Ag-specific recall of cytokine producing CD4 and CD8 T cells in humans immunized with genetically attenuated Plasmodium falciparum sporozoite vaccine (166.12)

Abstract

Abstract A Plasmodium falciparum (Pf) genetically attenuated parasite (Pf GAP) vaccine, engineered by deletion of 2 pre-erythrocytic genes, was administered to 6 subjects by bites from Anopheles mosquitoes. Previous studies of immune responses elicited by recombinant malaria vaccines show that protection is linked to Ag-specific T cells producing IFN-γ, TNF, and/or IL-2. In this study we asked if Pf GAP vaccine induced Ag-specific T cell responses characterized by inflammatory cytokines. We analyzed pre- and post vaccination PBMC for Ag-specific T cell responses to well characterized pre-erythrocytic and erythrocytic P. falciparum protein and peptide Ags. Additionally, we examined responses to several novel Pf liver-stage Ag (Pf LSA) because Pf LSA-dependent immunity might contribute to GAP-induced protection. IFN-γ and TNF responses to multiple antigens were significantly enhanced post vaccination; IFN-γ responses were primarily attributed to CD8+ T cells while TNF was secreted primarily by CD4+ T cells. Notably, a subject with a breakthrough peripheral parasitemia did show positive IFN-γ responses to erythrocytic-stage Ags, but no responses were recalled with the novel Pf LSA. In summary, two exposures to a Pf GAP vaccine induced persisting T cell responses specific for Pf LSA in humans. Future trials that assess the efficacy of Pf GAP vaccines should examine the role of LSA-specific responses in protection.