Human Leukocyte Antigen Class II Alleles Influence Levels of Antibodies to thePlasmodium falciparumAsexual-Stage Apical Membrane Antigen 1 but Not to Merozoite Surface Antigen 2 and Merozoite Surface Protein 1

Abstract

The apical membrane antigen 1 (AMA1), merozoite surface antigen 2 (MSA2), and merozoite surface protein 1 (MSP1) are asexual-stage proteins currently being evaluated for inclusion in a vaccine for Plasmodium falciparum. Accordingly, it is important to understand factors that control antibody responses to these antigens. Antibody levels in plasma from residents of Etoa, Cameroon, between the ages of 5 and 70 years, were determined using recombinant AMA1, MSA2, and the N-terminal region of MSP1 (MSP1-190L). In addition, antibody responses to four variants of the C-terminal region of MSP1 (MSP1 19 ) were assessed. Results showed that all individuals produced antibodies to AMA1, MSA2, and MSP1-190L; however, a proportion of individuals never produced antibodies to the MSP1 19 variants, although the percentage of nonresponders decreased with age. The influence of age and human leukocyte antigen (HLA)-DRB1/DQB1 alleles on antibody levels was evaluated using two-way analysis of variance. Age was correlated with levels of antibodies to AMA1 and MSP1 19 but not with levels of antibodies to MSA2 and MSP1-190L. No association was found between a single HLA allele and levels of antibodies to MSA2, MSP1-190L, or any of the MSP1 19 variants. However, individuals positive for DRB1*1201 had higher levels of antibodies to the variant of recombinant AMA1 tested than did individuals of all other HLA types. Since the effect was seen across all age groups, HLA influenced the level but not the rate of antibody acquisition. This association for AMA1, combined with the previously reported association between HLA class II alleles and levels of antibodies to rhoptry-associated protein 1 (RAP1) and RAP2, indicates that HLA influences the levels of antibodies to three of the five vaccine candidate antigens that we have evaluated.

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

“…The clear age dependence that we observed in the prevalence and levels of antibodies against AMA1, which parallels the development of protective immune responses, is in contrast with the results of previous studies that detected a small agerelated change in antibody levels of individuals from GuineaBisau and Cameroon and no age dependence in the levels of antibodies in individuals from Senegal (17,34). Although we cannot rule out the possibility that these results reflect real differences in the antibody responses to AMA1 between these African and Papua New Guinea populations, we consider it more likely that the different results are attributable to the different methodologies in these studies, because the antibody levels detected in these African settings where malaria is highly endemic were much lower than the levels detected in the Papua New Guinea population.…”

“…It might be of importance that the baculovirus-expressed AMA1 used in the previous studies was highly glycosylated, unlike authentic AMA1 (34). Also, one of those studies (34) used a capture ELISA method instead of the direct ELISA method used here and in the study with samples from Cameroon (17).…”

“…Individuals living in areas where malaria is endemic have antibodies against AMA1 (17,34), and these antibodies inhibit merozoite invasion in vitro (13). Immunization with correctly folded AMA1 conferred high levels of protection in murine and simian models (1,5,9,10,25,33).…”

Using Population Genetics to Guide Malaria Vaccine Design

“…Antibodies against AMA1 are found in people living in malaria endemic areas [81][82][83], and these have been shown to block the invasion process [84][85][86]. The potential of AMA1 as a malaria vaccine candidate has been demonstrated in rodent models of malaria with both strain-specific [87][88][89] and cross-protective [90] protection observed.…”

Major histocompatibility complex and its importance towards controlling infection

“…166 The first convincing association study was carried out in West Africans where the frequent HLA-Bw53 allele and the special DRB1*1302-DQB1*0501 haplotype were associated with reduced susceptibility to severe malaria. 166 By the turn of the 21 st century, some HLA-DR alleles had been associated with an increased antibody response to Nt47 (p126 aminoterminal portion), 167 to apical membrane antigen-1 (AMA-1) 168 of Plasmodium falciparum and to the VK247 CSP repetition of Plasmodium vivax. 169 The mechanistic link between malaria and the MHC seems evident from some population studies of humans and birds, in which each studied individual variation in the prevalence of certain alleles was associated with tolerance or susceptibility of infection.…”