Prime-Trap immunization with protective liver stage antigen, MIF-4G and Kb17 peptide, induces liver CD8 TRM cells and protection against Plasmodium berghei malaria

Abstract

Abstract Exposure to Plasmodium sporozoites (spz), the causative agent of malaria, induces anti-disease immunity, but fails to protect against repeated Plasmodium infections. In contrast, multiple immunizations with radiation-attenuated Plasmodium spz (RAS) induce sterile lasting protection in humans, non-human primates, and murine models. The mechanisms of protective immunity are multifactorial and CD8 T cells are considered sine qua none of protection. The Plasmodium berghei (Pb) RAS-induced protection in C57Bl/6 mice correlates with a network of liver stage antigens (LS Ags)-activated liver CD8 T cell subsets including resident memory (RM) CD8 TRM cells. A protective Pb LS Ag, termed MIF-4G, induced liver CD8 T cells that recognize H-2Kb-restricted epitope, Kb17. One of the current efforts to improve malaria vaccines focuses on maximizing the induction of liver CD8 TRM cells by Prime-Trap immunization regimen. Here we asked if priming with DNA-MIF-4G followed by trapping with Adenovirus serotype 5 (Ad5) vectored-Kb17 would induce Kb17-specific liver CD8 TRM cells as well as protection against Pb spz challenge. Liver Kb17-specific CD8 TRM cells (CD69+CXCR6+) exceeded the number of these cells in the spleens, 27% vs 2%, respectively. Protection measured by liver parasite burden was CD8 T cell dependent. In contrast, prime:boost immunization with DNA/Ad5 MIF-4G induced only 8% liver CD8 TRM cells, as did control immunization with DNA/Ad5 empty vector. Utilizing LS Ags and the corresponding CD8 T cell-inducing epitopes in Prime-Trap immunization lends itself for further explorations as an ancillary approach to malaria vaccine regimens where liver CD8 TRM may be crucial in preventing virulent blood stages by targeting LS parasites.