Towards a blood stage malaria vaccine, dealing with allelic polymorphism in the vaccine candidate apical membrane antihen 1

Abstract

A vaccine against Plasmodium falciparum is needed to augment currently available malaria control tools. A handful of parasite antigens are at various stages of pre-clinical and clinical development. Amongst these is P. falciparum apical membrane antigen 1 (PfAMA1), an antigen expressed by asexual stage parasites and believed to be important for the parasite__s invasion of both red blood cells and liver cells. The immune response to PfAMA1 is mediated mainly by antibodies that prevent parasite invasion of host cells. PfAMA1 however shows allelic polymorphism, with anti-PfAMA1 antibody responses exhibiting strain-specificity. This thesis investigated multi-allele vaccine formulation strategies that would overcome the strain-specificity of antibody responses to PfAMA1. The main findings of this thesis are that i) different PfAMA1 alleles share epitopes to which functional cross-strain antibodies can be induced, ii) a three-allele PfAMA1 formulation yields the greatest proportion of functional cross-strain antibodies, and iii) three PfAMA1 alleles, irrespective of the adjuvant used for formulation and whether they are administrated as a multi-allele formulation or sequentially, induce similar proportions of cross-strain antibodies. Overall, a multi-allele formulation with three in silico-designed PfAMA1 candidates yields antibodies that inhibit several parasites in vitro and warrant their development as a human blood stage vaccine.