Background The P. falciparum merozoite antigen apical membrane antigen 1 (AMA1) is involved in erythrocyte invasion and is a prominent target of naturally-acquired antibodies in malaria-exposed individuals. While such antibodies are thought to inhibit parasite growth by blocking invasion, the exact mechanism by which they contribute to protective immunity remains inconclusive because widely used ELISA-based methods do not specifically measure functional antibodies.
Methods The current study adopted a novel approach based on transgenic P. falciparum lines expressing different AMA1 alleles to measure the growth-inhibitory activity of naturally-acquired AMA1-specific antibodies amongst malaria-exposed children and adults from Papua New Guinea, and related AMA1-specific growth-inhibitory activity to antibodies measured by ELISA.
Results Differential growth inhibition of transfectant lines expressing different AMA1 alleles indicated AMA1 was the target of naturally-acquired strain-specific growth-inhibitory antibodies in a malaria-exposed human population. Despite a similarly high prevalence of antibodies to all AMA1 alleles by ELISA, two of the six AMA1 alleles had a higher prevalence of growth-inhibitory antibodies, highlighting the importance of measuring functional antibodies. There was a high prevalence of specific growth inhibition of single transfectant lines, suggesting that growth-inhibitory antibodies to AMA1 are commonly allele-specific rather than cross-reactive.
Conclusions Malaria-exposed individuals may need to acquire a repertoire of allele-specific, growth-inhibitory antibodies to confer broad immunity targeting AMA1. An AMA1 based vaccine will probably need to include multiple alleles, and this study indicates the potential for transfectant technology to help prioritize those alleles that are the most significant targets of functional antibody responses.