title: A Model to Study the Impact of Polymorphism Driven Liver-Stage Immune Evasion by Malaria Parasites, to Help Design Effective Cross-Reactive Vaccines.
abstract: 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.
authors.affiliation: Vaccines and Infectious Diseases Laboratory, Department of Immunology and Pathology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia.
authors.forename: Kirsty L
authors.initials: KL
authors.lastname: Wilson
authors.affiliation: Vaccines and Infectious Diseases Laboratory, Department of Immunology and Pathology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia.
authors.forename: Sue D
authors.initials: SD
authors.lastname: Xiang
authors.affiliation: Vaccines and Infectious Diseases Laboratory, Department of Immunology and Pathology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Plebanski
keywords: CD8 epitope; altered peptide ligands; circumsporozoite protein; cross reactivity; polymorphism; vaccines