Protective capacity of CD8 T cells targeting a spectrum of Plasmodium-specific epitopes (MPF6P.735)

Abstract

Despite decades of research, malaria remains a global health crisis. Currently, the most advanced anti-malarial vaccine in human clinical trials (RTS,S) does not provide long-term, sterilizing immunity against Plasmodium infection. Plasmodium-specific CD8 T cells can provide sterilizing immunity to Plasmodium infection in rodent models. However, the numerical requirements for memory CD8 T cell protection against a defined epitope, P. berghei CS252-260 (a CSP epitope) exceeds 1% of peripheral blood lymphocytes - a 103-104 fold higher number than required for protection against some bacterial or viral infections. Recently, three novel H-2b-restricted Plasmodium-specific CD8 T cell epitopes were described from the following antigens: GAP50, S20, and TRAP. Priming with peptide-loaded mature dendritic cells followed by boosting with recombinant L. monocytogenes expressing these epitopes results in antigen-specific CD8 T cell responses constituting 0.3-6% of the PBL in CB6.F1 mice. The capacity of these single CD8 T cell responses to provide protective immunity in a stringent model of liver stage infection with P. berghei will be described. Moreover, we are determining whether combining multiple epitope-specific responses can reduce the total numerical requirement for CD8 T cell-mediated protection. These studies may aid in the preclinical design of a sterilizing CD8 T cell based anti-Plasmodium subunit human vaccine containing multiple CD8 T cell epitopes.