Heightened innate immune state induced by viral vector leads to enhanced response to challenge and prolongs malaria vaccine protection

Cytomegalovirus is a promising vaccine vector; however, mechanisms promoting CD4 T cell responses to challenge, by CMV as a vector, are unknown. The ability of MCMV to prolong immunity generated by short-lived malaria vaccine was tested. MCMV provided non-specific protection to challenge with <i>Plasmodium</i> and increased interleukin-12 (IL-12) and CD8α⁺ dendritic cell (DC) numbers through prolonged MCMV-dependent interferon gamma (IFN-γ) production. This late innate response to MCMV increased IL-12 upon challenge and increased the polyclonal CD4 effector T cell response to <i>Plasmodium</i>, protecting in an IL-12-dependent manner. Although <i>Plasmodium</i>-vaccine-induced protection decayed by d200, MCMV restored protection through IFN-γ. Mechanistically, protection depended on MCMV-induced-IFN-γ increasing CD8α⁺ DCs and IL-12p40. MCMV expressing a <i>Plasmodium</i> epitope increased parasite-specific CD4 effector and effector memory T cells persisting after malaria vaccination, both phenotypes reported to protect. Overall, enhanced innate cell status, a mechanism of heterologous protection by MCMV, led to a stronger T cell response to challenge.