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

BMC Medicine

Research Article

Faith HA Osier¹  Kevin Marsh¹  Cleopatra K Mugyenyi¹  Robin F Anders²  Peter M Siba³  Nicolas Senn⁴  Nadia J Cross⁵  Damien R Drew⁵  Salenna R Elliott⁵  Ulrich Terheggen⁶  Jack S Richards⁷  James G Beeson⁷  Sheetij Dutta⁸  Anthony N Hodder⁹  Alyssa E Barry^1,10  Ivo Mueller^1,11  Danielle I Stanisic^1,12 

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

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

DOI  :  10.1186/s12916-014-0183-5

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

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Terheggen et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.