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Is Fc gamma receptor IIA (FcγRIIA) polymorphism associated with clinical malaria and Plasmodium falciparum specific antibody levels in children from Burkina Faso?

Authors:
K. Mariama Cherif at Université Nazi BONI
K. Mariama Cherif
  • Université Nazi BONI
Guillaume S Sanou at Centre National de Recherche et de Formation sur le Paludisme
Guillaume S Sanou
Edith Bougouma at Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
Edith Bougouma
  • Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
Amidou Diarra
Amidou Diarra
Amidou Diarra
  • This person is not on ResearchGate, or hasn't claimed this research yet.
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Abstract

In the present study, the influences of FcγRIIA polymorphism on susceptibility to malaria and antibody responses to Plasmodium falciparum antigens were analyzed in children. We recruited 96 healthy children between 3 and 10 years at the beginning of the high transmission season and we followed up for 5 months through the high transmission season to assess the parasitological, immunological and genetic endpoints in relation to clinical malaria status. There was a similar distribution of homozygous and heterozygous individuals carrying the FcγRIIA-131R/R and FcγRIIA-131R/H allele, whereas the number of FcγRIIA-131H/H homozygous individuals was lower. P. falciparum infection frequency was not associated with the FcγRIIa-131R/H polymorphism. Only IgG antibody responses to GLURP R0 showed a significant association between antibody levels and FcγRIIA polymorphism (p=0.02). IgG levels to MSP2a were significantly higher in children who did not experience any clinical malaria episode compared to those who experienced at least one malaria episode (p=0.019). Cytophilic and non-cytophylic IgG subclass levels were higher in children without malaria than those who experienced at least one malaria episode. This difference was statistically significant for IgG1 to MSP3 (p=0.003) and to MSP2a (p=0.006); IgG3 to MSP2a (p=0.007) and to GLURP R0 (p=0.044); IgG2 to MSP2b (p=0.007) and IgG4 to MSP3 (p=0.051) and to MSP2a (p=0.049). In this study, homozygous carriers of the FcγRIIA-131R/R allele had higher malaria-specific antibody levels compare to the heterozygous carriers FcγRIIA-131R/H alleles and to homozygous carriers of FcγRIIA-131H/H alleles. The pre-existing antibodies responses were related to a reduced subsequent risk of clinical malaria. Copyright © 2014 Elsevier B.V. All rights reserved.
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... In Burkina Faso, genetic epidemiology has demonstrated that the wild-type R131 allele (rs1801274) of the FcγRIIA (CD32) and tumour necrosis factor (TNF)-238G allele (rs361525) were associated with protection from clinical malaria and high parasitaemia, respectively, in infants and children until 10 years of age [27][28][29]. In contrast, in a family based-study, TNF mutations rs3093664 and rs3093662 were associated with increased risk of parasitaemia and clinical malaria [27]. ...
... A number of studies have explored the association between FcγRIIA/CD32 rs1801274 SNP and malaria susceptibility resulting in contradictory findings [28,29,40,[54][55][56][57][58][59]. However, only a limited number included infants and the majority of those focused on severe malaria (e.g. ...
Genetic variation in the immune system and malaria susceptibility in infants: a nested case–control study in Nanoro, Burkina Faso
Article
Full-text available
  • Feb 2021
  • MALARIA J
Background: Genetic polymorphisms in the human immune system modulate susceptibility to malaria. However, there is a paucity of data on the contribution of immunogenetic variants to malaria susceptibility in infants, who present differential biological features related to the immaturity of their adaptive immune system, the protective effect of maternal antibodies and fetal haemoglobin. This study investigated the association between genetic variation in innate immune response genes and malaria susceptibility during the first year of life in 656 infants from a birth cohort survey performed in Nanoro, Burkina Faso. Methods: Seventeen single nucleotide polymorphisms (SNPs) in 11 genes of the immune system previously associated with different malaria phenotypes were genotyped using TaqMan allelic hybridization assays in a Fluidigm platform. Plasmodium falciparum infection and clinical disease were documented by active and passive case detection. Case-control association analyses for both alleles and genotypes were carried out using univariate and multivariate logistic regression. For cytokines showing significant SNP associations in multivariate analyses, cord blood supernatant concentrations were measured by quantitative suspension array technology (Luminex). Results: Genetic variants in IL-1β (rs1143634) and FcγRIIA/CD32 (rs1801274)-both in allelic, dominant and co-dominant models-were significantly associated with protection from both P. falciparum infection and clinical malaria. Furthermore, heterozygote individuals with rs1801274 SNP in FcγRIIA/CD32 showed higher IL-1RA levels compared to wild-type homozygotes (P = 0.024), a cytokine whose production is promoted by the binding of IgG immune complexes to Fcγ receptors on effector immune cells. Conclusions: These findings indicate that genetic polymorphisms in genes driving innate immune responses are associated to malaria susceptibility during the first year of life, possibly by modulating production of inflammatory mediators.
