Abstract
Apical membrane antigen-1 of Plasmodium falciparum (PfAMA-1) is a leading malaria vaccine candidate antigen. However, the genetic diversity of pfama-1 and associated antigenic variation in global P. falciparum field isolates are major hurdles to the design of an efficacious vaccine formulated with this antigen. Here, we analyzed the genetic structure and the natural selection of pfama-1 in the P. falciparum population of Vietnam. A total of 37 distinct haplotypes were found in 131 P. falciparum Vietnamese isolates. Most amino acid changes detected in Vietnamese pfama-1 were localized in the ectodomain, domains I, II, and III. Overall patterns of major amino acid changes in Vietnamese pfama-1 were similar to those of global pfama-1, but the frequencies of the amino acid changes slightly differed by country. Novel amino acid changes were also identified in Vietnamese pfama-1. Vietnamese pfama-1 revealed relatively lower genetic diversity than currently analyzed pfama-1 in other geographical regions, and suggested a distinct genetic differentiation pattern. Evidence for natural selection was detected in Vietnamese pfama-1, but it showed purifying selection unlike the global pfama-1 analyzed so far. Recombination events were also found in Vietnamese pfama-1. Major amino acid changes that were commonly identified in global pfama-1 were mainly localized to predicted B-cell epitopes, RBC-binding sites, and IUR regions. These results provide important information for understanding the genetic nature of the Vietnamese pfama-1 population, and have significant implications for the design of a vaccine based on PfAMA-1.
Highlights
Despite remarkable reduction in global mortality and morbidity of malaria in recent years, the disease is still a global public health concern
Nucleotide sequence analysis of the 131 Vietnamese pfama-1 sequences based on pfama-1 from 3D7 reference strain (GenBank accession number: U65407) revealed 116 single nucleotide polymorphisms (SNPs), including 52 synonymous and 64 non-synonymous SNPs
The non-synonymous SNPs induced amino acid substitutions at 52 positions in Vietnamese pfama-1 sequences, resulting in 37 distinct haplotypes of pfama-1 in the amino acid levels (Figure 2). These amino acid changes were scattered throughout each haplotype of Vietnamese pfama-1, but most of the amino acid changes were detected in domain I (22 positions), domain II (12 positions), and domain III (6 positions)
Summary
Despite remarkable reduction in global mortality and morbidity of malaria in recent years, the disease is still a global public health concern. The ectodomain is further segmented into three distinct domains, domains I, II, and III [3] This protein is mainly expressed in the electron-dense neck of rhoptries of sporozoites and merozoites, and plays an important function in the invasion of hepatocytes and erythrocytes by contributing attachment of the target cells at the posterior end of Plasmodium parasites [4,5,6,7,8]. Genetic polymorphism of AMA-1 in global Plasmodium field isolates, and the resulting variants in different geographic areas, are major hurdles in the development of a global malaria vaccine based on this antigen. It is important to monitor genetic variations in the vaccine candidate antigen in the global Plasmodium isolates, since accumulated or newly emerging mutations can change the structure of the antigen, making it difficult to design optimized malaria vaccines
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