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An Old-World bat H9N2 influenza A virus (IAV) identified in Egypt exhibits high replication and transmission potential in ferrets, efficient infection of human lung explant cultures and marked escape from the antiviral activity of MxA. Together with low antigenic similarity to N2 of seasonal human strains, bat H9N2 meets key criteria for pre-pandemic IAVs.

Reports of waning immunity after COVID-19 vaccination (1-3) have recently led to large booster vaccination campaigns. Previous studies showed that basic immunization with two mRNA vaccine doses elicits a robust spike-specific CD8+ T cell response (4-6). The effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains, however, unclear. Indeed, very little is known about the efficacy, duration and effects on long-term immunity and recall responses in breakthrough infections. In this study, we show that spike-specific CD8+ T cells are immediately and vigorously activated and expanded in all tested individuals after the 3rd and 4th mRNA vaccine shots. However, this CD8+ T cell boost response is characterized by a steep contraction and lasts only for about 30-60 days compared to a prolonged contraction after natural infection. Booster vaccination did not affect long-term spike-specific CD8+ T cell immunity reflected by a stable stem cell memory pool that already reached maximum frequencies after basic immunization. Accordingly, rapid and full-fledged recall responses of boosted spike-specific CD8+ T cells were detectable after breakthrough infection with delta and omicron. Thus, in addition to the previously reported cross-reactivity (7-12) also a robust activation and effector response determines the efficacy of the CD8+ T cell response targeting emerging variants of concern. Neutralizing antibody responses displayed hardly any boost effect towards omicron, further highlighting the relevance of spike-specific CD8+ T cell immunity. In sum, these data will inform future vaccination strategies facing the next COVID-19 wave expected for late 2022/early 2023.

The SARS-CoV-2 variant of concern (VOC) omicron (B1.1.529) is associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. In omicron-infected individuals who have been vaccinated or infected before, severe disease seems to be relatively infrequent pointing towards protection by previously primed SARS-CoV-2-specific T cells that cross-recognize omicron. By performing a comprehensive in-depth comparison of the SARS-CoV-2-specific T cell epitope repertoire after natural infection versus after mRNA vaccination, we here demonstrate that spike-derived epitopes are not dominantly targeted in convalescents compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T cell response compared to convalescents reflected by a more diverse repertoire of dominantly targeted spike-specific T cell epitopes. Booster mRNA vaccination induced a broader spike-specific T cell response in convalescents but not in vaccinees with complete initial vaccination. In convalescents and vaccinees, the targeted T cell epitopes are broadly conserved between ancestral and omicron SARS-CoV-2 variants. Hence, our data emphasize the relevance of mRNA vaccine-induced spike-specific CD8+ T cell responses in combating emerging SARS-CoV-2 VOC including omicron and support the benefit of also boosting convalescent individuals with mRNA vaccines.

SARS-CoV-2 spike mRNA vaccines mediate protection from severe disease as early as 10 days post prime vaccination, when specific antibodies are hardly detectable and still lack neutralizing activity. Vaccine-induced T cells, especially CD8+ T cells, may thus be the main mediators of protection at this early stage. The details of antigen-specific CD8+ T cell induction after prime/boost vaccination, their comparison to naturally induced CD8+ T cell responses and their association with other arms of vaccine-induced adaptive immunity remain, however, incompletely understood. Here, we show on a single epitope level that both, a stable memory precursor pool of spike-specific CD8+ T cells and fully functional spike-specific effector CD8+ T cell populations, are vigorously mobilized as early as one week after prime vaccination when CD4+ T cell and spike-specific antibody responses are still weak and neutralizing antibodies are lacking. Boost vaccination after 3 weeks induced a full-fledged recall expansion generating highly differentiated CD8+ effector T cells, however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared to natural infection, vaccine-induced early memory T cells exhibited similar frequencies and functional capacities but a different subset distribution dominated by effector memory T cells at the expense of self-renewing and multipotent central memory T cells. Our results indicate that spike-specific CD8+ T cells may represent the major correlate of early protection after SARS-CoV-2 mRNA/bnt162b2 prime vaccination that precede other effector arms of vaccine-induced adaptive immunity and are stably maintained after boost vaccination.