Abstract
Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines.
Highlights
A malaria vaccine that prevents infection would reduce malaria morbidity and mortality and accelerate malaria eradication efforts [1]
The FMP2.1/AS01 vaccine had significant allele-specific efficacy against clinical malaria caused by parasites identical to the vaccine strain with respect to specific amino acid positions previously identified as important determinants of allele-specific natural immunity in vitro [8], in field trials [9] and in response to vaccination with a monovalent vaccine [7,10]
This recent result supports the idea that careful selection of vaccine strains and diversity-covering approaches may help to improve the modest efficacy of this leading malaria vaccine [33]
Summary
A malaria vaccine that prevents infection would reduce malaria morbidity and mortality and accelerate malaria eradication efforts [1]. Immunization with “Combination B” a vaccine (Table 1) based on merozoite surface protein 2 (MSP2), MSP1 and ring-infected erythrocyte surface antigen (RESA) had overall efficacy in reducing parasitemia, but efficacy was restricted to infections with vaccine-like alleles of MSP2 [4] Both blood stage vaccines, FMP2.1/AS01 and Combination B, selectively controlled the growth in the blood of parasites with vaccine-type variants of the target antigens (Table 1). Metaanalyses combining all available data [9,14] and studies of laboratory isolates from many different countries [15] have been useful in cataloging global diversity and identifying the most common haplotypes circulating locally and worldwide These studies have shown that antigen alleles can be sub-grouped on the basis of sequence similarity at codons for immunologically relevant amino acids into a manageable number of subgroups [14,15,16]. Measuring the genetic and antigenic diversity of P. falciparum antigens may facilitate the design of broadly cross-protective multi-strain malaria vaccines that include relevant diverse alleles of antigens addressing all life cycle stages [16]
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