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: 3.73). 06/2008; 76(5):2240-8. DOI: 10.1128/IAI.01585-07
Source: PubMed


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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    • "Antibody responses to MSP2 and EBA-175 have also been associated with protection from clinical malaria in adult subjects [22]. In this study, although the antibody levels in older age groups were higher for both MSP2 and EBA-175, the differences were only statistically significant for MSP2 due to the high variation within the age group. "
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    ABSTRACT: Background Malaria endemicity in the archipelago of Indonesia varies substantially across regions. Following the government’s plan for a malaria elimination programme in Indonesia, baseline malaria surveys were conducted in Mamuju District, West Sulawesi Province, Indonesia to re-assess the malaria situation prior to the establishment of an evidence-based malaria elimination programme in the area. The present study aims to determine the antibody response to three merozoite antigens among the inhabitants of the district. Methods Antibodies were measured following elution from filter-paper blood spots collected during cross-sectional surveys in the dry and wet season in 2010. Enzyme-linked immunosorbent assays using three merozoite antigens, MSP2, EBA175 and PfRh2a were conducted. A positivity threshold was determined by samples from unexposed individuals and the difference in antibody level against each antigen and correlation of antibody level in different age groups and seasons were statistically analysed. Results A total of 497 subjects, 248 in dry and 249 in wet season, aged between 0.6 and 78 years were included. The prevalence of positive antibody responses to MSP2, EBA175 and PfRh2a antigens in dry season were 27.82, 27.42 and 25.81%, respectively. In wet season, the antibody prevalences were 64.26, 64.66 and 61.45%. The antibody levels to the three antigens were all higher in older age groups and also significantly higher in the wet season. The antibody levels also correlated positively with the Plasmodium falciparum infection status of the subjects. Conclusion MSP2, EBA175 and PfRh2a induce antibody responses among the subjects in Mamuju District, and the prevalence is significantly higher in wet season. The level of antibody also correlates significantly with age and malaria positivity. The overall results indicate the antigens might be used as a target for vaccines against P. falciparum infection and as markers for malaria exposure.
    Malaria Journal 09/2014; 13(1):381. DOI:10.1186/1475-2875-13-381 · 3.11 Impact Factor
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    • "Using a prospective longitudinal study design in a population with medium-to-high malaria transmission levels, we found that children with high levels of opsonic phagocytosis antibodies had a greatly reduced risk of malaria compared to those with low levels. Furthermore, opsonic phagocytosis activity increased significantly as the breadth of the specific anti-merozoite response increased, supporting our previous findings that the breadth and magnitude of the anti-merozoite antibody response is important in immunity [6]. In contrast, total IgG or IgG-subclass reactivity to the surface of whole merozoites was not significantly associated with protection. "
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    ABSTRACT: Background An understanding of the mechanisms mediating protective immunity against malaria in humans is currently lacking, but critically important to advance the development of highly efficacious vaccines. Antibodies play a key role in acquired immunity, but the functional basis for their protective effect remains unclear. Furthermore, there is a strong need for immune correlates of protection against malaria to guide vaccine development. Methods Using a validated assay to measure opsonic phagocytosis of Plasmodium falciparum merozoites, we investigated the potential role of this functional activity in human immunity against clinical episodes of malaria in two independent cohorts (n = 109 and n = 287) experiencing differing levels of malaria transmission and evaluated its potential as a correlate of protection. Results Antibodies promoting opsonic phagocytosis of merozoites were cytophilic immunoglobulins (IgG1 and IgG3), induced monocyte activation and production of pro-inflammatory cytokines, and were directed against major merozoite surface proteins (MSPs). Consistent with protective immunity in humans, opsonizing antibodies were acquired with increasing age and malaria exposure, were boosted on re-infection, and levels were related to malaria transmission intensity. Opsonic phagocytosis was strongly associated with a reduced risk of clinical malaria in longitudinal studies in children with current or recent infections. In contrast, antibodies to the merozoite surface in standard immunoassays, or growth-inhibitory antibodies, were not significantly associated with protection. In multivariate analyses including several antibody responses, opsonic phagocytosis remained significantly associated with protection against malaria, highlighting its potential as a correlate of immunity. Furthermore, we demonstrate that human antibodies against MSP2 and MSP3 that are strongly associated with protection in this population are effective in opsonic phagocytosis of merozoites, providing a functional link between these antigen-specific responses and protection for the first time. Conclusions Opsonic phagocytosis of merozoites appears to be an important mechanism contributing to protective immunity in humans. The opsonic phagocytosis assay appears to be a strong correlate of protection against malaria, a valuable biomarker of immunity, and provides a much-needed new tool for assessing responses to blood-stage malaria vaccines and measuring immunity in populations.
    BMC Medicine 07/2014; 12(1):108. DOI:10.1186/1741-7015-12-108 · 7.25 Impact Factor
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    • "Breadth of antibody response has been suggested to be an important predictor of protection from clinical malaria in Kenyan children [9], with an inverse association between increasing breadth of IgG antibody specificities and risk of malaria, and none of the children who simultaneously had high antibody levels to five or more antigens experiencing a clinical episode. Studies assessing interaction between breadth and risk of malaria are limited. "
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    ABSTRACT: The impact of the age of first Plasmodium falciparum infection on the rate of acquisition of immunity to malaria and on the immune correlates of protection has proven difficult to elucidate. A randomized, double-blind, placebo-controlled trial using monthly chemoprophylaxis with sulphadoxine-pyrimethamine plus artesunate was conducted to modify the age of first P. falciparum erythrocytic exposure in infancy and assess antibodies and malaria risk over two years. Participants (n = 349) were enrolled at birth to one of three groups: late exposure, early exposure and control group, and were followed up for malaria morbidity and immunological analyses at birth, 2.5, 5.5, 10.5, 15 and 24 months of age. Total IgG, IgG subclasses and IgM responses to MSP-119, AMA-1, and EBA-175 were measured by ELISA, and IgG against variant antigens on the surface of infected erythrocytes by flow cytometry. Factors affecting antibody responses in relation to chemoprophylaxis and malaria incidence were evaluated. Generally, antibody responses did not vary significantly between exposure groups except for levels of IgM to EBA-175, and seropositivity of IgG1 and IgG3 to MSP-119. Previous and current malaria infections were strongly associated with increased IgG against MSP-119, EBA-175 and AMA-1 (p < 0.0001). After adjusting for exposure, only higher levels of anti-EBA-175 IgG were significantly associated with reduced clinical malaria incidence (IRR 0.67, p = 0.0178). Overall, the age of first P. falciparum infection did not influence the magnitude and breadth of IgG responses, but previous exposure was critical for antibody acquisition. IgG responses to EBA-175 were the strongest correlate of protection against clinical malaria.Trial registration: NCT00231452.
    Malaria Journal 03/2014; 13(1):121. DOI:10.1186/1475-2875-13-121 · 3.11 Impact Factor
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