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Review
. 2014 Jul 28:5:359.
doi: 10.3389/fimmu.2014.00359. eCollection 2014.

Strategies for designing and monitoring malaria vaccines targeting diverse antigens

Alyssa E Barry  1 , Alicia Arnott  1
Affiliations
Review

Strategies for designing and monitoring malaria vaccines targeting diverse antigens

Alyssa E Barry et al. Front Immunol. .

Abstract

After more than 50 years of intensive research and development, only one malaria vaccine candidate, "RTS,S," has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators' abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now cataloged the global diversity of leading Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarize the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximize the potential of future malaria vaccine candidates.

Keywords: Plasmodium falciparum; Plasmodium vivax; clinical trials; diversity; malaria; polymorphism; strain; vaccine.

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Figures

Figure 1
Figure 1
Malaria vaccine candidate antigens are shown. All candidate antigens for Plasmodium falciparum and Plasmodium vivax are superimposed on the Plasmodium lifecycle, to indicate the category of malaria vaccine being developed and the lifecycle stage targeted. Antigens indicated in bold are those that are currently being evaluated in pre-clinical trials or have entered at least Phase 1 clinical trials according to the WHO malaria vaccine rainbow tables (50). The P. vivax latent stages known as “hyponozoites” are not shown but these occur in the liver stage.
Figure 2
Figure 2
Understanding diversity and predicting serotypes using population genetic analyses. A flow chart describing the step-by-step methodology to define the extent and distribution of parasite diversity and to predict antigenic escape polymorphisms and serotypes (see text for more details).
Figure 3
Figure 3
Antigenic diversity, clinical malaria, and vaccine efficacy are shown. Simplified overview of the impact of parasite antigenic diversity on the dynamics of natural infection and the efficacy of vaccines. Peaks in parasitemia correspond with different clinical episodes and colors indicate different serotypes. Strain-specific acquired antibodies are shown in corresponding colors some time after each clinical episode. Solid lines represent a strong antibody response, while dashed lines represent limited antibody responses. (A) Dynamics of natural infection with recurrent episodes of clinical malaria in an individual that acquires only strain-specific antibodies after being infected. As individuals experience different strains through natural infection (or vaccination), they acquire strain-specific antibodies and have a lower risk of having a clinical episode due to the same strain. (B) Lack of vaccine efficacy in a vaccinated individual due to antigenic diversity. The syringe indicates vaccination with a single serotype (red). If a single-strain vaccine is given at baseline, individuals are more likely to experience clinical episodes due to other strains (blue, yellow, green) than the vaccine strain, until antibody responses decrease.
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