Abstract
The infection dynamics between different species of Plasmodium that infect the same human host can both suppress and exacerbate disease. This could arise from inter-parasite interactions, such as competition, from immune regulation, or both. The occurrence of protective, cross-species (heterologous) immunity is an unlikely event, especially considering that strain-transcending immunity within a species is only partial despite lifelong exposure to that species. Here we review the literature in humans and animal models to identify the contexts where heterologous immunity can arise, and which antigens may be involved. From the perspective of vaccine design, understanding the mechanisms by which exposure to an antigen from one species can elicit a protective response to another species offers an alternative strategy to conventional approaches that focus on immunodominant antigens within a single species. The underlying hypothesis is that certain epitopes are conserved across evolution, in sequence or in structure, and shared in antigens from different species. Vaccines that focus on conserved epitopes may overcome the challenges posed by polymorphic immunodominant antigens; but to uncover these epitopes requires approaches that consider the evolutionary history of protein families across species. The key question for vaccinologists will be whether vaccines that express these epitopes can elicit immune responses that are functional and contribute to protection against Plasmodium parasites.
Highlights
A malaria vaccine would have a tremendous impact on vulnerable populations, with the potential to save nearly half a million lives annually and prevent over 200 million cases [1]
In populations from a region in Brazil endemic for both species, peripheral blood mononuclear cells (PBMCs) were highly responsive to stimulation with either PfCSP or PvCSP [55]. Responses to both species were especially frequent in individuals recovering from a recent P. vivax infection; PBMCs from 35 to 54% of these individuals proliferated in response to PfCSP [55]. These findings suggested that PvCSP and PfCSP might share cross-reactive T-cell epitopes, while there was no evidence of heterologous antibody responses
The epitopes shared between the P. falciparum and P. yoelii proteins enable reciprocal immune recognition as antibodies from mice infected with P. yoelii recognized peptides from PfLSA3 yet given the absence of a PfLSA3 ortholog in P. yoelii, these antibodies may be targeting another related antigen or the crossreactivity is not specific
Summary
A malaria vaccine would have a tremendous impact on vulnerable populations, with the potential to save nearly half a million lives annually and prevent over 200 million cases [1]. Serological recognition of a HSP70 peptide was used to rule out antibodies specific to P. falciparum infection, but this family of proteins contains other epitopes that are shared across Plasmodium species [49] Given their ubiquitous nature, it is possible that these and other conserved housekeeping antigens underpinned some of the cross-reactivity discussed previously. The epitopes shared between the P. falciparum and P. yoelii proteins enable reciprocal immune recognition as antibodies from mice infected with P. yoelii recognized peptides from PfLSA3 yet given the absence of a PfLSA3 ortholog in P. yoelii, these antibodies may be targeting another related antigen or the crossreactivity is not specific This cross-reactivity is restricted to P. yoelii, as sera from mice infected with P. berghei did not cross-react with PfLSA3 and likewise, human PfLSA3 antibodies failed to recognize P. berghei sporozoites or block invasion of hepatocytes. This study demonstrated that a peptide vaccine based on a cryptic epitope can focus the immune response on conserved regions of the protein, with the potential to target related antigens in other stages of the parasite life cycle
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