Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

Abstract

The leading blood-stage malaria vaccine candidate antigen, Plasmodium falciparum merozoite surface protein-1 (MSP-1) occurs in two major allelic types worldwide. The molecular basis promoting this stable dimorphism is unknown. In this study, we have shown that allelic altered peptide ligand (APL) T cell epitopes of MSP-1 mutually inhibited IFN-c secretion as well as proliferation of CD4 + T cells in 27/34 malaria exposed Gambian volunteers. Besides this inhibition of malaria-specific immunity, the same variant epitopes were also able to impair the priming of human T cells in malaria naive individuals. Epitope variants capable of interfering with T cell priming as well as inhibiting memory T cell effector functions offer a uniquely potent combination for immune evasion. Indeed, enhanced co-habitation of parasites bearing such antagonistic allelic epitope regions was observed in a study of 321 West African children, indicating a survival advantage for parasites able to engage this inhibitory immune interference mechanism.

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

“…24 This data clearly suggests the need for designing minimal subunit-based vaccines (preferentially synthetic ones) so as not to fall into the genetic variant-induced immunological traps described above.…”

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…Previous data have suggested that cohabiting P. falciparum parasites could interfere with the priming of T cell responses by the phenomenon of immune interference as well as restimulation of memory responses by immune antagonism, whereby APL epitopes present in dimorphic Ags antagonize responses to each other (38). This led to concerns about the ability to prime and boost cellular immune responses with vaccines encoding more than one allele of an Ag.…”

“…4A), indicating that responses had been induced in vivo by vaccination to these epitopes and not completely prevented owing to immune interference or antagonism. In their studies, Lee et al (38) described antagonism as an arbitrary $30% reduction in the response following restimulation with both peptides. To increase stringency we increased the cut-off to a $50% reduction.…”

“…Although these strategies aim to confront the difficulties surrounding the induction of cross-strain humoral immunity, other reports have raised important concerns about this approach in the context of T cell immunity (36). Such studies utilizing malaria Ags have concluded that inclusion of multiple allelic variants in a vaccine may be detrimental to both the priming and in vivo restimulation of Ag-experienced T cells (37,38). These immunological studies arose from questions relating to the population dynamics of natural P. falciparum malaria infection, host/parasite coevolution, and how allelic dimorphisms are maintained.…”

“…+ T cells in naturally exposed Gambian volunteers, and that the same variant epitopes were also able to impair priming of T cells from malaria-naive individuals (38). This observed effect of priming bias, termed "immune interference" (37) is dependent on the presentation of APLs on the same APC.…”