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.