Specificity of the Protective Antibody Response to Apical Membrane Antigen 1

Autor: Robin F. Anders, P E Crewther, Anthony N. Hodder
Rok vydání: 2001
Předmět:
Zdroj: Infection and Immunity. 69:3286-3294
ISSN: 1098-5522
0019-9567
DOI: 10.1128/iai.69.5.3286-3294.2001
Popis: Plasmodium falciparum infections in malaria-naive individuals can lead to severe morbidity, which may be life threatening if untreated. Continued exposure to infection leads to a degree of immunity, and consequently, older children and adults living in areas of endemicity are protected from the severe clinical consequences of infection with P. falciparum. The effector mechanisms that mediate naturally acquired immunity to malaria are not completely understood, but antibodies to the asexual blood stage parasites play a role. This has been most clearly demonstrated by the reduction of parasitemias following the passive immunization of children with clinical malaria with immunoglobulin G (IgG) from malaria-immune adults (6, 7, 32). Antigens recognized by antibodies that are active in passive-immunization experiments are prime candidates for testing in a vaccine. Studies with an assay for antibody-dependent cellular inhibition have identified antibodies to MSP3 as an active component of passively transferred human IgG (28), but much evidence indicates that other merozoite antigens are capable of inducing antibodies that limit parasite development (13–15, 17, 26, 29, 33, 34). One of the prime candidate antigens for inclusion in a malaria vaccine is apical membrane antigen 1 (AMA1). AMA1 is an 83-kDa antigen that is synthesized in mature stages of the parasite and is initially localized in the necks of the rhoptry organelles (9, 30). At about the time of merozoite release, the full-length 83-kDa molecule is localized at the apical pole, and an N-terminally processed form of 66 kDa can be detected distributed around the merozoite surface (27, 30). Although the biological function of AMA1 is unknown, its location and stage specificity suggest that it may be involved in the process of erythrocyte invasion. AMA1 is one of only a few asexual blood stage antigens that have been identified in all Plasmodium species examined (42), and this has enabled the vaccine potential of AMA1 to be investigated using various animal models. Active immunization of monkeys or mice with either native (11) or recombinant (2, 8) forms of AMA1 has protected these animals against simian and rodent parasites, respectively. Much evidence indicates that anti-AMA1 antibodies mediate protection. Monoclonal antibodies raised against P. falciparum AMA1 and against PK66, the Plasmodium knowlesi homologue of AMA1, inhibit merozoite invasion in vitro (20, 35). Furthermore, passive immunization of AMA1-specific polyclonal antibodies into Plasmodium chabaudi-infected mice prevented lethal parasitemias (2). These protective antibodies react with conformational epitopes stabilized by disulfide bonds, as immunization with the reduced and alkylated AMA1 failed to protect mice against challenge with P. chabaudi (10). The sequence of AMA1 is relatively conserved among various Plasmodium spp., with the level of amino acid sequence identity exceeding 50% in pairwise comparisons among all known sequences (5, 12, 24, 25, 31, 42). AMA1 lacks the sequence repeats and marked polymorphisms found in other malaria antigens, such as the merozoite surface antigens MSP1 and MSP2 (3). However, some sequence variation, resulting from point mutations, is observed among alleles of AMA1 in P. falciparum (25, 30, 36), P. knowlesi (43), Plasmodium vivax (5), and P. chabaudi (10), and studies with the P. chabaudi-mouse model indicate that this variation is immunologically significant. Mice immunized with AMA1 or receiving passively transferred anti-AMA1 antibodies were not protected from a heterologous strain of P. chabaudi parasites, indicating that the protective antibodies recognized strain-specific epitopes. Early clinical trials with AMA1 have commenced, and it is important to determine the effect of sequence diversity on the efficacy of the recombinant AMA1 as a vaccine against P. falciparum. In this study, we demonstrate that immunization of rabbits with the refolded P. falciparum AMA1 ectodomain (the vaccine molecule) induces antibodies that inhibit merozoite invasion in vitro. The refolded antigen has also been used to affinity purify AMA1-specific antibodies from the plasma of individuals who have been exposed to chronic malaria infections. These naturally occurring human antibodies were also able to inhibit the invasion of erythrocytes by P. falciparum merozoites.
Databáze: OpenAIRE
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