Introduction
The high efficacy of the BNT162b2 (Pfizer-BioNTech)1and mRNA-1273 (Moderna)2 lipid-nanoparticle
encapsulated messenger RNA (mRNA) vaccines at preventing COVID-19
infection, severe disease, hospitalizations, and death, and the
subsequent rapid global vaccination campaign, offered hope that
herd-immunity to SARS-CoV-2 could be attained, and the COVID-19 pandemic
successfully controlled. However, a combination of waning natural or
vaccine-induced humoral immunity3 and the evolution of
SARS-CoV-2 variants led to decreased vaccine efficacy and increased
breakthrough infections in fully vaccinated populations and reinfections
in recovered populations4. Consequently, third-dose
booster immunizations were assessed and implemented during a high
incidence of infections globally to respond to the resurgent epidemic
wave5.
High immunoglobulin G (IgG) and protective neutralizing antibodies (nAb)
in human serum are induced by natural infection or vaccination, but
antibody (Ab) titers wane in the six months following the second dose of
mRNA vaccines allowing increased SARS-CoV-2 infection rates in fully
vaccinated populations3. The mRNA vaccines were
designed against the ancestral SARS-CoV-2 Wuhan/HU-1/2019 strain
prefusion stabilized full-length spike (S-) protein6.
Consequently, antigenic evolution of the S-protein through point
mutations and recurrent deletions particularly in the receptor binding
domain (RBD) enabled immune evasion caused by reduced Ab neutralization
of new variants7. The emergence of immune-escape
variants including the Omicron (B.1.1.529) BA.1 and BA.2 variants
ensured herd immunity was not attainable and rendered monoclonal
antibody therapies ineffective8. A third-dose
homologous or heterologous booster vaccination with either mRNA-1272 or
BNT162b2 mRNA vaccines reduced symptomatic COVID-19 infections,
hospitalization, and death for Delta (B.1.617.2) and Omicron variants,
although efficacy against asymptomatic and mild symptomatic Omicron
variant infection was reduced9,10. The titer and
breadth of the nAb response against the ancestral strain and both
variants were significantly recalled in individuals following a
homologous third-dose booster vaccination, although titers were lower
against the variants, indicating cross-reactive broadly neutralizing
nAbs constitute a subset of all nAbs11,12.
Nevertheless, breakthrough infections with the Omicron variant following
booster vaccinations were reported for individuals within weeks of a
third dose13.
Understanding Ab responses to natural SARS-CoV-2 infection or
vaccination by enzyme-linked immunosorbent assay (ELISA) assays has
primarily relied on patient serum derived from blood, but this has
limitations associated with the invasiveness of the procedure and
specimen processing14. Alternatively, oral mucosal
fluid (saliva) specimens are non-invasive, enable self-collection, and
require less processing, reducing cost14. Multiple
studies demonstrated that anti-S-protein IgG levels can be robustly
measured in saliva specimens with high sensitivity and specificity from
infected or vaccinated individuals, even though salivary Ab
concentrations are 100-10,000-fold lower than in
serum15,16. IgG titers for serum and saliva are
strongly correlated, indicating they represent a surrogate for
anti-S-protein IgG levels in serum15,16. In contrast,
anti-S-protein IgA Abs are not reliably detected in saliva, although
serum IgA titers increase in response to infection or vaccination and
are consistently detected in specimens16.
We previously reported the anti-S-protein IgG Ab response in two cohorts
who received homologous vaccination regimens with two doses of either
the mRNA-1273 mRNA or BNT162b2 mRNA vaccine, in which participants
performed self-collection of saliva using the OraSure®oral fluid collection device at pre-determined time-points for ninety
days17. We report new results from those participants
who received a third-dose booster and continued to perform
self-collection of saliva at pre-determined time-points for up to
fifteen months following the first vaccination.