Contrasting Population Structures of the Genes Encoding Ten Leading Vaccine-Candidate Antigens of the Human Malaria Parasite, Plasmodium falciparum

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.

Evidence That the Erythrocyte Invasion Ligand PfRh2 is a Target of Protective Immunity against Plasmodium falciparum Malaria

“…The identification of only two main sequence clusters shows that many of these PfRh2 haplotypes may be antigenically similar, and both of these were found among the PNG PfRh2 sequences that we obtained. This pattern of high within-population diversity for PfRh2 in this study was also found in several other merozoite Ags known to be important targets of host immunity (38,54). Merozoite Ags seem to have little regional diversification, but diversification has been observed for other Ags (38,54).…”

“…This pattern of high within-population diversity for PfRh2 in this study was also found in several other merozoite Ags known to be important targets of host immunity (38,54). Merozoite Ags seem to have little regional diversification, but diversification has been observed for other Ags (38,54). Our analysis did not clarify whether the observed changes occurred in PfRh2a or PfRh2b because the polymorphic region is contained within the common region of PfRh2.…”

Back to the future for antiparasite vaccines?

“…No blood-stage vaccine candidates have progressed beyond Phase II trials. Major challenges for subunit vaccines are the degree of antigenic polymorphism [8] and the need for a high antibody titer.…”

Using Population Genetics to Guide Malaria Vaccine Design

“…Typically, alleles from one or two reference strains (3D7 or FVO) are used in www.intechopen.com vaccine formulations, but this only partially represents the diversity of alleles circulating in the parasite population (Figure 1 [8]). Moreover, if vaccine alleles are found at low frequencies, the power to measure the success of vaccine trials is limited.…”

“…1. Worldwide frequency of alleles represented in ten leading malaria vaccine candidates (adapted from [8]). MSP1 19 3D7 and FVO are being developed as a combination vaccine as well as in isolation.…”