Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria infection.

Abstract

Abstract Immunization with whole pre-erythrocytic stage malaria parasites that infect hepatocytes but are unable to cause blood stage infection constitutes one of the most promising strategies to protect against malaria infection. In rodent malaria models, whole parasite vaccines that exhibit substantial replication within hepatocytes engender superior, long-lasting strain- and stage-transcending immunity as compared to replication-deficient whole parasite vaccines. Liver stage infection with replication-competent Plasmodium parasites induces an innate immune response that is dependent on type I Interferon (IFN-1) signaling. However, it remains unknown how this IFN-1 response contributes to vaccine-engendered adaptive immunity. Using a replication-competent genetically attenuated parasite vaccine in an immunization regimen that confers partial protection in wildtype (WT) mice, we examined vaccine efficacy in mice lacking IRF3 or IFNAR. Surprisingly, IRF3−/− and IFNAR−/− mice showed superior protection against an infectious sporozoite challenge when compared to WT mice. Better protection correlated with a greater frequency of liver-resident memory CD8 T cells in immunized IFNAR−/− mice. Furthermore, IFNAR−/− mice exhibited lower levels of the T cell co-inhibitory receptors, PD-1 and LAG-3, a greater percentage of IFNγ-producing CD8 T cells, and eliminated liver stages more effectively. Taken together, we show that the Plasmodium engendered IFN-1 response impairs the generation of an optimal memory T cell response. To our knowledge, this study is the first description of a detrimental role for IFN-1 signaling on malaria vaccine efficacy and as such may necessitate a paradigm shift in rational malaria vaccine design.