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

BMC Medicine

James G Beeson³  Jack S Richards³  Ivo Mueller¹  Peter M Siba¹  Kevin Marsh⁴  Danielle I Stanisic¹  Nicolas Senn⁸  Salenna R Elliott⁹  Faith HA Osier⁴  Sheetij Dutta⁶  Robin F Anders⁵  Alyssa E Barry²  Cleopatra K Mugyenyi⁴  Nadia J Cross⁹  Anthony N Hodder⁷  Damien R Drew⁹  Ulrich Terheggen³ 

[1] Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea;Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia;Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia;Centre for Geographic Medicine, Coast, Kenya Medical Research Institute, Kilifi, Kenya;La Trobe University, Melbourne, Australia;Walter Reed Army Institute, Silver Spring, MD, USA;Walter and Eliza Hall Institute, Melbourne, Australia;Swiss Tropical and Public Health Institute, Basel, Switzerland;The Burnet Institute of Medical Research and Public Health, 85 Commercial Road, Melbourne 3004, Victoria, Australia

关键词: Cross-reactive antibodies;    Apical membrane antigen 1;    Immunity;    Vaccines;    Plasmodium falciparum;    Malaria;   

Others  :  1121394
DOI  :  10.1186/s12916-014-0183-5

 received in 2014-07-16, accepted in 2014-09-10,  发布年份 2014

【 摘 要 】

Background

Polymorphism 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.

Methods

We 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.

Results

We 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.

Conclusions

Antigenic 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.

【 授权许可】

   
2014 Terheggen et al.; licensee BioMed Central Ltd.

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