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... While a meta-analysis suggested that the H allelic variants resulting from the rs101274 variation may be protective against blood-stage malaria infection [28], our study in adults and infants from Burkina Faso did not observe such an association. This finding aligns with previous reports by Cherif et al., who found no significant association between the rs1801274 variant and P. falciparum prevalence in children from the Mossi ethnic group in Burkina Faso [52]. In that study, a frequency of 14.6% was documented for the FCGR2A-131HH (rs1801274-AA) homozygous genotype. ...
A Non-Coding Fc Gamma Receptor Cis-Regulatory Variant within the 1q23 Gene Cluster Is Associated with Plasmodium falciparum Infection in Children Residing in Burkina Faso
Article
Full-text available
  • Oct 2023
  • INT J MOL SCI
Antibodies play a crucial role in activating protective immunity against malaria by interacting with Fc-gamma receptors (FcγRs). Genetic variations in genes encoding FcγRs can affect immune cell responses to the parasite. In this study, our aim was to investigate whether non-coding variants that regulate FcγR expression could influence the prevalence of Plasmodium falciparum infection. Through bioinformatics approaches, we selected expression quantitative trait loci (eQTL) for FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B genes encoding FcγRs (FCGR),in whole blood. We prioritized two regulatory variants, rs2099684 and rs1771575, located in open genomic regions. These variants were identified using RegVar, ImmuNexUT, and transcription factor annotations specific to immune cells. In addition to these, we genotyped the coding variants FCGR2A/rs1801274 and FCGR2B/rs1050501 in 234 individuals from a malaria-endemic area in Burkina Faso. We conducted age and family-based analyses to evaluate associations with the prevalence of malarial infection in both children and adults. The analysis revealed that the regulatory rs1771575-CC genotype was predicted to influence FCGR2B/FCGR2C/FCGR3A transcripts in immune cells and was the sole variant associated with a higher prevalence of malarial infection in children. In conclusion, this study identifies the rs1771575 cis-regulatory variant affecting several FcγRs in myeloid and neutrophil cells and associates it with the inter-individual capacity of children living in Burkina Faso to control malarial infection.
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... Facteurs liés au groupe ethnique et à la susceptibilité génétiquees dans des groupes spécifiques de la réponse immunitaire au paludisme chez les Peuls a établi une immunité différente par rapport aux Dogons du Mali ou aux Mossi du Burkina Faso malgré une exposition similaire au parasite . Les Peuls réagissent mieux aux Ag de P. falciparum s que leurs homologues vivant en sympatrie(Cherif et al., 2017(Cherif et al., , 2016(Cherif et al., , 2015Arama et al., 2015;Boström et al., 2012;Vafa et al., 2009; Bolad et al., 2005). Cette réactivité active aux Ag de P. falciparum implique un nombre élevé de certaines cytokines pro-inflamatoires (IL-6, IL-8, IL-10, IL-12, TNF etIFN-(Arama et al., 2011) et des Ac cytophiles (IgG1 etIgG3)(Boström et al., 2012). ...
