Limited antigenic diversity of Plasmodium falciparumapical membrane antigen 1 supports the development of effective multi-allele vaccines

Abstract

BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0183-5) contains supplementary material, which is available to authorized users.

Genetic diversity of the Plasmodium falciparum apical membrane antigen I gene in parasite population from the China–Myanmar border area

“…Additional neutrality tests provided corroborating findings indicative of positive diversifying selection operating at PfAMA1 DI and possibly the entire ectodomain. Though the value of Tajima’s D test was not significant in either total region or DI–III, the positive values of this test also indicated departure from neutral evolution and the tendency of positive diversifying selection, together with other studies, reflecting the importance of PfAMA1 as a target of host protective immunity (Cortes et al, 2003; Healer et al, 2004; Remarque et al, 2008; Terheggen et al, 2014). …”

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

“…AMA-1 is known for its extensive antigenic polymorphism and to cause strain-specific immunity (42,43). Nevertheless, there is a significant antigenic overlap between AMA-1 alleles allowing for cross-reactivity across different strains, both in terms of functional activity and recognition, which affects mainly the magnitude of the response (42,(44)(45)(46). Based on these data, we consider it unlikely that assessment of AMA-1 responses using the NF54 or 3D7 sequence would have yielded different qualitative results.…”

Clinical Variation ofPlasmodium falciparum eba-175,ama-1, andmsp-3Genotypes in Young Children Living in a Seasonally High Malaria Transmission Setting in Burkina Faso

“…These findings highlight the relevance of analyzing the polymorphism of the P. falciparum parasite based on subclasses with closer interval of age instead of large range of age. Previous studies analyzing the age-allele specific immunity constitute a perfect illustration of that complexity of malaria antigen polymorphism [33] in which polymorphism is a common mechanism for immune evasion used by the parasite [34]. …”