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.