Discussion
We report the combined results from two longitudinal prospective
clinical studies measuring SARS-CoV-2 anti-S-protein IgG titers by ELISA
in self-collected saliva following homologous two-dose vaccine regimen
and subsequent third-dose booster vaccination with either mRNA-1273 and
BNT162b2. We only included those participants in the analysis who
received the homologous third-dose booster and completed the entire
self-collection series. Our results for BNT162b2 and mRNA-1273 vaccine
show IgG titers in saliva wane gradually from the second dose peak in
the subsequent 6-9 months up to 150-fold. These results correlate with
efficacy studies demonstrating that protection against a new SARS-CoV-2
infection and serum IgG titers wane over time in uninfected recipients
of two doses of mRNA vaccines4. Administration of a
third dose stimulates a robust recall of anti-S-protein IgG titer before
waning in the subsequent months.
The approval and rollout of mRNA-1273 and BNT162b2 vaccine booster doses
in September 2021 preceded the emergence of the omicron wave of
infections during December 2021 in the USA, and fully vaccinated
individuals with a booster dose had a lower COVID-19 case rate than
recipients of the two-dose regimen, or unvaccinated
individuals18. However, vaccine effectiveness of the
booster dose against symptomatic infection by omicron was reduced
compared to the primary series against earlier variants, and protection
further declined within five to nine weeks of
vaccination18,19. Therefore, break-through infections
of participants in our clinical study led to increased drop-out rate
over its duration. Twenty-four mRNA-1273 vaccine recipients and fifteen
BNT162b2 vaccine recipients were excluded from our study due to COVID-19
infection, of these, sixteen (66.7 %) and nine (60 %) participants
self-reported a COVID-19 infection after receiving a booster dose of
their respective vaccines. Four study participants (two mRNA-1273 and
two BNT162b2 vaccine recipients) had an unexplained increase in
anti-S-protein IgG titers, months after a booster vaccination, since
none self-reported a COVID-19 infection, we suspect these to be
asymptomatic infections. In addition, a high percentage of participants
were unenrolled over time due to missed sample collection (49 %
mRNA-1273 and 54 % BNT162b2 cohorts). This could be attributed to our
clinical study requiring multiple collections over varying amounts of
time, whereas a consistent collection cycle could have encouraged more
participants to remain enrolled.
Finally, the updated bivalent fourth dose (second booster) became
available September 2nd, 2022, in the USA, but our
study reached its endpoint in May 2022. Both bivalent booster mRNA
vaccines encode the S-protein antigen for the original Wuhan strain as
well as for the BA.4 and BA.5 omicron variants for BNT162b2, and the
BA.1 omicron variant for mRNA-1273.21420. Therefore,
these updated bivalent booster mRNA vaccines induce a greater diversity
of anti-S-protein Abs in recipients. We would expect saliva specimens to
continue to be useful for measuring anti-S-protein IgG titers for this
bivalent booster, and every future booster, but the ELISA assay would
need updating with a mutated S-protein antigen to retain its high
sensitivity.