DISCUSSION
Majority of the global population have been exposed to SARS-CoV-2 through infection or vaccination to date. As SARS-CoV-2 share common epitopes with other HCoVs, it is anticipated that SARS-CoV-2 exposure may boost cross-reactive antibodies towards other HCoV. Using the pre- and post- vaccination sera of un-infected subjects, we show that both the mRNA vaccine (BNT) and the inactivated vaccine (CV) increased cross-reactive antibodies against the S2 protein of the two Betacoronaviruses, OC43 and MERS-CoV, but not Alphacoronavirus 229E. CV vaccination further boosted anti-N protein antibodies against MERS-CoV and 229E. The antibody response against S2 protein of MERS-CoV were also detected from 41 out of 60 (71.7%) convalescent sera of SARS-CoV-2 patients with or without COVID-19 vaccination history. Our results are in line with a recent study that detected high prevalence of cross-reactive antibodies to spike proteins of viruses in theOrthocoronavirinae among the post-COVID-19 population (17). Taken together, these results suggest that SARS-CoV-2 exposure may modulate population antibody response towards other human coronaviruses.
The high level pre-existing antibodies against OC43 and 229E generated from prior infection or vaccination have been shown to impact on the de novo humoral responses against SARS-CoV-2 (5). Among our study subjects, no negative impact was observed in the correlation analysis between pre-vaccination antibody levels against OC43 or 229E and the post-vaccination antibody levels against SARS-CoV-2. Due to various public health and social measures implemented in Hong Kong during COVID-19 pandemic, the activity of various respiratory viruses have been reduced, which may limit recent exposure of our study population to common cold HCoVs. As co-circulation of SARS-CoV-2 and other HCoVs is anticipated, follow up studies are needed to understand how pre-existing immunity may shape the antibody landscapes of various HCoVs.
Both COVID-19 vaccines back-boosted antibodies against the S2 domain of OC43, which aligned with the results reported from previous studies (9, 10, 11, 12, 13). Furthermore, the de novo antibody response to SARS-CoV-2 generated after vaccination or infection were cross-reactive with S2 of MERS-CoV. The conserved region on S2 stem-helix domains across Betacoronaviruses may explain the high cross reactivity of anti-S2 antibodies (18), while other studies identified cross-reactive neutralizing antibody that targets S2 region (19, 20, 21, 22). By comparing the anti-MERS-CoV antibodies from infected subjects with or without vaccination history, we noted that those who have been vaccinated, followed by a SARS-CoV-2 breakthrough infection generally showed higher anti-MERS S2 AUC than those who were infected without vaccination history. These study subjects were vaccinated with the prototype virus followed by infection with the BA.2 Omicron variant in 2022. In addition, higher anti-MERS S2 AUC was detected from those infected followed by BNT vaccination compared to those who were infected without vaccination or those infected followed by CV vaccination. These results suggest that BNT vaccine may stimulate broader antibody response than CV among those who were previously infected. Taken together, these findings have implications for future sero-epidemiological studies on MERS-CoV. While binding antibody responses to MERS-CoV S1 is still likely to be specific for MERS-CoV infection, binding antibody to MERS-CoV S2 should no longer be considered as a specific marker for MERS-CoV infection.
Using the ppNT assay that specifically detect neutralizing antibodies targeting the receptor binding domain (RBD) of MERS-CoV, we showed that the anti-MERS-CoV antibodies were non-neutralizing. However, other neutralising mechanisms such as inhibition of fusion peptide cannot be ruled out (19). Further studies are needed to evaluate if these cross-reactive antibodies possess Fc-mediated effector functions and if they confer protection in vivo.