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Ogobara K Doumbo

Publications and source records attributed to Ogobara K Doumbo.

At least 19 recordsLinked to original sources
PubMed2006

Safety and allele-specific immunogenicity of a malaria vaccine in Malian adults: results of a phase I randomized trial.

OBJECTIVES: The objectives were to evaluate the safety, reactogenicity, and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels. DESIGN: We conducted a randomized, double-blind, controlled phase I clinical trial. SETTING: Bandiagara, Mali, West Africa, is a rural town with intense seasonal transmission of Plasmodium falciparum malaria. PARTICIPANTS: Forty healthy, malaria-experienced Malian adults aged 18-55 y were enrolled. INTERVENTIONS: The FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 (MSP-1(42)) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The control vaccine was a killed rabies virus vaccine (Imovax). Participants were randomized to receive either FMP1/AS02A or rabies vaccine at 0, 1, and 2 mo and were followed for 1 y. OUTCOME MEASURES: Solicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-1(42) and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured. RESULTS: Transient local pain and swelling were more common in the malaria vaccine group than in the control group (11/20 versus 3/20 and 10/20 versus 6/20, respectively). MSP-1(42) antibody levels rose during the malaria transmission season in the control group, but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group. Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-1(42) alleles and their subunits. CONCLUSIONS: FMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones. Anti-MSP-1(42) antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine.

Journal Article↗
PubMed2006

Space-time clustering of childhood malaria at the household level: a dynamic cohort in a Mali village.

BACKGROUND: Spatial and temporal heterogeneities in the risk of malaria have led the WHO to recommend fine-scale stratification of the epidemiological situation, making it possible to set up actions and clinical or basic researches targeting high-risk zones. Before initiating such studies it is necessary to define local patterns of malaria transmission and infection (in time and in space) in order to facilitate selection of the appropriate study population and the intervention allocation. The aim of this study was to identify, spatially and temporally, high-risk zones of malaria, at the household level (resolution of 1 to 3 m). METHODS: This study took place in a Malian village with hyperendemic seasonal transmission as part of Mali-Tulane Tropical Medicine Research Center (NIAID/NIH). The study design was a dynamic cohort (22 surveys, from June 1996 to June 2001) on about 1300 children (<12 years) distributed between 173 households localized by GPS. We used the computed parasitological data to analyzed levels of Plasmodium falciparum, P. malariae and P. ovale infection and P. falciparum gametocyte carriage by means of time series and Kulldorff's scan statistic for space-time cluster detection. RESULTS: The time series analysis determined that malaria parasitemia (primarily P. falciparum) was persistently present throughout the population with the expected seasonal variability pattern and a downward temporal trend. We identified six high-risk clusters of P. falciparum infection, some of which persisted despite an overall tendency towards a decrease in risk. The first high-risk cluster of P. falciparum infection (rate ratio = 14.161) was detected from September 1996 to October 1996, in the north of the village. CONCLUSION: This study showed that, although infection proportions tended to decrease, high-risk zones persisted in the village particularly near temporal backwaters. Analysis of this heterogeneity at the household scale by GIS methods lead to target preventive actions more accurately on the high-risk zones identified. This mapping of malaria risk makes it possible to orient control programs, treating the high-risk zones identified as a matter of priority, and to improve the planning of intervention trials or research studies on malaria.

Animals↗
PubMed2006

Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia.

The Plasmodium falciparum variant erythrocyte surface antigens known as PfEMP1, encoded by the var gene family, are thought to play a crucial role in malaria pathogenesis because they mediate adhesion to host cells and immuno-modulation. Var genes have been divided into three major groups (A, B and C) and two intermediate groups (B/A and B/C) on the basis of their genomic location and upstream sequence. We analysed expressed sequence tags of the var gene DBLalpha domain to investigate var gene transcription in relation to disease severity in Malian children. We found that P. falciparum isolates from children with cerebral malaria (unrousable coma) predominantly transcribe var genes with DBLalpha1-like domains that are characteristic of Group A or B/A var genes. In contrast, isolates from children with equally high parasite burdens but no symptoms or signs of severe malaria (hyperparasitaemia patients) predominantly transcribe var genes with DBLalpha0-like domains that are characteristic of the B and C-related var gene groups. These results suggest that var genes with DBLalpha1-like domains (Group A or B/A) may be implicated in the pathogenesis of cerebral malaria, while var genes with DBLalpha0-like domains promote less virulent malaria infections.

