CD4 T cell phenotype after AS01-adjuvanted immunization is shaped by prior antigen or pathogen exposure.

CD4 T-cell responses are important for the protection conferred by many infectious disease vaccines and can be quantitatively and qualitatively improved by adjuvants. The AS01 adjuvant is present in critical licensed or candidate vaccines against, amongst others, zoster, respiratory syncytial virus, malaria and tuberculosis. During their clinical development, these vaccines have been evaluated in populations ranging from immunologically naïve to strongly pathogen-primed individuals. We dissected the vaccine-induced CD4 T-cell responses across these studies, to elucidate how pre-existing immune memory in the host drives the polyfunctional phenotype of the vaccine-induced CD4 T cells. Across the investigated vaccines, a consistent pattern emerged, in which the capacity of antigen-specific vaccine-induced CD4 T cells to produce interferon-γ appeared to depend on increased levels of prior exposure, leading to pre-existing memory T cells. As the dominant origin of a vaccine-induced CD4 T-cell response (i.e., memory cells with a pre-existing T-cell receptor repertoire, or newly recruited naïve cells) remains to be clarified, this observation helps to guide future research into efficacious next-generation vaccines tailored to the specific immune priming status of the target population.