RESULTS
COVID-19 vaccination increased cross-reactive antibody responses against other Betacoronaviruses. We first compared the pre- and post- COVID-19 vaccination antibody responses towards various HCoVs among individuals who have not been previously infected with SARS-CoV-2. Both BNT (Figure 1A) and CV (Figure 1B) vaccinees showed significant increase of antibody AUC against the spike protein of Betacoronaviruses after vaccination, including SARS-CoV-2 (S1+S2), MERS-CoV (S2), OC43 (S2). In contrast, the post-vaccination sera showed a modest, but significant decrease in median antibody AUC against Alphacoronavirus 229E (S2), possible suggesting a waning antibody response over time. Only CV vaccinees showed significantly increased antibody AUC against the nucleocapsid (N) protein of SARS-CoV-2, MERS-CoV and 229E (Figure 1B). Comparing the BNT and CV vaccination responses (Figure 1C), BNT induced significantly greater S-binding antibody for SARS-CoV-2 (S1+S2) and MERS-CoV (S2), while CV induced significantly greater N-binding antibodies for SARS-CoV-2, MERS-CoV, OC43, and 229E.
Pre-vaccination sera showed high baseline binding antibodies for OC43 and 229E (Figure 1A & 1B). As the baseline antibody titres towards common cold HCoVs may affect the post-exposure antibody response against SARS-CoV-2 (5), we analysed the correlation between the pre-vaccination antibody levels against other HCoVs versus the post-vaccination antibody response against SARS-CoV-2. For BNT vaccinees, their post-vaccination antibody AUC against S of SARS-CoV-2 was not affected by the pre-vaccination antibody against OC43 or 229E (Figure 2A). For CV vaccinees, their post-vaccination antibody AUC against S of SARS-CoV-2 was marginally correlated with the pre-vaccination antibody against 229E-S1+S2 (Spearman’s ρ=0.46, p<0.05) and 229E-S2 (Spearman’s ρ=0.44, p<0.05). The post-vaccination antibody AUC against the N protein of SARS-CoV-2 did not correlate with the pre-vaccination antibody responses against the N proteins of OC43 or 229E. These results suggest that the de novo antibody response against SARS-CoV-2 after vaccination was not negatively affected by the baseline antibody responses against previously exposed HCoV.
The BNT vaccinees’ post-vaccination antibody AUC against S of SARS-CoV-2 was positively correlated with the post-vaccination anti-MERS-CoV-S2 (Spearman’s ρ=0.63, p<0.01) and anti-OC43-S1+S2 (Spearman’s ρ=0.57, p<0.01) responses (Figure 2B). For CV vaccinees, the post-vaccination antibody AUC against S of SARS-CoV-2 was positively correlated with anti-OC43-S1+S2 response (Spearman’s ρ=0.47, p<0.05), and their post-vaccination antibody AUC against N of SARS-CoV-2 was positively correlated with anti-MERS-N response (Spearman’s ρ=0.73, p<0.001) (Figure 2B). Taken together, both the mRNA or inactivated COVID-19 vaccines may boost antibody responses against conserved epitopes shared with previously exposed (OC43) or novel (MERS-CoV) Betacoronaviruses.
SARS-CoV-2 infection increased cross-reactive antibody responses against MERS-CoV. We further investigated if SARS-CoV-2 infection may similarly boost cross-reactive antibody response against MERS-CoV S and N proteins (Figure 3A). Convalescent sera from SARS-CoV-2 patients without a history of COVID-19 vaccination (n=20), those who have been infected and vaccinated (n=20), and those who were vaccinated and had a breakthrough infection (n=20) were compared with pre-pandemic sera collected from healthy adults in 2019 (n=20). Compared to the pre-pandemic sera (using the mean+3SD AUC value as threshold), 41 out of 60 (71.7%) convalescent sera showed increased antibody against MERS-CoV S2, while 6 of 60 (10%) showed increased antibody against MERS-CoV S1. In regard to the antibody response to the S2 protein of MERS-CoV-2, those who were vaccinated followed by a breakthrough infection generally showed higher AUC than those who were infected without vaccination history, although the differences were not significant. In addition, those who were infected followed by BNT vaccination showed greater anti-S2 antibody response than those who were infected followed by CV vaccination, suggesting that BNT vaccination may better expand the breath of antibody response than CV vaccination among those who were infected. Compared to the pre-pandemic sera, increase in the anti-N protein antibody AUC was also observed from those who were infected followed by CV vaccination or those who were CV vaccinated followed by breakthrough infection.
Cross-reactive antibody against MERS-CoV S2 were non-neutralizing. Pseudoparticle neutralization test (ppNT) was used to evaluate if the cross-reactive anti-S2 antibodies possess neutralizing activity against MERS-CoV (Figure 3B). None, except one subject who was vaccinated with BNT followed by SARS-CoV-2 infection, showed neutralizing antibody at 1:10 dilution using ppNT assay. Despite of non-neutralizing, sera from subjects with CV vaccination followed by infection (mean ± SD % inhibition = 44.6 ± 27.8) showed greater inhibition against MERS-CoV than the sera of pre-pandemic controls (15.3 ± 16.9) (Kruskal-Wallis test, p=0.0435). Taken together, these results suggest that the majority of the cross-reactive anti-MERS-CoV-S2 antibodies detected after vaccination or infection were non-neutralizing.