Abstract
The extensive diversity of Plasmodium falciparum antigens is a major obstacle to a broadly effective malaria vaccine but population genetics has rarely been used to guide vaccine design. We have completed a meta-population genetic analysis of the genes encoding ten leading P. falciparum vaccine antigens, including the pre-erythrocytic antigens csp, trap, lsa1 and glurp; the merozoite antigens eba175, ama1, msp's 1, 3 and 4, and the gametocyte antigen pfs48/45. A total of 4553 antigen sequences were assembled from published data and we estimated the range and distribution of diversity worldwide using traditional population genetics, Bayesian clustering and network analysis. Although a large number of distinct haplotypes were identified for each antigen, they were organized into a limited number of discrete subgroups. While the non-merozoite antigens showed geographically variable levels of diversity and geographic restriction of specific subgroups, the merozoite antigens had high levels of diversity globally, and a worldwide distribution of each subgroup. This shows that the diversity of the non-merozoite antigens is organized by physical or other location-specific barriers to gene flow and that of merozoite antigens by features intrinsic to all populations, one important possibility being the immune response of the human host. We also show that current malaria vaccine formulations are based upon low prevalence haplotypes from a single subgroup and thus may represent only a small proportion of the global parasite population. This study demonstrates significant contrasts in the population structure of P. falciparum vaccine candidates that are consistent with the merozoite antigens being under stronger balancing selection than non-merozoite antigens and suggesting that unique approaches to vaccine design will be required. The results of this study also provide a realistic framework for the diversity of these antigens to be incorporated into the design of next-generation malaria vaccines.
Highlights
Infection with the protozoan parasite Plasmodium falciparum causes more than 500 million episodes of clinical malaria and two million deaths each year [1]
Small sample sizes were available for glurp and pfs48/45 so we caution that the results for these antigens may be biased and should be interpreted with care
To focus the analysis on the putative antigenic diversity the nonsynonymous single nucleotide polymorphism haplotypes were derived for all antigen sequences, except for msp1, for which the majority of the data comprised only a 5 amino acid haplotype, so the remaining msp1 DNA sequences were converted to the corresponding amino acid
Summary
Infection with the protozoan parasite Plasmodium falciparum causes more than 500 million episodes of clinical malaria and two million deaths each year [1]. Over the past 40 years, an intensive international effort has led to the development of several antigens from P. falciparum as malaria vaccine candidates They include surface exposed proteins from morphologically distinct developmental stages of the parasite lifecycle within the human host namely the Circumsporozoite Surface Antigen (CSP), Thrombospondin Related Adhesion Protein (TRAP), Liver Stage Antigen 1 (LSA1), Apical Membrane Antigen 1 (AMA1), Erythrocyte Binding Antigen 175 (EBA175), Merozoite Surface Proteins (MSPs 1–5), Glutamate Rich Protein (GLURP) and Pfs48/45 ([2]; Table 1). There is increasing recognition that a malaria vaccine may need to contain multiple variants of the target antigen to be effective against an entire parasite population [7]
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