Influence des piqûres de moustiques sur les réponses anticorps spécifiques aux antigènes de Plasmodium falciparum
Thesis
Full-text available
  • Dec 2021
Les populations humaines vivant dans les zones endémiques pour le paludisme développent une immunité protectrice qui est majoritairement médiée par les anticorps contre Plasmodium falciparum. Cette immunité peut être modulée par différents facteurs relatifs à l’hôte, au parasite et à l’environnement. Ces populations humaines sont fréquemment exposées aux piqûres des insectes hématophages, notamment aux différentes espèces de moustiques Anopheles, Culex et Aedes. Certains composants salivaires de ces moustiques, contenus dans la salive injectée à l’hôte à chaque repas sanguin, ont des propriétés immunomodulatrices, et sont donc capables de moduler le système immunitaire de l’hôte. Cette thèse s’intéresse aux relations immunologiques hôte-vecteur-pathogène et notre objectif était d’évaluer l’influence de l’exposition aux piqûres de moustiques sur les réponses anticorps spécifiques à Plasmodium falciparum chez des populations humaines qui résident en zone d’endémie pour le paludisme. Pour ce faire, des échantillons sanguins prélevés au cours de deux études multidisciplinaires réalisées à Bouaké (Côte d’Ivoire) nous ont servi pour évaluer les réponses IgG et isotypiques (IgG1 et IgG3) à certains antigènes candidats vaccins (PfAMA1, PfMSP1, PfMSP3 et PfGLURP-R0) et aux extraits de schizontes (Pfshz) de Plasmodium falciparum. L’exposition aux piqûres de moustique a été définie au niveau individuel par une approche sérologique basée sur la quantification de la réponse IgG à certains antigènes salivaires spécifiques de chaque genre de moustique et qui représentent un proxy du niveau d’exposition à ces moustiques. La relation entre les réponses anticorps aux antigènes de P. falciparum et les facteurs démographiques, parasitaires, et les facteurs environnementaux a été réalisée par l’utilisation d’analyses univariées et multivariées.Lors de la première étude transversale, les réponses anticorps anti-Plasmodium falciparum étaient différentes selon le niveau d'exposition des enfants, ceux fortement exposés à Anopheles présentaient des réponses IgG et IgG3 significativement plus faibles à PfMSP1. Nous n'avons pas trouvé d'association entre les réponses anticorps à PfAMA1 et le niveau d’exposition aux Anopheles. La deuxième étude nous a permis de suivre l’évolution de la réponse IgG anti-P. falciparum 42 jours après une infection. Les personnes qui étaient plus exposées aux piqûres d'Anopheles ou d'Aedes (exposition considérée à un genre unique) présentaient une plus forte augmentation de la réponse IgG anti-PfShz en comparaison aux personnes moins exposées. Une association positive entre la réponse IgG à PfShz et le niveau individuel d'exposition aux deux genres de moustiques combinée a également été observé au cours du suivi. L’évolution de cette réponse immune était également associée à l'âge, à la densité parasitaire et à la réponse immunitaire préexistante anti-Plasmodium à l'inclusion de l'étude longitudinale. L’exposition aux moustiques (unique ou combinée) n’était pas associée aux dynamiques d’évolution des réponses spécifiques aux antigènes de mérozoites.L’ensemble de ces résultats suggère que l’exposition aux piqûres de moustiques est associée à l’acquisition et à la dynamique des réponses anticorps dirigées contre certains antigènes de Plasmodium falciparum. Ces observations « de terrain » peuvent constituer le point de départ de travaux complémentaires pour appréhender le rôle de la salive de moustique sur la transmission du paludisme en combinant des études immunologiques sur le terrain et ex-vivo.
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... Studies examining specific characteristics of the immune response to malaria in the Fulani have established, despite similar exposure to the parasite, a number of differences from other sympatric ethnic groups. Fulani are more responsive to P.falciparum antigens, with higher levels of P.falciparum specific IgG, IgM, and IgE antibodies [6,[17][18][19][20][21][22][23][24]; Fulani have more activated memory B-cells and plasma cells [25]; Fulani have less activated and fewer circulating regulatory T-cells [26,27]; Fulani have higher levels of cytokines and chemokines, with higher ratios of proinflammatory to anti-inflammatory cytokines [20,[27][28][29]; Fulani have increased activation of dendritic cells correlating with their lower frequency in the circulating blood [29]. Collectively, this suggest a model in which Fulani have more effective innate immune responses to P.falciparum infection, driving more effective adaptive immunity [7]. ...
What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?
Article
Full-text available
  • Jul 2020
There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub‐Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa relies not only on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.
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... 62 However, the contribution of parasitereactive IgG2 antibodies to protection against clinical malaria is suggested in some epidemiological settings. 61,63,64 By contrast, several studies have suggested that lgG4 antibodies most likely do not protect against the disease. [65][66][67][68] In Brazil, an analysis of the antibody isotypes specific for several P. falciparum proteins revealed that all four IgG subclasses are present and, for some proteins, such as the N-terminal region of the P126 protein, individuals with higher levels of the anti-Nt47 cytophilic IgG antibody had significantly lower parasitemia levels. ...
