Additive effects of booster mRNA vaccination and SARS-CoV-2 Omicron infection on T cell immunity across immunocompromised states.

Suboptimal immunity to SARS-CoV-2 mRNA vaccination has frequently been observed in individuals with various immunodeficiencies. Given the increased antibody evasion properties of emerging SARS-CoV-2 subvariants, it is necessary to assess whether other components of adaptive immunity generate resilient and protective responses against infection. We assessed T cell responses in 279 individuals, covering five different immunodeficiencies and healthy controls, before and after booster mRNA vaccination, as well as after Omicron infection in a subset of patients. We observed robust and persistent Omicron-reactive T cell responses that increased markedly upon booster vaccination and correlated directly with antibody titers across all patient groups. Poor vaccination responsiveness in immunocompromised or elderly individuals was effectively counteracted by the administration of additional vaccine doses. Functionally, Omicron-reactive T cell responses exhibited a pronounced cytotoxic profile and signs of longevity, characterized by CD45RA⁺ effector memory subpopulations with stem cell–like properties and increased proliferative capacity. Regardless of underlying immunodeficiency, booster-vaccinated and Omicron-infected individuals appeared protected against severe disease and exhibited enhanced and diversified T cell responses against conserved and Omicron-specific epitopes. Our findings indicate that T cells retain the ability to generate highly functional responses against newly emerging variants, even after repeated antigen exposure and a robust immunological imprint from ancestral SARS-CoV-2 mRNA vaccination. Editor's summary: The efficacy of SARS-CoV-2 mRNA vaccines in immunocompromised individuals has been questioned because of emerging variants that are not specifically targeted by vaccine-induced antibodies. Here, Müller et al. examined T cell responses in both immunocompromised individuals and healthy controls before and after booster vaccination and in a subset of individuals after Omicron infection. Booster vaccination effectively induced robust Omicron-reactive T cell responses in immunocompromised individuals. Importantly, boosters were associated with overall protection from severe disease and counteracted poor initial vaccine responses in elderly and immunocompromised individuals. Additional Omicron infection induced Omicron-specific T cell responses and diversified the SARS-CoV-2–reactive T cell repertoire. These findings provide evidence that T cell responses, even to new variants, are strengthened by ancestral-based booster vaccination and also retain potency to dynamically adapt to mutated strains upon infection. —Christiana Fogg [ABSTRACT FROM AUTHOR]