Publications & Reports

Immunodampening to overcome diversity in the malarial vaccine candidate apical membrane antigen 1.

Harris KS, Adda CG, Khore M, Drew DR, Valentini-Gatt A, Fowkes FJ, Beeson JG, Dutta S, Anders RF, Foley M
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.


Apical membrane antigen 1 (AMA1) is a leading malarial vaccine candidate however its polymorphic nature may limit its success in the field. This study aimed to circumvent AMA1 diversity by dampening the antibody response to the highly polymorphic loop Id, previously identified as a major target of strain-specific, invasion-inhibitory antibodies. To achieve this, five polymorphic residues within this loop were mutated to alanine, glycine or serine on a 3D7 and FVO AMA1 backbone. Initially the corresponding antigens were displayed on the surface of bacteriophage where the alanine and serine but not glycine mutants folded correctly. The alanine and serine AMA1 mutants were expressed in E. coli, refolded in vitro and used to immunize rabbits. Serological analyses indicated that immunization with a single mutated form of 3D7 AMA1 was sufficient to increase the cross-reactive antibody response. Targeting the corresponding residues in an FVO backbone did not achieve this outcome. The inclusion of at least one engineered form of AMA1 in a bi-allelic formulation resulted in an antibody response with broader reactivity against different AMA1 alleles than combining the wild type forms of 3D7 and FVO AMA1 alleles. For one combination, this extended to enhanced relative growth inhibition of a heterologous parasite line, although this was at the cost of reduced overall inhibitory activity. These results suggest that targeted mutagenesis of AMA1 is a promising strategy for overcoming antigenic diversity in AMA1 and reducing the number of variants required to induce an antibody response that protects against a broad range of P. falciparum AMA1 genotypes However, optimization of the immunization regime and mutation strategy will be required for this potential to be realized.

Full text available at PubMed Central at


  • Journal: Infection and Immunity
  • Published: 25/08/2014
  • Volume: 82
  • Issue: 11
  • Pagination: 4707-4711


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