Synthetic Antigens Derived from Plasmodium falciparum Sporozoite, Liver, and Blood Stages: Naturally Acquired Immune Response and Human Leukocyte Antigen Associations in Individuals Living in a Brazilian Endemic Area
Article
Full-text available
  • Sep 2017
Peptide vaccine strategies using Plasmodium-derived antigens have emerged as an attractive approach against malaria. However, relatively few studies have been conducted with malaria-exposed populations from non-African countries. Herein, the seroepidemiological profile against Plasmodium falciparum of naturally exposed individuals from a Brazilian malaria-endemic area against synthetic peptides derived from vaccine candidates circumsporozoite protein (CSP), liver stage antigen-1 (LSA-1), erythrocyte binding antigen-175 (EBA-175), and merozoite surface protein-3 (MSP-3) was investigated. Moreover, human leukocyte antigen (HLA)-DRB1* and HLA-DQB1* were evaluated to characterize genetic modulation of humoral responsiveness to these antigens. The study was performed using blood samples from 187 individuals living in rural malaria-endemic villages situated near Porto Velho, Rondônia State. Specific IgG and IgM antibodies and IgG subclasses were detected by enzyme-linked immunosorbent assay, and HLA-DRB1* and HLA-DQB1* low-resolution typing was performed by PCR-SSP. All four synthetic peptides were broadly recognized by naturally acquired antibodies. Regarding the IgG subclass profile, only CSP induced IgG1 and IgG3 antibodies, which is an important fact given that the acquisition of protective immunity appears to be associated with the cytophilicity of IgG1 and IgG3 antibodies. HLA-DRB1*11 and HLA-DQB1*7 had the lowest odds of responding to EBA-175. Our results showed that CSP, LSA-1, EBA, and MSP-3 are immunogenic in natural conditions of exposure and that anti-EBA antibody responses appear to be modulated by HLA class II antigens.
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... The association of GLURP R2 IgG2 titres with reduced risk of malaria in the Burkinabe cohort may be due to the observation that IgG2 binds with high affinity to Fc gamma receptor IIA-131H (FcγRIIA-131H) allele on immune cells of individuals expressing this variant [49][50][51]. Although FcγRIIA was not genotyped in the present study, other studies in the same district in Burkina Faso reported FcγRIIA-131H-allele frequency to be 28.6 % in the population [52]. Thus, individuals with this FcγRIIA-131H polymorphism could benefit from GLURP R2 IgG2 mediated cellular effector functions that may afford protection against malaria. ...
Antibody levels against GLURP R2, MSP1 block 2 hybrid and AS202.11 and the risk of malaria in children living in hyperendemic (Burkina Faso) and hypo-endemic (Ghana) areas
Article
Full-text available
  • Feb 2016
  • MALARIA J
Background: Differences in parasite transmission intensity influence the process of acquisition of host immunity to Plasmodium falciparum malaria and ultimately, the rate of malaria related morbidity and mortality. Potential vaccines being designed to complement current intervention efforts therefore need to be evaluated against different malaria endemicity backgrounds. Methods: The associations between antibody responses to the chimeric merozoite surface protein 1 block 2 hybrid (MSP1 hybrid), glutamate-rich protein region 2 (GLURP R2) and the peptide AS202.11, and the risk of malaria were assessed in children living in malaria hyperendemic (Burkina Faso, n = 354) and hypo-endemic (Ghana, n = 209) areas. Using the same reagent lots and standardized protocols for both study sites, immunoglobulin (Ig) M, IgG and IgG sub-class levels to each antigen were measured by ELISA in plasma from the children (aged 6-72 months). Associations between antibody levels and risk of malaria were assessed using Cox regression models adjusting for covariates. Results: There was a significant association between GLURP R2 IgG3 and reduced risk of malaria after adjusting age of children in both the Burkinabe (hazard ratio 0.82; 95 % CI 0.74-0.91, p < 0.0001) and the Ghanaian (HR 0.48; 95 % CI 0.25-0.91, p = 0.02) cohorts. MSP1 hybrid IgM was associated (HR 0.85; 95 % CI 0.73-0.98, p = 0.02) with reduced risk of malaria in Burkina Faso cohort while IgG against AS202.11 in the Ghanaian children was associated with increased risk of malaria (HR 1.29; 95 % CI 1.01-1.65, p = 0.04). Conclusion: These findings support further development of GLURP R2 and MSP1 block 2 hybrid, perhaps as a fusion vaccine antigen targeting malaria blood stage that can be deployed in areas of varying transmission intensity.
