Antibodies to Polymorphic Invasion-Inhibitory and Non-Inhibitory Epitopes of Plasmodium falciparum Apical Membrane Antigen 1 in Human Malaria

Mugyenyi, Cleopatra K; Elliott, Salenna R.; McCallum, Fiona; Anders, Robin F.; Marsh, Kevin; Beeson, James G.

doi:10.1371/journal.pone.0068304

Cited by 29 publications

(33 citation statements)

References 55 publications

(103 reference statements)

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“…IgG responses were substantially lower in the younger cohort. The concept of a quantitative correlate of protection for malaria-specific antibodies has been briefly explored in African populations (22,44,(57)(58)(59). Our results support those of a recent study demonstrating the requirement for a "protective threshold" concentration of merozoite-specific antibodies for protection from clinical episodes of malaria (57).…”

Section: Discussionsupporting

confidence: 83%

“…Samples collected from the enrollment bleed were used in the enzyme-linked immunosorbent assay (ELISA). Recombinant MSP1-19 (3D7 sequence), full-length MSP2 (FC27 and 3D7), and AMA-1 (full ectodomain; 3D7) were generated as 6His-tagged proteins in Escherichia coli using established methods (42,43); the correct conformation of AMA-1 was confirmed by binding with monoclonal antibodies (MAbs) 1F9 and 2C5, which recognize conformationally dependent epitopes (44,45). Erythrocyte binding antigens (EBA) EBA175, EBA140, and EBA181 were expressed as glutathione S-transferase (GST) fusion proteins in E. coli (23).…”

Section: Study Populationmentioning

confidence: 99%

“…Prior studies observed that IgG antibodies against the EBAs were among the responses most strongly associated with protective immunity in the cohort of older children, even after adjusting for potential confounders (23,44). In the cohort of 1-to 4-year-old children, we measured total IgG responses to EBA175, EBA140, and EBA181 and found that high levels of IgG were associated with an increased prospective risk of malaria episodes (IRR, 1.58 to 1.99, P Յ 0.005; Table 3), as seen for other merozoite antigens; this re- and P ϭ 0.033 and aIRR ϭ 1.58 and P ϭ 0.029, respectively).…”

Section: Figmentioning

confidence: 99%

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Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

et al. 2015

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i Individuals in areas of Plasmodium falciparum endemicity develop immunity to malaria after repeated exposure. Knowledge of the acquisition and nature of protective immune responses to P. falciparum is presently limited, particularly for young children. We examined antibodies (IgM, IgG, and IgG subclasses) to merozoite antigens and their relationship to the prospective risk of malaria in children 1 to 4 years of age in a region of malaria endemicity in Papua New Guinea. IgG, IgG1, and IgG3 responses generally increased with age, were higher in children with active infection, and reflected geographic heterogeneity in malaria transmission. Antigenic properties, rather than host factors, appeared to be the main determinant of the type of IgG subclass produced. High antibody levels were not associated with protection from malaria; in contrast, they were typically associated with an increased risk of malaria. Adjustment for malaria exposure, using a novel molecular measure of the force of infection by P. falciparum, accounted for much of the increased risk, suggesting that the antibodies were markers of higher exposure to P. falciparum. Comparisons between antibodies in this cohort of young children and in a longitudinal cohort of older children suggested that the lack of protective association was explained by lower antibody levels among young children and that there is a threshold level of antibodies required for protection from malaria. Our results suggest that in populations with low immunity, such as young children, antibodies to merozoite antigens may act as biomarkers of malaria exposure and that, with increasing exposure and responses of higher magnitude, antibodies may act as biomarkers of protective immunity. In areas of malaria endemicity, immunity that protects from high (H)-density parasitemia and symptomatic disease develops over a number of years (1). Knowledge of the precise nature of the protective immune responses to Plasmodium falciparum, in terms of the immune mechanisms, the specific target antigens, the nature of responses, and the rate of acquisition of immunity, has been sought, and while advances have been made, our current understanding is still limited (2, 3). Past experiments involving the passive transfer of immunoglobulin from immune adults into P. falciparum-infected individuals provided strong evidence that antibodies (Abs) play an important role in mediating immunity and target the blood stages of infection (4-6). Targets of antibodies include antigens expressed by the merozoite stage of the parasite, and these antibodies function by inhibiting merozoite invasion of red blood cells and by opsonizing merozoites for uptake by phagocytes and antibody-dependent cellular inhibition (7)(8)(9)(10)(11)(12)(13)(14).An important approach for identifying antigens as targets of protective immunity in humans is to assess the acquisition of antibodies and the association between antigen-specific responses and protection from symptomatic malaria in malariaexposed populations (3), particularly in lo...

