Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria.

KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya.
Infection and immunity (Impact Factor: 4.16). 06/2008; 76(5):2240-8. DOI: 10.1128/IAI.01585-07
Source: PubMed

ABSTRACT Individuals living in areas where malaria is endemic are repeatedly exposed to many different malaria parasite antigens. Studies on naturally acquired antibody-mediated immunity to clinical malaria have largely focused on the presence of responses to individual antigens and their associations with decreased morbidity. We hypothesized that the breadth (number of important targets to which antibodies were made) and magnitude (antibody level measured in a random serum sample) of the antibody response were important predictors of protection from clinical malaria. We analyzed naturally acquired antibodies to five leading Plasmodium falciparum merozoite-stage vaccine candidate antigens, and schizont extract, in Kenyan children monitored for uncomplicated malaria for 6 months (n = 119). Serum antibody levels to apical membrane antigen 1 (AMA1) and merozoite surface protein antigens (MSP-1 block 2, MSP-2, and MSP-3) were inversely related to the probability of developing malaria, but levels to MSP-1(19) and erythrocyte binding antigen (EBA-175) were not. The risk of malaria was also inversely associated with increasing breadth of antibody specificities, with none of the children who simultaneously had high antibody levels to five or more antigens experiencing a clinical episode (17/119; 15%; P = 0.0006). Particular combinations of antibodies (AMA1, MSP-2, and MSP-3) were more strongly predictive of protection than others. The results were validated in a larger, separate case-control study whose end point was malaria severe enough to warrant hospital admission (n = 387). These findings suggest that under natural exposure, immunity to malaria may result from high titers antibodies to multiple antigenic targets and support the idea of testing combination blood-stage vaccines optimized to induce similar antibody profiles.

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    ABSTRACT: Merozoite surface protein 2 (MSP2) of Plasmodium falciparum is an abundant, intrinsically disordered protein that is GPI-anchored to the surface of the invasive blood stage of the malaria parasite. Recombinant MSP2 has been trialled as a component of a malaria vaccine, and is one of several disordered proteins that are candidates for inclusion in vaccines for malaria and other diseases. Nonetheless, little is known about the implications of protein disorder for the development of an effective antibody response. We have therefore undertaken a detailed analysis of the conformational dynamics of the two allelic forms of MSP2 (3D7 and FC27) using NMR spectroscopy. Chemical shifts and NMR relaxation data indicate that conformational and dynamic properties of the N- and C-terminal conserved regions in the two forms of MSP2 are essentially identical, but significant variation exists between and within the central variable regions. We observe a strong relationship between the conformational dynamics and the antigenicity of MSP2, as assessed with antisera to recombinant MSP2. Regions of increased conformational order in MSP2, including those in the conserved regions, are more strongly antigenic, while the most flexible regions are minimally antigenic. This suggests that modifications that increase conformational order may offer a means to tune the antigenicity of MSP2 and other disordered antigens, with implications for vaccine design.
    PLoS ONE 03/2015; 10(3):e0119899. DOI:10.1371/journal.pone.0119899 · 3.53 Impact Factor
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    ABSTRACT: . Infectious diseases such as aspergillosis, avian malaria, and viral infections are significant threats to the conservation of penguins, leading to morbidity and mortality of these birds both in captivity and in the wild. The immune response to such infectious diseases is dependent on different mechanisms mediated by cells and soluble components such as antibodies. Antibodies or immunoglobulins are glycoproteins that have many structural and functional features that mediate distinct effector immune functions. Three distinct classes of antibodies have been identified in birds: immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin Y (IgY). In this study we aim to establish an efficient laboratory method to obtain IgM and IgY antibodies from plasma samples of healthy adult Magellanic penguins (Spheniscus magellanicus). The protocol was developed combining plasma delipidation, sequential precipitation with caprylic acid and ammonium sulfate, and size-exclusion chromatography. The efficiency of the protocol and the identity of the purified IgM and IgY antibodies were confirmed through enzyme-linked immunosorbent assay, Western blotting, one-dimensional and two-dimensional polyacrylamide gel electrophoresis, and lectin binding assay. Structural and physicochemical properties of IgM and IgY from Magellanic penguins were consistent with those of other avian species. This purification protocol will allow for more detailed studies on the humoral immunity of penguins and for the development of high specificity serologic assays to test Magellanic penguins for infectious pathogens. RESUMEN. Aislamiento y caracterización de anticuerpos del tipo IgM e IgY del plasma de pingüinos de Magallanes (Spheniscus magellanicus). Las enfermedades infecciosas, como la aspergilosis, la malaria aviar, y las infecciones virales son amenazas significativas a la conservación de los pingüinos y provocan morbilidad y mortalidad de estas aves, tanto en cautiverio como en vida silvestre. La respuesta inmune a este tipo de enfermedades infecciosas depende de diferentes mecanismos mediados por células y componentes solubles, tales como anticuerpos. Los anticuerpos o inmunoglobulinas son glicoproteínas que tienen muchas características estructurales y funcionales que median diferentes funciones inmunes efectoras. Tres clases distintas de anticuerpos se han identificado en las aves: inmunoglobulina A (IgA), inmunoglobulina M (IgM) e inmunoglobulina Y (IgY). En este estudio se pretende establecer un método de laboratorio eficiente para obtener anticuerpos IgM e IgY de muestras de plasma de pingüinos de Magallanes (Spheniscus magellanicus) adultos sanos. El protocolo fue desarrollado combinando la eliminación de lípidos del plasma, la precipitación secuencial con a ´cido caprílico y sulfato de amonio y por cromatografía de exclusión por tamaño. La eficacia del protocolo y la identidad de los anticuerpos IgM e IgY purificados fue confirmada a través de pruebas de inmunoensayo con enzimas ligadas, por inmunoelectrotransferencia, mediante electroforesis en geles de poliacrilamida unidimensionales y bidimensionales y por el ensayo de unión a la lectina. Las propiedades estructurales y fisicoquímicas de las inmunoglobulinas IgM e IgY de los pingüinos de Magallanes fueron consistentes con las de otras especies aviares. Este protocolo de purificación permitirá estudios más detallados sobre la inmunidad humoral de pingüinos y para el desarrollo de ensayos serológicos de alta especificidad para el análisis de los pingüinos de Magallanes para la detección de agentes patógenos infecciosos.
    Avian Diseases 10/2014; 59:79. · 1.11 Impact Factor
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    ABSTRACT: Background Naturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria.Methods Malian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-119, MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR.ResultsAntibody titres to all antigens, except MSP-119, and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition.Conclusions The present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria.
    Malaria Journal 02/2015; 14(1):56. DOI:10.1186/s12936-015-0567-9 · 3.49 Impact Factor

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