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Phenotype and function of IL-10 producing NK cells in individuals with malaria experience
Preprint
  • May 2024
Plasmodium falciparum infection can trigger high levels of inflammation that lead to fever and sometimes severe disease. People living in malaria-endemic areas gradually develop resistance to symptomatic malaria and control both parasite numbers and the inflammatory response. We previously found that adaptive natural killer (NK) cells correlate with reduced parasite load and protection from symptoms. We also previously found that murine NK cell production of IL-10 can protect mice from experimental cerebral malaria. Human NK cells can also secrete IL-10, but it was unknown what NK cell subsets produce IL-10 and if this is affected by malaria experience. We hypothesize that NK cell immunoregulation may lower inflammation and reduce fever induction. Here, we show that NK cells from subjects with malaria experience make significantly more IL-10 than subjects with no malaria experience. We then determined the proportions of NK cells that are cytotoxic and produce interferon gamma and/or IL-10 and identified a signature of adaptive and checkpoint molecules on IL-10-producing NK cells. Lastly, we find that co-culture with primary monocytes, Plasmodium-infected RBCs, and antibody induces IL-10 production by NK cells. These data suggest that NK cells may contribute to protection from malaria symptoms via IL-10 production.
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Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria
Article
Full-text available
  • Sep 2017
  • eLife
The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups. However, the basis for this lower susceptibility to malaria by the Fulani is unknown. The incidence of classic malaria resistance genes are lower in the Fulani than in other sympatric ethnic populations, and targeted SNP analyses of other candidate genes involved in the immune response to malaria have not been able to account for the observed difference in the Fulani susceptibility to P.falciparum. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection.
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Development, validation and comparison of NIR and Raman methods for the identification and assay of poor-quality quinine drops
Article
Full-text available
  • Mar 2015
  • J PHARMACEUT BIOMED
Poor quality antimalarial drugs are one of the public’s major health problems in Africa. The depth of this problem may be explained in part by the lack of effective enforcement and the lack of efficient local drug analysis laboratories. To tackle part of this issue, two spectroscopic methods with the ability to detect and to quantify quinine dihydrochloride in children’s oral drops formulations were developed and validated. Raman and Near Infrared (NIR) spectroscopy were selected for the drug analysis due to their low cost, non-destructive and rapid characteristics. Both of the methods developed were successfully validated using the total error approach in the range of 50-150% of the target concentration (20% W/V) within the 10% acceptance limits. Samples collected on the Congolese pharmaceutical market were analyzed by both techniques to detect potentially substandard drugs. After a comparison of the analytical performance of both methods, it has been decided to implement the method based on NIR spectroscopy to perform the routine analysis of quinine oral drop samples in the Quality Control Laboratory of Drugs at the University of Kinshasa (DRC).
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Difference in Susceptibility to Malaria Between Two Sympatric Ethnic Groups in Mali
Article
Full-text available
  • Mar 2005
We compared malaria indicators among sympatric groups to study human heterogeneities in the response to Plasmodium falciparum malaria infection. Four cross-sectional surveys and two longitudinal surveys in two sympatric ethnic groups (Dogon and Fulani) in Mali were carried out from 1998 to 2000. Spleen and parasite rates were evaluated during the cross-sectional surveys and disease incidence was assessed during longitudinal surveys. In spite of similar sociocultural factors and entomologic inoculation rates between ethnic groups, the Fulani had a significantly higher spleen enlargement rate, lower parasite rate, and were less affected by the disease than the Dogon group, whose frequency of hemoglobin C was higher than that recorded among the Fulani group. The Fulani group had significantly higher levels of IgG and IgE against crude malaria antigen than the Dogon group, suggesting a role of anti-malaria antibodies in the immune protection seen in this group.
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Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso
Article
Full-text available
  • Mar 2012
  • MALARIA J
Patient immune status is thought to affect the efficacy of anti-malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml) was obtained from each child to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. IgG levels to MSP3 were always higher in the successfully treated group than in the group with treatment failure. The same observation was made for GLURP but the reverse observation was noticed for MSP1-19. Cytophilic and non-cytophilic antibodies were significantly associated with protection against all three antigens, except for IgG4 to MSP1-19 and GLURP. Acquired anti-malarial antibodies may play an important role in the efficacy of anti-malarial drugs in younger children more susceptible to the disease.
