Research Article: A Challenge for the Development of Malaria Vaccines: Polymorphic Target Antigens

Date Published: March 13, 2007

Publisher: Public Library of Science

Author(s): Colin Sutherland

Abstract: None

Partial Text: Parasites of the genus Plasmodium cause many hundreds of millions of cases of malaria worldwide optimism that in the future effective vaccination will join the current strategies of preventive and therapeutic uses of antimalarials, and of reduction in human–vector contact, as part of the global malaria control toolkit.

The complex life cycle of the malaria parasite, a protozoan of the phylum Apicomplexa, requires a sophisticated array of proteins. These are encoded by a genome of 23 Mb distributed across 14 chromosomes in P. falciparum [1], significantly larger than the genome of any human pathogen for which effective vaccines have been successfully developed. Vaccine candidates for P. falciparum and P. vivax that have advanced to clinical trials in recent years are targeted against two distinct stages of the parasite life cycle. The first is the sporozoite, which is injected by the bite of a mosquito into the human host as a haploid, free-living unicellular form, and which seeks out the liver, where it invades a hepatocyte and undergoes intracellular multiplication. Among key target antigens at this stage are thrombospondin-related adhesive protein (TRAP), liver-stage antigen 1 (LSA-1) and circumsporozoite protein (CSP). The most successful malaria vaccine to date, the recombinant protein RTS,S administered with the adjuvant AS02A, afforded sustained protection to ~30% of children under five years of age in a large proof-of-principle Phase II trial in Mozambique [2]. This vaccine is based on the CSP antigen, and is designed to prevent infection.

Renewed interest in the testing of malaria vaccines at a number of clinical trial sites in sub-Saharan Africa has lead to development of the infrastructure and expertise required for Phase II and Phase III studies of vaccine safety, immunogenicity, and efficacy. One of these sites is at Bandiagara, Mali, where malaria transmission is intense but highly seasonal. In this month’s PLoS Medicine, Shannon Takala and colleagues present a detailed longitudinal analysis of polymorphisms in the msp-1 genes of parasite isolates taken from a cohort of a broad age range in Bandiagara [3]. Monthly peripheral blood samples (n = 2,309) from a random selection of 100 cohort participants across three age strata were analysed through three malaria transmission seasons from 1999 to 2001. This group of 100 individuals provided a staggering 1,375 parasite-positive events during this time, and these isolates were analysed for msp-1 polymorphisms by pyrosequencing. The authors use the data to present an analysis of the population-level dynamics of 14 different haplotypes encoding MSP-119. The study provides novel and important information on three levels.

The data presented by Takkala et al., gathered in the absence of any intervention with a vaccine, demonstrate the potential impact that parasite population diversity could have on the outcome of MSP-119 vaccine trials. Confirmation in other endemic settings is required to verify the evidence that certain residues in this antigen may be particularly important in eliciting sequence-specific protection, and that particular haplotypes are associated with lower parasite densities. Nevertheless, this study provides ample warning that analysis of antigen diversity in the target parasite population should not only be gathered as part of postintervention evaluation in vaccine trials [4], but should be part of the intelligence gathering undertaken when planning intervention studies in the first place.



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