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.