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Safety and Immunogenicity of the Malaria Vaccine Candidate MSP3 Long Synthetic Peptide in 12–24 Months-Old Burkinabe Children
Article
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A Phase Ia trial in European volunteers of the candidate vaccine merozoite surface protein 3 (MSP3), a Plasmodium falciparum blood stage membrane, showed that it induces biologically active antibodies able to achieve parasite killing in vitro, while a phase Ib trial in semi-immune adult volunteers in Burkina Faso confirmed that the vaccine was safe. The aim of this study was to assess the safety and immunogenicity of this vaccine candidate in children aged 12-24 months living in malaria endemic area of Burkina Faso. The study was a double-blind, randomized, controlled, dose escalation phase Ib trial, designed to assess the safety, reactogenicity and immunogenicity of three doses of either 15 or 30 microg of MSP3-LSP adsorbed on aluminum hydroxide in 45 children 12 to 24 months of age randomized into three equal groups. Each group received 3 vaccine doses (on days 0, 28 and 56) of either 15 microg of MSP3-LSP, 30 microg of MSP3-LSP or of the Engerix B hepatitis B vaccine. Children were visited at home daily for the 6 days following each vaccination to solicit symptoms which might be related to vaccination. Serious adverse events occurring during the study period (1 year) were recorded. Antibody responses to MSP3-LSP were measured on days 0, 28, 56 and 84. All 45 enrolled children received three MSP3 vaccine doses. No serious adverse events were reported. Most of the adverse events reported were mild to moderate in severity. The only reported local symptoms with grade 3 severity were swelling and induration, with an apparently dose related response. All grade 3 adverse events resolved without any sequelae. Both MSP3 doses regimens were able to elicit high levels of anti-MSP3 specific IgG1 and IgG3 antibodies in the volunteers with very little or no increase in IgG2, IgG4 and IgM classes: i.e. vaccination induced predominantly the isotypes involved in the monocyte-dependent mechanism of P. falciparum parasite-killing. Our results support the promise of MSP3-LSP as a malaria vaccine candidate, both in terms of tolerability and of immunogenicity. Further assessment of the efficacy of this vaccine is recommended. ClinicalTrials.gov NCT00452088.
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Polymorphism of the Fcγ receptor IIA and malaria morbidity
Article
Full-text available
  • Jul 2005
  • J Mol Genet Med
Fc receptors (FcRs) are expressed on the surface of all types of cells of the immune system. They bind the Fc portion of immunoglobulin (Ig), thereby bridging specific antigen recognition by antibodies with cellular effector mechanisms. FcgammaRIIA, one of the three receptors for human IgG, is a low-affinity receptor for monomeric IgG, but binds IgG immune complexes efficiently. FcgammaRIIA is believed to play a major role in eliciting monocyte- and macrophage-mediated effector responses against blood-stage malaria parasites. A G --> A single nucleotide polymorphism, which causes an arginine (R) to be replaced with histidine (H) at position 131, defines two allotypes which difer in their avidity for complexed human IgG(2) and IgG(3). Because FcgammaRIIA-H131 is the only FcgammaR allotype which interacts efficiently with human IgG(2,) this polymorphism may determine whether parasite-specific IgG(2) may or may not elicit cooperation with cellular imune responses during blood-stage malaria infection. Here, we review data from four published case-control studies describing associations between FcgammaRIIA R/H131 polymorphism and malaria-related outcomes and discuss possible reasons for some incongruities found in these available results.
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FcγRIIa (CD32) polymorphism and anti-malarial IgG subclass pattern among Fulani and sympatric ethnic groups living in eastern Sudan
Article
Full-text available
  • Feb 2009
  • MALARIA J
A SNP at position 131, in the FcgammaRIIa gene, affects the binding of the different IgG subclasses and may influence the clinical variation seen in patients with falciparum malaria. This study confirms and extends previous findings, analysing the FcgammaRIIa (CD32) polymorphism in relation to the IgG subclass distribution seen among two sympatric tribes living in eastern Sudan, characterized by marked differences in susceptibility to Plasmodium falciparum malaria. Two hundred and fifty Fulani subjects living in an area of meso-endemic P. falciparum malaria infection were genotyped for the FcgammaRIIa-131 polymorphism. For comparison, 101 non-Fulani donors - (Masaleit, Hausa and Four) - living in the same study area, were genotyped. The levels of plasma antibodies (IgG and subclasses) to four malaria antigens (AMA-1, MSP 2 - 3D7 & FC27, Pf332-C231) were measured using indirect enzyme-linked immunosorbent assays. The FcgammaRIIa-H/H131 genotype was found to be significantly more prevalent in the Fulani as compared to the non-Fulani ethnic groups (36.0% for Fulani versus 17.8% for non-Fulani, adjusted OR 3.10, 95% CI 1.61-5.97, P value < 0.001). The Fulani showed lower anti-malarial IgG1 and IgG3 antibody levels as compared to the non-Fulani and higher levels of IgG2 antibodies. The FcgammaRIIa-H/H131 genotype and H131 allele is at higher frequency in the Fulani ethnic group. The H/H131 genotype was consistently associated with higher levels of anti-malarial IgG2 and IgG3 antibodies, while the R/R131 genotype was associated with higher levels of IgG1 antibodies.