Amino Acid Sequence↗
PubMed2006

A high-throughput method for quantifying alleles and haplotypes of the malaria vaccine candidate Plasmodium falciparum merozoite surface protein-1 19 kDa.

BACKGROUND: Malaria vaccine efficacy may be compromised if the frequency of non-target alleles increases following vaccination with a genetically polymorphic target. Methods are needed to monitor genetic diversity in polymorphic vaccine antigens, but determining which genetic variants of such antigens are present in infected individuals is complicated by the frequent occurrence of mixed infections. METHODS: Pyrosequencing was used to determine allele frequencies at each of six single nucleotide polymorphisms in the Plasmodium falciparum blood-stage vaccine antigen merozoite surface protein 1 19 kDa (MSP-119) in field samples from a vaccine-testing site in Mali. Mixtures of MSP-119 clones were created to validate a haplotype-estimating algorithm that uses maximum likelihood methods to determine the most probable combination of haplotypes given the allele frequencies for an infection and the haplotypes known to be circulating in the population. RESULTS: Fourteen unique MSP-119 haplotypes were identified among 351 genotyped infections. After adjustment to a standard curve, Pyrosequencing provided accurate and precise estimates of allele frequencies in mixed infections. The haplotype-estimating algorithm provided accurate estimates of haplotypes in mixed infections containing up to three haplotypes. Based on the MSP-119 locus, approximately 90% of the 351 infections contained two or fewer haplotypes. CONCLUSION: Pyrosequencing in conjunction with a haplotype-estimating algorithm provides accurate estimates of haplotypes present in infections with up to 3 haplotypes, and can be used to monitor genetic diversity in parasite populations prior to and following introduction of MSP-1-based malaria vaccines.

Adult↗
PubMed2006

Epilepsy as a consequence of cerebral malaria in area in which malaria is endemic in Mali, West Africa.

PURPOSE: Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas, but little information is available. The purpose of this study was to evaluate the role of CM in epilepsy among children in Mali. METHODS: An exposed-nonexposed study was performed to identify children who had epilepsy after malaria in the 0- to 15-year age group. The exposure factor was CM defined according to World Health Organization (WHO) criteria, and the nonexposure factor was symptomatic malaria without the characteristics of CM (NCM). All the children underwent a screening questionnaire and were examined by a medical physician. After the screening phase, a specialist in neuropediatrics examined the children suspected to have epilepsy. EEG and computed tomography (CT) scans were performed in some of these patients. RESULTS: In total, 101 subjects who had had CM and 222 who had had NCM were included. Fifty-four children (CM, 34; NCM, 20) were suspected to have epilepsy, and six were confirmed (CM, five; NCM, one). The incidence rate was 17.0 per 1000 person-years in the CM group and 1.8 per 1000 person-year in the NCM group; thus the relative risk (RR) was 9.4 [95% confidence interval (CI), 1.3-80.3; p = 0.02]. After adjustment on age and duration of follow-up, the RR was 14.3 (95% CI, 1.6-132.0; p = 0.01). CONCLUSIONS: The risk of sequelar epilepsy is significantly higher in the CM group compared with the NCM group. A reevaluation of this cohort should be carried out later to search for temporal epilepsy that appeared after age 10 years.

Age Factors↗
PubMed2006

Filaria-induced monocyte dysfunction and its reversal following treatment.

