Plasmodium falciparum apical membrane antigen 1 (AMA1) is a prime malaria vaccine candidate. Antigenic diversity within parasite populations is one of the main factors potentially limiting the efficacy of any asexual-stage vaccine, including one based on AMA1. The DNA coding for the most variable region of this antigen, domain I, was sequenced in 168 samples from the Wosera region of Papua New Guinea, including samples from symptomatic and asymptomatic infections. Neutrality tests applied to these sequences provided strong evidence of selective pressure operating on the sequence of ama1 domain I, consistent with AMA1 being a target of protective immunity. Similarly, a peculiar pattern of geographical diversity and the particular substitutions found were suggestive of strong constraints acting on the evolution of AMA1 at the population level, probably as a result of immune pressure. In addition, a strong imbalance between symptomatic and asymptomatic infections was detected in the frequency of particular residues at certain polymorphic positions, pointing to AMA1 as being one of the determinants of the morbidity associated with a particular strain. The information yielded by this study has implications for the design and assessment of AMA1-based vaccines and provides additional data supporting the importance of AMA1 as a malaria vaccine candidate.
Antibody responses against proteins located on the surface or in the apical organelles of merozoites are presumed to be important components of naturally acquired protective immune responses against the malaria parasite Plasmodium falciparum. However, many merozoite antigens are highly polymorphic, and antibodies induced against one particular allelic form might not be effective in controlling growth of parasites expressing alternative forms. The apical membrane antigen 1 (AMA1) is a polymorphic merozoite protein that is a target of naturally acquired invasion-inhibitory antibodies and is a leading asexual-stage vaccine candidate. We characterized the antibody responses against AMA1 in 262 individuals from Papua New Guinea exposed to malaria by using different allelic forms of the full AMA1 ectodomain and some individual subdomains. The majority of individuals had very high levels of antibodies against AMA1. The prevalence and titer of these antibodies increased with age. Although antibodies against conserved regions of the molecule were predominant in the majority of individuals, most plasma samples also contained antibodies directed against polymorphic regions of the antigen. In a few individuals, predominantly from younger age groups, the majority of antibodies against AMA1 were directed against polymorphic epitopes. The D10 allelic form of AMA1 apparently contains most if not all of the epitopes present in the other allelic forms tested, which might argue for its inclusion in future AMA1-based vaccines to be tested. Some important epitopes in AMA1 involved residues located in domain II or III but depended on more than one domain.
B19 infections play a significant role in the etiology of severe anemia in this area of malarial endemicity. Given the high levels of morbidity and mortality associated with severe anemia in such regions, the prevention of B19 infection with a vaccine might be a highly effective public health intervention.
Malaria during pregnancy, which is characterized by the accumulation of infected erythrocytes in the placenta, often has severe consequences for the mother and newborn. We assessed the effect of the genetic trait South-East Asian ovalocytosis (SAO) on placental malaria in women from Papua New Guinea. In children, this trait confers protection against cerebral malaria, but not against mild malaria disease, malaria parasitemia, or severe malaria anemia. Using a case-control approach, we found that SAO women suffer from placental malaria, and SAO-infected erythrocytes can sequester in the placenta, but heavy placental infections tended to be less common in SAO than in control pregnant women. Reduced prevalence and severity of placental infection associated with SAO were observed only for primigravid women, who are the group at highest risk of suffering from severe manifestations of placental malaria. Furthermore, we found that the prevalence of the SAO trait was lower among pregnant women than among non-pregnant controls.
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