Secreted heat shock protein gp96-Ig vaccine induces malaria specific intrahepatic CD8 T cell responses

Abstract

Abstract A highly-efficacious and durable malaria vaccine is an essential tool for global malaria eradication. One promising strategy to develop such a vaccine is to induce robust CD8+ T cell-mediated protective immunity against malaria liver stage parasites. We developed and tested a novel malaria vaccine platform based on the secreted form of the heat shock protein gp96 immunoglobulin, (gp96-Ig) to induce malaria antigen-specific liver resident memory CD8+ T cells. Gp96-Ig has ideal properties as an antigen carrier and vaccine adjuvant to activate antigen presenting cells (APCs) and effectively chaperone antigens for cross presentation via MHC I to CD8+ T lymphocytes. Our study shows that vaccination of mice and non-human primate (NHP) animal models with HEK-293 cells transfected with gp96-Ig and two well-known Plasmodium falciparum (Pf) vaccine candidate antigens, circumsporozoite protein (CSP) and apical membrane antigen 1 (AMA1), induce liver infiltrating, antigen-specific, cytotoxic memory CD8+ T cell responses. The majority of the CSP and AMA specific intrahepatic CD8+ T cells expressed CD69 and CXCR3, hallmarks of tissue resident memory T cells (TRM). Also, we found an increased frequency of intrahepatic CD8+ T cells secreting IL-2, which is relevant for maintenance of effective memory responses. Our findings are strongly supportive of a novel gp96-Ig-based malaria vaccine as a unique systemic and liver-homing, liver-stage antigen-specific CD8+ cytotoxic T lymphocyte (CTL) vaccine strategy.