Yeast antigens source modulates vaccine potency and immunity mediated by CD8+ T cells in CD4+ T cell-deficient hosts 2305523

Abstract Introduction Given the global rise in fungal infections, which primarily occur in hosts with CD4+ T cell deficiency or dysfunction, and the lack of FDA-approved vaccines, it is imperative to develop novel vaccine platforms. Our previous studies indisputably showed that an attenuated fungal strain vaccine bestowed sterilizing immunity by CD8+ T cells in CD4+ T cell deficiency. Since live vaccines are contraindicated, we delved to identify the cellular source of fungal antigens that impart immunity. Yeast antigens are primarily sourced from the cytoplasm and cell wall, the latter often being glycosylated. Yet, the cross-presentation ability of vaccine and eukaryotic pathogen to confer immunity is not studied. We hypothesize that protective immunity is dictated by the matching of T cell epitopes during vaccine responses with those cross-presented during fungal infection. Methods We vaccinated cohorts of mice subcutaneously with fungal cell wall/membrane (CW/M) and cytosol extract (YCE) antigens, adjuvanted with alum under CD4+ T cell-depleted condition. We assessed CD8+ T cell vaccine responses in lymph nodes and spleen, lung recall responses after pulmonary challenge, and vaccine immunity. Results CW/M antigens elicited superior polycytokine+ CD8+ T cell vaccine responses than YCE antigens. This enhanced immunogenicity of CW/M antigens did not translate into stronger early recall responses. Nevertheless, intriguingly, we found that CW/M Ag vaccination conferred significantly better survival than YCE Ag vaccination. Conclusion Our findings reveal a mismatch between CD8+ T cell vaccine potency and protective efficacy, and immunogenicity readouts do not accurately predict immunity, a factor contributing to vaccine failures in clinical trials. Thus, it is essential to identify matching epitopes in a vaccine that are potentially cross-presented during eukaryotic pathogen infection to impart sterilizing immunity for safer, potent, and efficacious vaccines targeting CD8+ T cells tailored for immunocompromised hosts. Funding Source NIH-NIAID R01153522 (to SGN) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)