A model to study the impact of polymorphism driven liver-stage immune evasion by malaria parasites, to help design effective cross-reactive vaccines

Malaria parasites engage a multitude of strategies to evade the immune system of the host, including the generation of polymorphic T cell epitope sequences, termed altered peptide ligands (APLs). Herein we use an animal model to study how single amino acid changes in the sequence of the circumsporozoite protein (CSP), a major target antigen of pre-erythrocytic malaria vaccines, can lead to a reduction of cross reactivity by T cells. For the first time in any APL model, we further compare different inflammatory adjuvants (Montanide, Poly I:C), non-inflammatory adjuvants (nanoparticles), and peptide pulsed dendritic cells (DCs) for their potential capacity to induce broadly cross reactive immune responses. Results show that the capacity to induce a cross reactive response is primarily controlled by the T cell epitope sequence and cannot be modified by the use of different adjuvants. Moreover, we identify how specific amino acid changes lead to a one-way cross reactivity: Where variant-x induced responses are re-elicited by variant-x and not variant-y, but variant-y induced responses can be re-elicited by variant-y and variant-x. We discuss the consequences of the existence of this one-way cross reactivity phenomenon for parasite immune evasion in the field, as well as the use of variant epitopes as a potential tool for optimized vaccine design.