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Section: Discussionsupporting

confidence: 83%

Section: Study Populationmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

et al. 2015

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“…Within this cluster, residues located in the highly polymorphic loop Id made the largest contribution to escape. This group of polymorphisms, termed C1-L, forms a large part of the epitope recognized by the strain-specific, inhibitory monoclonal antibody (MAb) 1F9 and is a target of naturally acquired antibodies to AMA1 (17,18). Human antibodies to this epitope are acquired with increasing exposure to malaria and are…”

mentioning

confidence: 99%

Use of Immunodampening To Overcome Diversity in the Malarial Vaccine Candidate Apical Membrane Antigen 1

Harris¹,

Adda²,

Khore³

et al. 2014

Infect Immun

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c Apical membrane antigen 1 (AMA1) is a leading malarial vaccine candidate; however, its polymorphic nature may limit its success in the field. This study aimed to circumvent AMA1 diversity by dampening the antibody response to the highly polymorphic loop Id, previously identified as a major target of strain-specific, invasion-inhibitory antibodies. To achieve this, five polymorphic residues within this loop were mutated to alanine, glycine, or serine in AMA1 of the 3D7 and FVO Plasmodium falciparum strains. Initially, the corresponding antigens were displayed on the surface of bacteriophage, where the alanine and serine but not glycine mutants folded correctly. The alanine and serine AMA1 mutants were expressed in Escherichia coli, refolded in vitro, and used to immunize rabbits. Serological analyses indicated that immunization with a single mutated form of 3D7 AMA1 was sufficient to increase the cross-reactive antibody response. Targeting the corresponding residues in an FVO backbone did not achieve this outcome. The inclusion of at least one engineered form of AMA1 in a biallelic formulation resulted in an antibody response with broader reactivity against different AMA1 alleles than combining the wild-type forms of 3D7 and FVO AMA1 alleles. For one combination, this extended to an enhanced relative growth inhibition of a heterologous parasite line, although this was at the cost of reduced overall inhibitory activity. These results suggest that targeted mutagenesis of AMA1 is a promising strategy for overcoming antigenic diversity in AMA1 and reducing the number of variants required to induce an antibody response that protects against a broad range of Plasmodium falciparum AMA1 genotypes. However, optimization of the immunization regime and mutation strategy will be required for this potential to be realized.T he apicomplexan parasite Plasmodium falciparum, the causative agent of the most severe form of human malaria, is responsible for Ͼ0.5 million deaths annually. There are currently no licensed vaccines for malaria; however, the development of clinical immunity in naturally exposed individuals suggests that a vaccine that reduces the morbidity and mortality associated with malaria is likely to be achievable (1). RTS,S/ASO1, a vaccine targeting the preerythrocytic stages of P. falciparum, is showing partial efficacy in a large multicenter phase III trial in Africa (2), but ultimately, an improved vaccine with higher efficacy and longer duration of protection will be required (3). This may be achieved through new vaccine approaches or by incorporating one or more asexual blood-stage antigens into a vaccine containing RTS,S.Of the asexual blood-stage antigens assessed as potential vaccine components, apical membrane antigen 1 (AMA1) has been considered particularly promising, and a large body of preclinical data supported the decision by several groups to take AMA1 vaccines into clinical development (recently reviewed in reference 4). Additionally, AMA1 is an important target of acquired immunity; antibodies t...

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“…Another recent report used two mouse MAbs specific for invasion-inhibitory or noninhibitory epitopes of the Plasmodium falciparum protein apical membrane antigen 1 as reporters in competition ELISA to detect antibodies that inhibit the antigen binding of each MAb in the serum samples of malaria patients (40). Although the human antibodies measured in this assay with the invasion-inhibitory MAb are not necessarily targeting the same epitope as the MAb, most of them probably target overlapping epitopes, many of which likely include the protective epitope segment.…”

Section: Resultsmentioning

confidence: 99%

Antibodies to Both Terminal and Internal B-Cell Epitopes of Francisella tularensisO-Polysaccharide Produced by Patients with Tularemia

Perkins

Sharon

2013

Clin. Vaccine Immunol.

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Francisella tularensis, the Gram-negative bacterium that causes tularemia, is considered a potential bioterrorism threat due to its low infectivity dose and the high morbidity and mortality from respiratory disease. We previously characterized two mouse monoclonal antibodies (MAbs) specific for the O-polysaccharide (O antigen [OAg]) of F. tularensis lipopolysaccharide (LPS): Ab63, which targets a terminal epitope at the nonreducing end of OAg, and Ab52, which targets a repeating internal OAg epitope. These two MAbs were protective in a mouse model of respiratory tularemia. To determine whether these epitope types are also targeted by humans, we tested the ability of each of 18 blood serum samples from 11 tularemia patients to inhibit the binding of Ab63 or Ab52 to F. tularensis LPS in a competition enzyme-linked immunosorbent assay (ELISA). Although all serum samples had Ab63-and Ab52-inhibitory activities, the ratios of Ab63 to Ab52 inhibitory potencies varied 75-fold. However, the variation was only 2.3-fold for sequential serum samples from the same patient, indicating different distributions of terminalversus internal-binding antibodies in different individuals. Western blot analysis using class-specific anti-human Ig secondary antibodies showed that both terminal-and internal-binding OAg antibodies were of the IgG, IgM, and IgA isotypes. These results support the use of a mouse model to discover protective B-cell epitopes for tularemia vaccines or prophylactic/therapeutic antibodies, and they present a general strategy for interrogating the antibody responses of patients and vaccinees to microbial carbohydrate epitopes that have been characterized in experimental animals.

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Antibodies to Polymorphic Invasion-Inhibitory and Non-Inhibitory Epitopes of Plasmodium falciparum Apical Membrane Antigen 1 in Human Malaria

Cited by 29 publications

References 55 publications

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Acquisition of Antibodies against Plasmodium falciparum Merozoites and Malaria Immunity in Young Children and the Influence of Age, Force of Infection, and Magnitude of Response

Use of Immunodampening To Overcome Diversity in the Malarial Vaccine Candidate Apical Membrane Antigen 1

Antibodies to Both Terminal and Internal B-Cell Epitopes of Francisella tularensisO-Polysaccharide Produced by Patients with Tularemia

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