Allele Specificity of Naturally Acquired Antibody Responses against Plasmodium falciparum Apical Membrane Antigen 1

Abstract

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.

Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research

“…Sero-epidemiologic evidence [35], and the limited GIA data presented here, suggest a PfAMA-1-based vaccine may elicit allele-specific antibodies. Consequently, in addition to monovalent PfAMA-1 vaccines [14][15][16][17]21] there are also bivalent PfAMA-1 vaccines in development in an effort to broaden protective immune responses [18,19,21].…”

In Immunization with Plasmodium falciparum Apical Membrane Antigen 1, the Specificity of Antibodies Depends on the Species Immunized

“…Immunization by infection may alter the specificity of the response, and repeated infection with different parasite strains may favor B-cell clonotypes producing antibodies against conserved determinants; thus, infants and young children may produce more allelespecific antibody responses and selective pressures may primarily act on parasites in these individuals. Also, it is clear that some adults in areas of endemicity produce a larger proportion of allele-specific antibodies (7,40), and these antibodies may provide selective advantages for some parasites. Previous studies with other malaria proteins (CSP and MSP2) have suggested that T-cell responses could be the source of immune selection pressure (15,16).…”

The Most Polymorphic Residue on Plasmodium falciparum Apical Membrane Antigen 1 Determines Binding of an Invasion-Inhibitory Antibody

“…These competing effects would create clusters of polymorphisms along the polypeptide chain where polymorphic positions represent mutation-tolerant, surface-exposed residues interspersed with non-surface-exposed and/or functionally critical but mutationintolerant residues. This is the case in P. falciparum AMA1 (8,32,33), with polymorphisms particularly clustered in domain I. A majority of the P. falciparum AMA1 sequence polymorphisms described are dimorphic; i.e., there are only two alternative amino acids at a residue position in the primary sequence.…”

“…Despite the conserved tertiary structure, sequence polymorphisms exist at more than 60 residue positions in the ectodomain (8,9,32,33). The characterization of these polymorphisms and of their distribution in P. falciparum populations suggests that they have arisen as a result of positive selection (2,14), most probably exerted by the immune response of the human host.…”