SARS-CoV-2 spike mRNA vaccines^1–3 mediate protection from severe disease as early as ten days after prime vaccination³, when neutralizing antibodies are hardly detectable^4–6. Vaccine-induced CD8⁺ T cells may therefore be the main mediators of protection at this early stage^7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8⁺ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4⁺ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8⁺ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8⁺ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.

Immunization with two mRNA vaccine doses elicits robust spike-specific CD8⁺ T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8⁺ T cell response remains unclear. Here we show that spike-specific CD8⁺ T cells are activated and expanded in all analyzed individuals receiving the 3^rd and 4^th mRNA vaccine shots. This CD8⁺ T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8⁺ T memory stem cell pool is not affected by the 3^rd vaccination. Both 4^th vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8⁺ T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8⁺ T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern.

Zoonotic infections of humans with influenza A viruses (IAVs) from animal reservoirs can result in severe disease in individuals and, in rare cases, lead to pandemic outbreaks; this is exemplified by numerous cases of human infection with avian IAVs (AIVs) and the 2009 swine influenza pandemic. In fact, zoonotic transmissions are strongly facilitated by manmade reservoirs that were created through the intensification and industrialization of livestock farming. This can be witnessed by the repeated introduction of IAVs from natural reservoirs of aquatic wild bird metapopulations into swine and poultry, and the accompanied emergence of partially- or fully-adapted human pathogenic viruses. On the other side, human adapted IAV have been (and still are) introduced into livestock by reverse zoonotic transmission. This link to manmade reservoirs was also observed before the 20th century, when horses seemed to have been an important reservoir for IAVs but lost relevance when the populations declined due to increasing industrialization. Therefore, to reduce zoonotic events, it is important to control the spread of IAV within these animal reservoirs, for example with efficient vaccination strategies, but also to critically surveil the different manmade reservoirs to evaluate the emergence of new IAV strains with pandemic potential.

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8⁺ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document excessive FcγRIIIA/CD16A activation in patients developing severe or critical COVID-19 but not in those with mild disease. We identify two independent ligands mediating extreme FcγRIIIA/CD16A activation. Soluble circulating IgG immune complexes (sICs) are detected in about 80% of patients with severe and critical COVID-19 at levels comparable to active systemic lupus erythematosus (SLE) disease. FcγRIIIA/CD16A activation is further enhanced by afucosylation of SARS-CoV-2 specific IgG. Utilizing cell-based reporter systems we provide evidence that sICs can be formed prior to a specific humoral response against SARS-CoV-2. Our data suggest a cycle of immunopathology driven by an early formation of sICs in predisposed patients. These findings suggest a reason for the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19. The involvement of circulating sICs in the promotion of immunopathology in predisposed patients opens new possibilities for intervention strategies to mitigate critical COVID-19 progression.