Letter
Delta or Omicron BA.1/2-neutralizing antibody levels and T-cell
reactivity after triple-vaccination or infection
To the editor,
In Germany, SARS-CoV-2 infections in fall 2021 were caused by the Delta
variant of concern (VOC B.1.617.2), which was completely replaced by the
Omicron VOC (BA.1, B.1.529.1/BA.2, B.1.529.2) in winter. Meanwhile, the
BA.2 sublineage dominates, apparently having a selection advantage1.
We studied the kinetics of anti-spike (S) protein IgG and Delta
neutralizing antibodies (NA) as well as the release of interferon-gamma
(IFN-γ) from SARS-CoV-2-specific T-cells in 152 individuals (117 women,
35 men, median age 41 years) who received two doses of vector vaccine
(AstraZeneca, AZD, N=34), mRNA vaccine (BioNTech or Moderna, mRNA,
N=62), or a combination of both (N=56) followed by an mRNA vaccine boost
(N=81). In a subset of 15 age- and gender-matched vaccinees and in ten
triple-vaccinated and two unvaccinated patients with previous BA.1
infection, the Delta- and Omicron BA.1/BA.2 NAs and T-cell reactivity
were examined. For comparison, variant-specific antibody responses of
unvaccinated patients after infection with Alpha- (N=10) or Beta VOCs
(N=1) were included.
Within 279 days after the second vaccination, a decrease in anti-S IgG
concentrations (Figures S 1A-C) and Delta NA titers (Figure 1A) was
measured regardless of the immunization regimen. The booster vaccination
led to a significant increase of anti-S IgG concentrations (Figures S1
D-F) and of Delta NA titers (Figure 1B). The IgG levels and Delta NAs
reached four weeks after the mRNA vaccine booster were 1.3 - 1.7-fold
higher than after the second mRNA dose, but this difference was
significant only for IgG (Figures 1A, C; Figures S 1A-C, G-I). The
release of IFN-γ as a measure of SARS-CoV-2 T-cell reactivity was
demonstrated for months after second vaccination. In contrast to the
Delta NA levels, IFN-γ concentrations were independent of the underlying
vaccination schedule and increased slightly after the third immunization
(Figures 1D, E). The parameters of humoral and cellular immunity
decreased again after the booster vaccination (Figures 1C, F; Figures S
1G-I).
As reported by others 1-4, NAs to Omicron BA.1 were
induced by the mRNA vaccine booster, but also against the predominant
BA.2 sublineage, which was previously unclear. The BA.2 NA geometric
mean titer (GMT) was higher than the BA.1 NA GMT (Figure 2A). With
respect to the results presented in Figures 1C and 2B, we suspect that
NAs against the Omicron VOC will decline rapidly after booster
vaccination alone. High NA titers against Omicron BA.1/BA.2 and against
Delta VOC were exclusively observed in triple-vaccinated individuals two
to three weeks after Omicron breakthrough infection (Figure 2A). This
indicates broadened immunity covering additional viral variants and may
also explain why few BA.2 infections have occurred in this group of
individuals to date 5. Because Omicron is a distinct
serotype 6, only NAs against this VOC were detectable
in two unvaccinated BA.1-infected individuals (Figure 2A), while
unvaccinated Alpha- and Beta VOC patients developed isolated NAs against
the antigenically more related Delta VOC (Figure S 2A). Accordingly,
both BA.1 patients had very low IgG levels against the receptor-binding
domain (RBD) of a Wuhan-like virus (Figure S 2B), whereas IgGs against
the higher preserved nucleocapsidprotein were barely affected (Figures S
2C, D). The results of a surrogate neutralization assay confirmed very
limited humoral immunity after Omicron infection alone (Figure S 2E).
The increase of IFN-γ release by mRNA booster vaccination was moderate
(Figures 1D, E), while the breakthrough infection insignificantly
increased IFN-γ release by a factor of 1.9 - 2.6 (Figure 2C).
In conclusion, the importance of pre-existing vaccine-induced immunity
is clearly demonstrated. The booster vaccination with the conventional
mRNA vaccine resulted in measurable BA.1/BA.2 NAs. However, a
multivalent vaccine could induce higher titers, which could provide
better protection.