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George M Warimwe,
Linda M Murungi,
Gathoni Kamuyu,
George M Nyangweso,
Juliana Wambua,
Vivek Naranbhai,
Helen A Fletcher,
Adrian V S Hill,
Philip Bejon, Faith H A Osier,
Kevin Marsh
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ABSTRACT: Plasmodium falciparum malaria remains a major cause of illness and death in sub-Saharan Africa. Young children bear the brunt of the disease and though older children and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P. falciparum infection. A better understanding of the host factors associated with immunity to clinical malaria and the ability to sustain asymptomatic P. falciparum infection will aid the development of improved strategies for disease prevention.
Here we investigate whether full differential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled at five annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured in peripheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up. This association is evident among children with asymptomatic P. falciparum infection at the time the cell counts are measured (Hazard ratio (HR) = 2.7 (95% CI 1.42, 5.01, P = 0.002) but not in those without detectable parasitaemia (HR = 1.0 (95% CI 0.74, 1.42, P = 0.9).
We propose that the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts, reflects an individual's capacity to mount an effective immune response to P. falciparum infection.
PLoS ONE 01/2013; 8(2):e57320. · 4.09 Impact Factor
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Philip Bejon,
Thomas N Williams,
Anne Liljander,
Abdisalan M Noor,
Juliana Wambua,
Edna Ogada,
Ally Olotu, Faith H A Osier,
Simon I Hay,
Anna Färnert,
Kevin Marsh
PLoS Medicine 02/2011; 8(2). · 16.27 Impact Factor
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Faith H A Osier,
Gareth D Weedall,
Federica Verra,
Linda Murungi,
Kevin K A Tetteh,
Pete Bull,
Bart W Faber,
Ed Remarque,
Alan Thomas,
Kevin Marsh,
David J Conway
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ABSTRACT: Although Plasmodium falciparum apical membrane antigen 1 (AMA1) is a leading malaria vaccine candidate, extensive allelic diversity may compromise its vaccine potential. We have previously shown that naturally acquired antibodies to AMA1 were associated with protection from clinical malaria in this Kenyan population. To assess the impact of allelic diversity on naturally acquired immunity, we first sequenced the ectodomain-encoding region of P. falciparum ama1 from subjects with asymptomatic, mild, and severe malaria and measured allele frequency distributions. We then measured antibodies to three allelic AMA1 proteins (AMA1_3D7, AMA1_FVO, and AMA1_HB3) and used competition enzyme-linked immunosorbent assays (ELISAs) to analyze allele-specific antibodies. Seventy-eight unique haplotypes were identified from 129 alleles sampled. No clustering of allelic haplotypes with disease severity or year of sampling was observed. Differences in nucleotide frequencies in clinical (severe plus mild malaria) versus asymptomatic infections were observed at 16 polymorphic positions. Allele frequency distributions were indicative of balancing selection, with the strongest signature being identified in domain III (Tajima's D = 2.51; P < 0.05). Antibody reactivities to each of the three allelic AMA1 proteins were highly correlated (P < 0.001 for all pairwise comparisons). Although antibodies to conserved epitopes were abundant, 48% of selected children with anti-AMA1 IgG (n = 106) had detectable reactivity to allele-specific epitopes as determined by a competition ELISA. Antibodies to both conserved and allele-specific epitopes in AMA1 may contribute to clinical protection.
Infection and immunity 11/2010; 78(11):4625-33. · 4.21 Impact Factor
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Philip Bejon,
Thomas N Williams,
Anne Liljander,
Abdisalan M Noor,
Juliana Wambua,
Edna Ogada,
Ally Olotu, Faith H A Osier,
Simon I Hay,
Anna Färnert,
Kevin Marsh
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ABSTRACT: Infectious diseases often demonstrate heterogeneity of transmission among host populations. This heterogeneity reduces the efficacy of control strategies, but also implies that focusing control strategies on "hotspots" of transmission could be highly effective.
In order to identify hotspots of malaria transmission, we analysed longitudinal data on febrile malaria episodes, asymptomatic parasitaemia, and antibody titres over 12 y from 256 homesteads in three study areas in Kilifi District on the Kenyan coast. We examined heterogeneity by homestead, and identified groups of homesteads that formed hotspots using a spatial scan statistic. Two types of statistically significant hotspots were detected; stable hotspots of asymptomatic parasitaemia and unstable hotspots of febrile malaria. The stable hotspots were associated with higher average AMA-1 antibody titres than the unstable clusters (optical density [OD] = 1.24, 95% confidence interval [CI] 1.02-1.47 versus OD = 1.1, 95% CI 0.88-1.33) and lower mean ages of febrile malaria episodes (5.8 y, 95% CI 5.6-6.0 versus 5.91 y, 95% CI 5.7-6.1). A falling gradient of febrile malaria incidence was identified in the penumbrae of both hotspots. Hotspots were associated with AMA-1 titres, but not seroconversion rates. In order to target control measures, homesteads at risk of febrile malaria could be predicted by identifying the 20% of homesteads that experienced an episode of febrile malaria during one month in the dry season. That 20% subsequently experienced 65% of all febrile malaria episodes during the following year. A definition based on remote sensing data was 81% sensitive and 63% specific for the stable hotspots of asymptomatic malaria.
Hotspots of asymptomatic parasitaemia are stable over time, but hotspots of febrile malaria are unstable. This finding may be because immunity offsets the high rate of febrile malaria that might otherwise result in stable hotspots, whereas unstable hotspots necessarily affect a population with less prior exposure to malaria.
PLoS Medicine 07/2010; 7(7):e1000304. · 16.27 Impact Factor
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ABSTRACT: Effective immunity to malaria has been clearly demonstrated among individuals naturally exposed to malaria, and can be induced by experimental infections in animals and humans. The large number of malaria antigens has presented a major challenge to identifying protective responses and their targets, and it is likely that robust immunity is mediated by responses to multiple antigens. These include merozoite surface antigens and invasion ligands, variant antigens on the surface of parasitized red blood cells, in addition to sporozoite and liver-stage antigens. Immunity seems to require humoral and cellular immune components, probably in co-operation, although the relative importance of each remains unclear. This review summarizes recent progress towards understanding the targets and mechanisms that are important for mediating immunity to malaria.
Trends in Parasitology 11/2008; 24(12):578-84. · 5.14 Impact Factor
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Faith H A Osier,
Gregory Fegan,
Spencer D Polley,
Linda Murungi,
Federica Verra,
Kevin K A Tetteh,
Brett Lowe,
Tabitha Mwangi,
Peter C Bull,
Alan W Thomas,
David R Cavanagh,
Jana S McBride,
David E Lanar,
Margaret J Mackinnon,
David J Conway,
Kevin Marsh
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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.
Infection and immunity 06/2008; 76(5):2240-8. · 4.21 Impact Factor
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Federica Verra,
Jacques Simpore,
George M Warimwe,
Kevin K Tetteh,
Tevis Howard, Faith H A Osier,
Germana Bancone,
Pamela Avellino,
Isa Blot,
Greg Fegan,
Peter C Bull,
Thomas N Williams,
David J Conway,
Kevin Marsh,
David Modiano
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ABSTRACT: A recently proposed mechanism of protection for haemoglobin C (HbC; beta6Glu-->Lys) links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA) encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i) total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS); ii) total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii) total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the beta-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria.
PLoS ONE 02/2007; 2(10):e978. · 4.09 Impact Factor