Monocyte dysfunction in filarial infection has been proposed as one mechanism underlying the diminished antigen-specific T-cell response seen in patent lymphatic filariasis. Cytokine/chemokine production and gene expression in monocytes from filaria-infected patients and uninfected healthy donors were assessed unstimulated and in response to stimulation with Staphylococcus aureus Cowan I bacteria plus gamma interferon both before and 8 months following treatment. Monocytes from filaria-infected individuals were studded with intracellular microfilarial antigens. Furthermore, monocytes from these individuals were less capable of producing interleukin-8 (IL-8), Exodus II, MIP-1alpha, MIP-1beta, and IL-1alpha and preferentially expressed genes involved in apoptosis and adhesion compared with monocytes from uninfected donors. Eight months following treatment with a single dose of ivermectin-albendazole, some of these defects were reversed, with monocyte production of IL-8, IL-1alpha, MIP-1alpha, and IL-10 being comparable to that seen in the uninfected controls. In addition, a marked increase in mRNA expression of genes associated with protein metabolism, particularly heat shock proteins, was seen compared with pretreatment expression. These data suggest that the function and gene expression of monocytes in filaria-infected patients are altered but that this dysfunction is partially reversible following antifilarial treatment.

Albendazole↗
PubMed2006

Effects of concomitant Schistosoma haematobium infection on the serum cytokine levels elicited by acute Plasmodium falciparum malaria infection in Malian children.

Polyparasitism is common in the developing world, and interactions that alter disease severity may occur. We previously demonstrated that infection with Schistosoma hematobium was associated with protection against Plasmodium falciparum infection in children who were 4 to 8 years old. In this study, we determined whether underlying helminth infections affected the cytokine responses to acute falciparum malaria. A total of 338 schistosomiasis-positive [Sch(+)] children who were 4 to 14 years old were matched by age, residence, and sex with 338 schistosomiasis-negative [Sch(-)] children and monitored for a malaria transmission season (25 weeks). Serologic cytokine levels were measured at the time of the first clinical malaria episode and in children who did not contract malaria. Elevated background levels of interleukin-6 (IL-6) (37.1 pg/ml versus 10.9 pg/ml [P = 0.04]), IL-4 (27.7 pg/ml versus 6.9 pg/ml [P = 0.02]), IL-10 (18.2 pg/ml versus 7.2 pg/ml [P < 0.001]), and gamma interferon (18.2 pg/ml versus 4.7 pg/ml [P = 0.006]) were noted in Sch(+) children compared to Sch(-) children without malaria. IL-6 and IL-10 levels were elevated in association with acute malaria, but the levels appeared to be blunted in Sch(+) children compared to Sch(-) children who were 4 to 8 years old (for IL-6, 96.2 pg/ml versus 137.2 pg/ml [P = 0.08]; for IL-10, 195.9 pg/ml versus 282.2 pg/ml [P = 0.06]). The level of IL-10 was similarly lower in Sch(+) children than in Sch(-) children who were 9 to 14 years old (91.2 pg/ml versus 141.2 pg/ml [P = 0.03]). IL-4 levels were inversely correlated with the time until the first malaria infection in both the Sch(+) children (P < 0.001) and the Sch(-) children (P < 0.001) who were 4 to 8 years old. We postulate that the Th2-enriched environment induced by schistosomiasis protects against malaria and alters the cytokine milieu during an actual infection.

Acute Disease↗
PubMed2006

Low multiplication rates of African Plasmodium falciparum isolates and lack of association of multiplication rate and red blood cell selectivity with malaria virulence.

Two potential malaria virulence factors, parasite multiplication rate (PMR) and red blood cell selectivity (measured as selectivity index [SI]), were assessed in Plasmodium falciparum clinical isolates from Mali and Kenya. At both sites, PMRs were low (Kenya median = 2.2, n = 33; Mali median = 2.6, n = 61) and did not differ significantly between uncomplicated and severe malaria cases. Malian isolates from hyperparasitemic patients had significantly lower PMRs (median = 1.8, n = 19) than other Malian isolates (uncomplicated malaria median = 3.1, n = 23; severe malaria median = 2.8, n = 19; P = 0.03, by Kruskal-Wallis test). Selective invasion occurred at both sites (Kenya geometric mean SI = 1.9, n = 98; Mali geometric mean SI = 1.6, n = 104), and there was no significant association between the SI and malaria severity. Therefore, in contrast to previous results from Thailand, we found no association of PMR and SI with malaria severity in African children. This raises the possibility of differences in the mechanisms of malaria virulence between sub-Saharan Africa and Asia.

