Discussion
This study showed that approximately 10 months after receiving the last
monovalent (booster) mRNA vaccination, ancestral SARS-CoV-RBD IgG
antibodies were present and a previous SARS-CoV-2 infection in addition
to vaccination led to higher T cell responses against SARS-CoV-2 S1.
Subsequently, an ancestral/Omicron BA.1 bivalent booster vaccination
significantly increased these T cell and antibody responses against
SARS-CoV-2, including serum antibody neutralization activity against
Omicron BA.5. Irrespective of bivalent booster vaccination, a recent
Omicron BA.5 infection increased the ratio of Omicron BA.5 to ancestral
strain neutralization activity.
nAbs are considered the first line of defense within adaptive immunity
against viruses as these bind external viral epitopes and thereby
prevent infection of host cells. After infection both the nAbs and T
cells contribute to limiting viral replication and preventing disease
progression.16 In our previous study, we similarly
assessed anti-RDB IgG antibody and S1-specific T cell responses up to
seven months post (booster) vaccinations and observed higher anti-RBD
IgG concentrations in individuals with a previous or a recent infection
in comparison to infection-naive individuals.12 In the
period from seven to 10 months post vaccination, the infection-induced
higher anti-RBD IgG levels seem to normalize towards infection-naive
levels. In this current study, a recent Omicron BA.5 infection was not
associated with statistically significant higher anti-RBD
concentrations, although the recently infected HCWs had 3-fold higher
anti-RBD IgG median concentrations than infection-naive HCWs.
Nevertheless, all HCWs had detectable anti-RBD IgG antibodies, which is
in line with other studies showing waning but yet sustained anti-RBD
antibodies levels up to nine months after mRNA
vaccinations.17–19
Protection against reinfection is considered to be reduced against the
Omicron variant in comparison to previous SARS-CoV-2
variants.20 The proportion of HCWs who were considered
positive for the presence of Omicron BA.5 nABs was increased in both
prior-infected groups, and inhibition activity was substantially higher
in the recently Omicron BA.5 infected individuals. In addition, a recent
Omicron BA.5 infection in combination with a bivalent vaccination led to
an increased ratio of Omicron BA.5 to ancestral strain neutralization
activity. Moreover, Omicron BA.5 partially escapes nAbs induced by
Omicron BA.1 vaccination, indicating that vaccine-induced Omicron
BA.1-specific nAbs might not optimally neutralize Omicron
BA.5.21,22 Nevertheless, we observed significantly
higher neutralization activity against Omicron BA.5 after Omicron BA.1
bivalent vaccination in comparison to no bivalent booster vaccination.
Infection plus vaccination, termed hybrid immunity, seemed to induce
higher T cell responses against spike S1 than vaccination alone.
Although the underlying mechanisms of hybrid immunity is not well
understood, it is known that a combination of infection and vaccination
induces more polyfunctional spike-specific T cells than infection or
vaccination alone.23–25 In addition, a SARS-CoV-2
infection also induces T cell responses against non-spike proteins such
as the nucleocapsid protein, allowing for a broader and more protective
T cell response against the virus.26 Notably, T cell
responses were similar between the recently Omicron BA.5 infected and
infection-naive HCWs, which is potentially explained by the mild disease
following Omicron BA.5 infection since mild COVID-19 elicits weak T cell
responses.27,28
CD4+ and CD8+ T cell epitopes in the
spike protein remain largely preserved accross SARS-CoV-2 variants,
including Omicron BA.5.29–32 This possibly explains
why we observed weak T cell responses against the Omicron BA.5 peptide
pool that solely consists of mutation-containing peptides. However,
broader T cell responses are likely to be cross-reactive against
different variants, as T cells may prevent severe COVID-19 even in the
absence of effective nAbs.30
Although this study is one of the first to investigate both SARS-CoV-2
ancestral and Omicron BA.5 specific humoral and cellular immune
responses after ancestral/Omicron BA.1 bivalent booster vaccination,
there are some limitations to consider. First, some subgroups were
limited in size, because only a small proportion of HCWs were recently
infected or received a bivalent booster vaccination. Second, we assessed
immune responses against Omicron BA.5, while the BA.5 sublineage BQ.1
and the BA.2 sublineage XBB1.5, became the global dominant variants as
of December 2022 and March 2023, respectively.2,33However, knowledge of Omicron BA.5-specific immunity is still relevant
since a considerable number of epitopes remain conserved among Omicron
subvariants, and BA.5 sublineages (such as BQ.1) may become more
prevalent in the future.32
In conclusion, SARS-CoV-2 specific nAb and T cell responses persist for
up to at least 10 months after monovalent booster mRNA vaccinations, and
hybrid immunity is associated with improved preservation of T cell
immunity. An ancestral/Omicron BA.1 bivalent booster mRNA vaccination
induces nAb and T cell responses against the ancestral strain and
cross-protective neutralization activity against Omicron BA.5. Future
studies must elucidate whether nAb and T cell responses induced by
prior-infection and bivalent vaccinations are protective against new
emerging subvariants.