Abstract
The malaria vaccine candidate RTS,S/AS01 is based on immunogenic regions of Plasmodium falciparum circumsporozoite protein (CSP) from the 3D7 reference strain and has shown modest efficacy against clinical disease in African children. It remains unclear what aspect(s) of the immune response elicited by this vaccine are protective. The goals of this study were to measure diversity in immunogenic regions of CSP, and to identify associations between polymorphism in CSP and the risk of P. falciparum infection and clinical disease. The present study includes data and samples from a prospective cohort study designed to measure incidence of malaria infection and disease in children in Bandiagara, Mali. A total of 769 parasite-positive blood samples corresponding to both acute clinical malaria episodes and asymptomatic infections experienced by 100 children were included in the study. Non-synonymous SNP data were generated by 454 sequencing for the T-cell epitopes, and repeat length data were generated for the B-cell epitopes of the cs gene. Cox proportional hazards models were used to determine the effect of sequence variation in consecutive infections occurring within individuals on the time to new infection and new clinical malaria episode. Diversity in the T-cell epitope-encoding regions Th2R and Th3R remained stable throughout seasons, between age groups and between clinical and asymptomatic infections with the exception of a higher proportion of 3D7 haplotypes found in the oldest age group. No associations between sequence variation and hazard of infection or clinical malaria were detected. The lack of association between sequence variation and hazard of infection or clinical malaria suggests that naturally acquired immunity to CSP may not be allele-specific.
Highlights
To date, malaria vaccine development and testing has generally not been informed by molecular epidemiologic evaluations of how genetic diversity in vaccine antigens in parasite populations may affect vaccine efficacy
With the aid of generation sequencing to help circumvent some of the issues encountered by previous studies of genetic diversity in circumsporozoite protein (CSP), this study has examined both the population level and within-host dynamics of polymorphism in this vaccine antigen
Molecular epidemiological studies are an important tool for evaluating the potential of polymorphic malaria vaccine antigens to provide strain-transcending protective efficacy [1]
Summary
Malaria vaccine development and testing has generally not been informed by molecular epidemiologic evaluations of how genetic diversity in vaccine antigens in parasite populations may affect vaccine efficacy. The malaria vaccine RTS,S/AS01 targets specific immunogenic epitopes of the P. falciparum circumsporozoite protein (CSP), encoded by the cs gene. The central repeat region of the cs gene contains tetrameric repeats that vary in both the sequence and number of tetramers. This region codes for epitopes recognized by anti-CSP antibodies [6,7]. The 39 regions of the cs gene, Th2R and Th3R, encode epitopes that are recognized by CD8+ and CD4+ T-cells [9] The diversity in these regions, which occurs in the form of nonsynonymous SNPs, increases as malaria transmission increases across distinct geographic areas [10,11], with the highest diversity occurring in Africa. RTS,S/AS01 has shown modest efficacy in Phase 2 trials [13,14,15,16] and a Phase 3 trial [17,18]
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