Clonality, specificity, and HLA restriction of human T cell receptors against Plasmodium falciparum CSP

Plasmodium falciparum malaria remains a significant global health challenge. Current vaccines elicit antibody responses against circumsporozoite protein (PfCSP) that prevent the infection of hepatocytes but offer only moderate protection. Cellular immunity has emerged as a critical component of pre-erythrocytic protection that might be leveraged to develop improved PfCSP vaccines. Here, we characterized the clonality, molecular features, epitope specificity, and HLA-restrictions of the human PfCSP-specific CD4 ⁺ and CD8 ⁺ T cell response to vaccination with an adjuvanted PfCSP vaccine, FMP013/ALFQ. Using TCR expression cloning, we identified novel conserved CD4 ⁺ T cell epitopes in the PfCSP N terminus and show that the C-terminal CS.T3 epitope was targeted by CD4 ⁺ and rare CD8 ⁺ T cells, which recognized this epitope co-receptor-independently presented on a class II HLA. Our findings provide insights into the utility of these epitopes as targets for strain-transcending immunity compared to the immunodominant but highly polymorphic epitopes in the PfCSP C terminus, offering guidance for the design of improved malaria vaccines.