Lack of cross-reactivity between variant T cell determinants from malaria circumsporozoite protein

The discovery of polymorphism in the T cell determinants of the protein that covers the surface of malaria sporozoites, the circumsporozoite protein (CSP), may have a negative effect on the course of development of a sporozoite-derived anti-malaria vaccine. Comparison of CSP gene sequences from Plasmodium falciparum suggests, based on the lack of silent (i.e., synonymous) substitutions, that polymorphism is being biologically selected for in the field. Thus, variation in T cell determinant sequences may actually be a means of immune evasion. The central question addressed here is whether or not the natural polymorphisms found in three identified T cell determinants in the CSP gene of P. falciparum are immunologically significant with regard to T cell stimulation. In support of the immune evasion hypothesis, we show here that animals immunized with peptides based on one sequence (i.e., the 7G8 isolate) will not significantly respond when challenged with variant peptides based on other CSP sequences (i.e., the LE5 and We1 isolates). Polymorphism in T cell determinants thus indicates that infection with sporozoites will not necessarily boost immune (antibody help and/or proliferative) responses stimulated by prior infections or by a particular vaccine construct based on these determinants. The implications of these findings in regard to vaccine development are discussed.