Responses to SARS-CoV-2 Infection

“…It was proposed that these higher adaptive immune responses to SARS-CoV-2 may be related to higher preexisting immunity to endemic common cold coronaviruses (HCoVs) in children as compared with adults [ 5 , 19 , 20 ]. Indeed, SARS-CoV-2 cross-reactive T cells and antibodies have been detected in samples collected before the COVID-19 pandemic, and upregulation, or back-boosting, of these responses was observed following SARS-CoV-2 infection [ 21 ]. Evidence for a role of back-boosting of immunity to HCoVs was recently provided by Dowell et al, who showed higher levels of antibodies to beta HCoVs (OC43 and HKU-1) in children as compared with adults following mild or asymptomatic SARS-CoV-2 infection [ 19 ].…”