Are Extensive T Cell Epitope Polymorphisms in the Plasmodium falciparum Circumsporozoite Antigen, a Leading Sporozoite Vaccine Candidate, Selected by Immune Pressure?

Abstract

Protective cellular immune responses depend on MHC presentation of pathogen-derived Ag fragments. MHC diversity renders this process sensitive to point mutations coding for altered amino acid sequence of the short target Ag-derived peptides epitopes. Thus, in a given host, a pathogen with an altered epitope sequence will be more likely to escape detection and elimination by the immune system. At a population level, selection by immune pressure will increase the likelihood of polymorphism in important pathogen antigenic epitopes. This mechanism of immune evasion is found in viruses and other pathogens. The detection of polymorphic hot spots in an Ag is often taken as a strong indication of its role in protective immunity. We provide evidence that polymorphisms in the T cell epitopes of a malaria vaccine candidate are unlikely to have been selected by immune pressure in the human host.

Antigenic Diversity of the Plasmodium vivax Circumsporozoite Protein in Parasite Isolates of Western Colombia

“…The limited sequence variation found here for P. vivax is in contrast with the high level of non-synonymous mutations at the sequences encoding the Th2R and Th3R epitopes of the P. falciparum CS in African isolates considered to be the result of host immune selection, 30,31 However, it appears that polymorphism, at least in gene sequences coding for T-cell epitopes are unlikely to be selected by immune pressure in the human host. 25 The great sequence conservation of this region appears to be similar to that observed for …”

Human CD4+ T Cells Induced by Synthetic Peptide Malaria Vaccine Are Comparable to Cells Elicited by AttenuatedPlasmodium falciparumSporozoites

“…At the present time, it is not known what structural or functional requirements limit variability in position and in amino acid usage in this region of the CS protein. The fact that all substitutions maintain an amphipathic ␣ helix secondary structure suggests that this region is critical for protein function, potentially maintaining conformation needed for CS ligand interaction with cellular receptors of the mammalian host or mosquito vector (27,44).…”

High Degree of Plasmodium vivax Diversity in the Peruvian Amazon Demonstrated by Tandem Repeat Polymorphism Analysis

“…24 Of the remaining 74 individuals infected by a single genotype of P. vivax, 68 genotypes could be distinguished by combining both genetic markers. Thus, the use of PCR-RFLP on P. vivax genes encoding proteins subject to immune selection in the human host 27 has been shown to discriminate among infecting malaria parasite strains, at least in Papua New Guinea and Thailand, where the intensity of malaria transmission is relatively high and complex infections that facilitate genetic out-crossing are relatively common.…”