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Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria
Article
Full-text available
  • Oct 2008
  • MALARIA J
The development of protective immunity against malaria is slow and to be maintained, it requires exposure to multiple antigenic variants of malaria parasites and age-associated maturation of the immune system. Evidence that the protective immunity is associated with different classes and subclasses of antibodies reveals the importance of considering the quality of the response. In this study, we have evaluated the humoral immune response against Plasmodium falciparum blood stages of individuals naturally exposed to malaria who live in endemic areas of Brazil in order to assess the prevalence of different specific isotypes and their association with different malaria clinical expressions. Different isotypes against P. falciparum blood stages, IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgE and IgA, were determined by ELISA. The results were based on the analysis of different clinical expressions of malaria (complicated, uncomplicated and asymptomatic) and factors related to prior malaria exposure such as age and the number of previous clinical malaria attacks. The occurrence of the H131 polymorphism of the FcgammaIIA receptor was also investigated in part of the studied population. The highest levels of IgG, IgG1, IgG2 and IgG3 antibodies were observed in individuals with asymptomatic and uncomplicated malaria, while highest levels of IgG4, IgE and IgM antibodies were predominant among individuals with complicated malaria. Individuals reporting more than five previous clinical malaria attacks presented a predominance of IgG1, IgG2 and IgG3 antibodies, while IgM, IgA and IgE antibodies predominated among individuals reporting five or less previous clinical malaria attacks. Among individuals with uncomplicated and asymptomatic malaria, there was a predominance of high-avidity IgG, IgG1, IgG2 antibodies and low-avidity IgG3 antibodies. The H131 polymorphism was found in 44.4% of the individuals, and the highest IgG2 levels were observed among asymptomatic individuals with this allele, suggesting the protective role of IgG2 in this population. Together, the results suggest a differential regulation in the anti-P. falciparum antibody pattern in different clinical expressions of malaria and showed that even in unstable transmission areas, protective immunity against malaria can be observed, when the appropriated antibodies are produced.
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Differences in Fcγ receptor IIa genotypes and IgG subclass pattern of anti-malarial antibodies between sympatric ethnic groups in Mali
Article
Full-text available
  • Oct 2008
  • MALARIA J
The Ig Fc receptor family is an important link between the humoral and cellular immune systems. The association of a dimorphism in amino acid 131 (R/H) of the FcgammaRIIa with malaria severity, the R-allele being associated with a milder disease outcome, led to the investigation of the possible impact of this polymorphism in the interethnic difference in malaria susceptibility seen between the Fulani and Dogon in Mali. Plasma from individuals from Mali (164 Fulani and 164 Dogon) were analysed for malaria-reactive and total IgG subclass antibodies using ELISA, and the same individuals were also genotyped for the FcgammaRIIa R131H polymorphism using RFLP-PCR. Statistical analyses of the IgG subclass levels were done by unpaired t-test and ANOVA, and genotype differences were tested by chi2-test. While the two ethnic groups showed a similar frequency of the FcgammaRIIa 131 R/H heterozygote genotype, 131R/R dominated over the 131 H/H genotype in the Dogon whereas the Fulani presented a similar frequency of the two homozygote genotypes. The two alleles were evenly distributed in the Fulani, while the Dogon were clearly biased towards the R-allele. The Fulani showed higher levels of anti-malarial IgG1, -2 and -3 antibodies, with a higher proportion of IgG2, than the Dogon. In the Fulani, H-allele carriers had higher anti-malarial IgG2 levels than R/R homozygotes, while in the Dogon, the R-allele carriers showed the higher IgG2 levels. For anti-malarial IgG3, the R-allele carriers in the Fulani had higher levels than the H/H homozygotes. Taken together, the results showed marked interethnic differences in FcgammaRIIa R131H genotypes. Furthermore, the results indicate that the FcgammaRIIa R131H genotype may influence the IgG subclass responses related to protection against malaria, and that IgG2 may be of importance in this context.
