Development and validation of a novel tool to assess naturally acquired and vaccine induced antibody diversity to Plasmodium falciparum apical membrane antigen 1 in a pediatric and adult cohort in Bandiagara, Mali: Implications for vaccine design

Abstract

Immunity to clinical malaria disease is acquired after years of exposure to malaria pathogens, but sterile immunity is not achieved. Malaria parasite surface antigens have used antigenic diversity in an arms race to subvert the host immune system. Nearly all vaccines targeting individual malaria antigens have proven ineffective at preventing infection or disease. Plasmodium falciparum apical membrane antigen 1 is a parasite surface antigen that is crucial for erythrocyte invasion, and a leading vaccine target. Antibodies against AMA1 have been shown in vitro, as well as in murine, non-human primate, and human models to prevent homologous parasite infection after challenge. AMA1 is an antigenically diverse molecule, with a seemingly limitless number of unique variants surveyed in the field. We populated a protein microarray with 263 unique whole-ectodomain variants of AMA1 proteins isolated from parasite genomic DNA from malaria-infected blood samples collected during a phase 2 malaria vaccine trial conducted in Bandiagara, Mali. We screened Malian children and adults at seasonal time points to measure the diversity of their immune response. Age, parasitemia, and seasonality were significant predictors of the seroreactivity to PfAMA1 variants. Children and adults vaccinated with monovalent, AMA1 subunit vaccine FMP2.1/AS02A saw a dramatic increase in seroreactivity to all AMA1 variants on the array, regardless of genetic similarity to the vaccine strain 3D7 compared to rabies vaccinated control cohorts. Seroreactivity to PfAMA1 variants is extremely collinear, and genetic variation of the strain isolated at the time of a single acute infection did not correlate with antibody seroreactivity. In a post-hoc analysis, we saw a positive correlation with preseason seroreactivity to AMA1 and odds of symptomatic versus asymptomatic infection using multivariable logistic regression. The research demonstrates the need to have an understanding of both parasite antigenic diversity in the field and a functional epitope map prior to the development of a vaccine based on AMA1.