Abstract
BackgroundNon-human primates, such as the rhesus macaques, are the preferred model for down-selecting human malaria vaccine formulations, but the rhesus model is expensive and does not allow for direct efficacy testing of human malaria vaccines. Transgenic rodent parasites expressing genes of human Plasmodium are now routinely used for efficacy studies of human malaria vaccines. Mice have however rarely predicted success in human malaria trials and there is scepticism whether mouse studies alone are sufficient to move a vaccine candidate into the clinic.MethodsA comparison of immunogenicity, fine-specificity and functional activity of two Alum-adjuvanted Plasmodium falciparum circumsporozoite protein (CSP)-based vaccines was conducted in mouse and rhesus models. One vaccine was a soluble recombinant protein (CSP) and the other was the same CSP covalently conjugated to the Qβ phage particle (Qβ-CSP).ResultsMice showed different kinetics of antibody responses and different sensitivity to the NANP-repeat and N-terminal epitopes as compared to rhesus. While mice failed to discern differences between the protective efficacy of CSP versus Qβ-CSP vaccine following direct challenge with transgenic Plasmodium berghei parasites, rhesus serum from the Qβ-CSP-vaccinated animals induced higher in vivo sporozoite neutralization activity.ConclusionsDespite some immunologic parallels between models, these data demonstrate that differences between the immune responses induced in the two models risk conflicting decisions regarding potential vaccine utility in humans. In combination with historical observations, the data presented here suggest that although murine models may be useful for some purposes, non-human primate models may be more likely to predict the human response to investigational vaccines.
Highlights
Non-human primates, such as the rhesus macaques, are the preferred model for down-selecting human malaria vaccine formulations, but the rhesus model is expensive and does not allow for direct efficacy testing of human malaria vaccines
The animal studies were based on previously published reports of circumsporozoite protein (CSP) vaccine selection in mice [45] and in rhesus [21]
While there were differences in vaccine schedule and vaccine dose between species, the two models agreed on several immunologic outcomes: (1) Qβ-CSP vaccine had overall higher immunogenicity; (2) within the CSP molecule, the relative immunogenicity of the repeat NANP epitope was improved by particulate presentation on Qβ; and, (3) Qβ-CSP was better at priming antibody responses, but soluble CSP was able to boost antibody levels after subsequent doses, against the NANP repeat
Summary
Non-human primates, such as the rhesus macaques, are the preferred model for down-selecting human malaria vaccine formulations, but the rhesus model is expensive and does not allow for direct efficacy testing of human malaria vaccines. The rodent model for malaria is based on Plasmodium berghei, Plasmodium chabaudi or Plasmodium yoelii parasites that naturally infect African thicket rats [2]. These parasites have been adapted to grow in mouse strains for routine laboratory experiments and provide easy access to blood and liver stages. The P. yoelii merozoite surface protein-1 (MSP1) [7] and P. chabaudi apical membrane antigen-1 (AMA1) [8] candidates have been known to protect mice, but human-use formulations of PfMSP1 [9] and PfAMA1 [10] vaccines confer limited protection in humans
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