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Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children
Article
Full-text available
  • Feb 2008
  • MALARIA J
Antigen-specific antibody-mediated immune responses play an important role in natural protection against clinical malaria, but conflicting estimates of this association have emerged from immuno-epidemiological studies in different geographical settings. This study was aimed at assessing in a standardized manner the relationship between the antibody responses to four malaria vaccine candidate antigens and protection from clinical malaria, in a cohort of Ghanaian children. Standardized ELISA protocols were used to measure isotype and IgG subclass levels to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1-19 (MSP119), Merozoite Surface Protein 3 (MSP3) and Glutamate Rich Protein (GLURP) antigens in plasma samples from 352 Ghanaian children, aged three to 10 years with subsequent malaria surveillance for nine months. This is one of a series of studies in different epidemiological settings using the same standardized ELISA protocols to permit comparisons of results from different laboratories. The incidence rate of malaria was 0.35 episodes per child per year. Isotype and IgG subclasses for all antigens investigated increased with age, while the risk of malaria decreased with age. After adjusting for age, higher levels of IgG to GLURP, MSP119, MSP3 and IgM to MSP119, MSP3 and AMA1 were associated with decreased malaria incidence. Of the IgG subclasses, only IgG1 to MSP119 was associated with reduced incidence of clinical malaria. A previous study in the same location failed to find an association of antibodies to MSP119 with clinical malaria. The disagreement may be due to differences in reagents, ELISA and analytical procedures used in the two studies. When IgG, IgM and IgG subclass levels for all four antigens were included in a combined model, only IgG1 [(0.80 (0.67-0.97), p = 0.018)] and IgM [(0.48 (0.32-0.72), p < 0.001)] to MSP119 were independently associated with protection from malaria. Using standardized procedures, the study has confirmed the importance of antibodies to MSP119 in reducing the risk of clinical malaria in Ghanaian children, thus substantiating its potential as a malaria vaccine candidate.
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On the interaction of IgG subclasses with the low affinity fc??RIIa (CD32) on human monocytes, neutrophils, and platelets: Analysis of a functional polymorphism to human IgG2
Article
Full-text available
  • Oct 1992
An allotypic form of the low affinity IgG Fc receptor Fc gamma RIIa (CD32), termed low responder (LR) because of its weak reactivity with mouse (m) IgG1, interacts efficiently with human (h) IgG2. Fc gamma RIIaLR is the first known human FcR that binds this IgG subclass. In this study, we analyzed the role of Fc gamma RIIa in binding of stable hIgG-subclass dimers, and in induction of T cell mitogenesis using chimeric anti-CD3 mAb. We demonstrate that the functional polymorphism to hIgG2 is expressed on the majority of Fc gamma R-bearing peripheral blood cells: monocytes, neutrophils, and platelets. We were able to assess Fc gamma RII-mediated IgG-binding without interference of other Fc gamma R-classes, by blockade of Fc gamma RI on monocytes, and by using neutrophils of an individual deficient for the Fc gamma RIIIB gene. This study indicates as subclass specificity: hIgG3 >hIgG1,hIgG2 > hIgG4 for Fc gamma RIIaLR and hIgG3,hIgG1 > hIgG2 > hIgG4 for Fc gamma RIIaHR. Comparing the serum hIgG levels of individuals homozygous for the two fc gamma RIIa allotypic forms, we observed significantly lower hIgG2 serum levels in individuals expressing the hIgG2-binding LR allotypic form. This observation may implicate that Fc gamma RIIa regulates hIgG subclass production or turnover in man.
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FcγRIIa Polymorphism and Anti-Malaria-Specific IgG and IgG Subclass Responses in Populations Differing in Susceptibility to Malaria in Burkina Faso
Article
  • Jan 2012
  • SCAND J IMMUNOL
FcγRIIa is known to be polymorphic; and certain variants are associated with different susceptibilities to malaria. Studies involving the Fulani ethnic group reported an ethnic difference in FcγRIIa-R131H genotype frequencies between the Fulani and other sympatric groups. No previous studies have addressed these questions in Burkina Faso. This study aimed to assess the influence of FcγRIIa-R131H polymorphism on anti-falciparum malaria IgG and IgG subclass responses in the Fulani and the Mossi ethnic groups living in Burkina Faso. Healthy adults more than 20 years old belonging to the Mossi or the Fulani ethnic groups were enrolled for the assessment of selected parasitological, immunological and genetic variables in relation to their susceptibility to malaria. The prevalence of the Plasmodium falciparum infection frequency was relatively low in the Fulani ethnic group compared to the Mossi ethnic group. For all tested antigens, the Fulani had higher antibody levels than the Mossi group. In both ethnic groups, a similar distribution of FcγRIIa R131H polymorphism was found. Individuals with the R allele of FcγRIIa had higher antibody levels than those with the H allele. This study confirmed that malaria infection affected less the Fulani group than the Mossi group. FcγRIIa-R131H allele distribution is similar in both ethnic groups, and higher antibody levels are associated with the FcγRIIa R allele compared to the H allele.
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