Animals↗
PubMed2006

Serum antibody levels to glycosylphosphatidylinositols in specimens derived from matched Malian children with severe or uncomplicated Plasmodium falciparum malaria and healthy controls.

Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum surface protein anchor molecules implicated in malaria pathogenesis, are thought to protect against symptomatic malaria. Index cases of severe malaria in Malian children 3 months to 14 years of age were matched by age and residence to uncomplicated malaria and healthy controls. Serum antibodies to GPI (IgM and IgG) were measured at the time of severe malaria and after the malaria transmission season. The mean optical density values for IgM and IgG antibodies were higher in children with severe or uncomplicated malaria compared with healthy controls. Similarly, higher percentages of children with IgM and IgG antibodies to GPI were observed in the severe malaria group compared with matched healthy controls. IgG antibody levels to GPI were highest among children with cerebral malaria and children who died. The IgG antibody levels to GPI peaked during periods of malaria transmission and decreased after malaria transmission ended. A direct correlation between age and parasitemia and IgG antibodies to GPI was observed. In summary, higher levels of IgM and IgG antibodies to GPI in young children were associated with disease severity and were short-lived.

Adolescent↗
PubMed2006

A randomized trial of artesunate-sulfamethoxypyrazine-pyrimethamine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali.

The choice of artemisinin-based combination that is being adopted for malaria treatment in sub-Saharan Africa may depend on several factors, including cost, efficacy, side effects, and simplicity of administration. We tested the hypothesis that artesunate-sulfamethoxypyrazine-pyrimethamine is as efficacious as the four-dose regimen of artemether-lumefantrine for treatment of Plasmodium falciparum malaria. The study was carried out during two transmission seasons (2003 and 2004) in Sotuba, Mali. Participants at least 6 months of age with uncomplicated P. falciparum malaria were randomly assigned to receive artesunate-sulfamethoxypyrazine-pyrimethamine or artemether-lumefantrine. Treatment efficacy was assessed using the World Health Organization 28-day protocol. A total of 606 (303 in each arm) patients were enrolled. The cure rate was higher for artesunate-sulfamethoxypyrazine-pyrimethamine than for artemether-lumefantrine (98.7% versus 89.6%; P < 0.0001). After correction for cases of re-infection, the cure rates were 100% and 99.0%, respectively (P = 0.08). No serious adverse events occurred. Artesunate-sulfamethoxypyrazine-pyrimethamine is well-tolerated and effective against P. falciparum malaria. It showed an additional benefit of preventing new infections.

Adolescent↗
PubMed2005

Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease.

BACKGROUND: Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for persons living with human immunodeficiency virus infection and acquired immunodeficiency syndrome in Africa. TS and the antimalarial combination sulfadoxine-pyrimethamine (SP) share mechanisms of action and resistance patterns, and concerns about the impact of TS resistance on SP efficacy have contributed to reluctance to implement TS prophylaxis in Africa. METHODS: To determine whether TS prophylaxis impairs SP efficacy for treatment of uncomplicated falciparum malaria, we conducted a randomized, controlled, open-label study of TS prophylaxis. Two hundred and forty children 5-15 years old were randomized in a 2 : 1 fashion to receive either thrice-weekly TS for 12 weeks or no prophylaxis and were treated with SP for subsequent episodes of malaria. The incidence of malaria, SP efficacy, and the prevalence of parasite mutations that confer antifolate drug resistance were measured. RESULTS: TS prophylaxis had a 99.5% protective efficacy against episodes of clinical malaria, with 97% efficacy against infection. Four SP treatment failures occurred in the control group, and none occurred in the TS group. No evidence was seen for selection by TS of antifolate resistance-conferring mutations in parasite dihydrofolate reductase or dihydropteroate synthase during subclinical infections. CONCLUSIONS: In this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites.

Adolescent↗
PubMed2005

Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria.

Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature.

Animals↗
PubMed2005

Community permission for medical research in developing countries.

The realization of the need for community consent, or more accurately community permission, for research has occurred relatively recently. Practical experience with it is scarce. This article describes the Malian experience at a malaria vaccine study site. We describe a process that we used to obtain community permission. The process had 6 steps: (1) a study of the community, (2) an introductory meeting with leaders, (3) formal meetings with leaders, (4) personal visits with leaders, (5) meetings with traditional health practitioners, and (6) recognition that obtaining permission is a dynamic process. We discuss documentation of community permission for research and outline the reasons why the community-level process we used was practically necessary and ethically appropriate. Far from competing with the individual informed consent process, the process of obtaining community permission both initiated and facilitated the process of disclosure for individual informed consent.

Biomedical Research↗
PubMed2005

Familial aggregation of cerebral malaria and severe malarial anemia.

BACKGROUND: The predominant manifestations of severe malaria in African children are cerebral malaria (CM) and severe malarial anemia (SMA). As a first step toward a family-based approach to identify the environmental and genetic pathways that contribute to severe malaria, we tested whether it aggregates within families. METHODS: Family history of severe malaria was explored during face-to-face interviews with parents. Logistic regression was used to determine whether CM and SMA aggregate within individuals and within families. The pattern of familial aggregation was then expressed as familial odds ratios that were adjusted for relevant risk factors. RESULTS: This study was of 2811 inhabitants of Bamako, Mali, clustered in 407 nuclear families. The probands were 136 children with severe malaria and 271 healthy children from the community. Within-person association of CM and SMA was significant (odds ratio, 6.15 [95% confidence interval (CI), 2.62-14.41]). Over a lifetime, with each additional affected relative, the odds of a person contracting CM increased by 1.98 times (95% CI, 1.59-2.45), and the odds of having SMA increased by 1.91 times (95% CI, 1.05-3.47). Over a lifetime, for a child whose sibling had a history of CM, the odds of having CM were 2.49 times greater (95% CI, 1.51-4.10) than the odds for a child whose sibling had no such history; for a child whose sibling had a history of SMA, the odds of having SMA were 4.92 times greater (95% CI, 1.21-19.9) than the odds for a child whose sibling had no such history. CONCLUSION: Our data suggest strong familial aggregation of CM and SMA.

Adolescent↗
PubMed2005

Season, fever prevalence and pyrogenic threshold for malaria disease definition in an endemic area of Mali.

BACKGROUND: Modelling malaria parasitaemia as function of fever has been proposed as best alternative to estimate the attributable fraction of malaria fever and the sensitivity and specificity of different case definitions of malaria disease. OBJECTIVES: To determine the prevalence of fever and its relation to malaria parasitaemia and to establish a pyrogenic threshold for malaria disease in the area. METHODS: We conducted two cross-sectional surveys in children of 6 months to 9 years of age (2434 during the rainy season of 1993 and 2353 during the dry season of 1994) randomly selected from 21 areas of Bandiagara district, Mali. RESULTS: The relationship between fever and Plasmodium falciparum parasitaemia depends strongly on the season, thus affecting the malaria-attributable fraction of fever cases and the sensitivity and specificity of malaria case definitions. The overall proportion of fever attributable to malaria parasitaemia was 33.6% during the rainy season and 23.3% during the dry season, with the highest proportion occurring among the youngest children. The cut-off value, where the sensitivity curve crosses the specificity curve, was around 3200 pf/microl for all age categories during the rainy season and 200 pf/microl during the dry season. CONCLUSIONS: Malaria remains a main cause of fever in this area of Mali. The pyrogenic threshold of parasitaemia depends strongly on the season, and different cut-off levels of parasitaemia should be used during the two seasons to define malaria cases in this area.

Age Distribution↗
PubMed2005

Inverse associations of human leukocyte antigen and malaria parasite types in two West African populations.

Differences in allelic associations between populations continue to cause difficulties in the mapping and identification of susceptibility genes for complex polygenic diseases. Although well recognized, the basis of such interpopulation differences is poorly understood. We present an example of an inverse allelic association of an immune response genotype to an infectious disease in two neighboring West African populations. In this case, both the key environmental contributor, i.e., the malaria parasite, and a major biological mechanism are well defined. We show that this surprising result fits well with the predictions of a mathematical model describing the population genetics and dynamics of this interaction.

Animals↗