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ABSTRACT: Nitric oxide (NO) is highly reactive, produced in endothelial cells by endothelial NO synthase (eNOS) and has been implicated in sickle cell pathophysiology. We evaluated the distribution of functionally significant eNOS variants (the T786C variant in the promoter region, the Glu298Asp variant in exon 7, and the variable number of tandem repeats (VNTR) in intron 4) in Africans, African Americans and Caucasians. The C-786 variant was more common in Caucasians than in Africans and African Americans. Consistent with other findings, the Asp-298 variant had the highest frequency in Caucasians followed by African Americans, but was completely absent in Africans. The very rare intron 4 allele, eNOS 4c, was found in some Africans and African Americans, but not in Caucasians. eNOS 4d allele was present in 2 Africans. These findings suggest a consistent and widespread genomic diversity in the distribution of eNOS variants in Africans, comparative to African Americans and Caucasians.
Gene regulation and systems biology 01/2013; 7:1-10.
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Merepen A Guindo,
Joseph P Shott,
Renion Saye,
Moussa L Diakité,
Sintry Sanogo,
Moussa B Dembele,
Sekouba Keita,
Mary C Nagel,
Ruth D Ellis,
Joan A Aebig, Dapa A Diallo,
Ogobara K Doumbo
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ABSTRACT: Laboratory capacity in the developing world frequently lacks quality management systems (QMS) such as good clinical laboratory practices, proper safety precautions, and adequate facilities; impacting the ability to conduct biomedical research where it is needed most. As the regulatory climate changes globally, higher quality laboratory support is needed to protect study volunteers and to accurately assess biological parameters. The University of Bamako and its partners have undertaken a comprehensive QMS plan to improve quality and productivity using the Clinical and Laboratory Standards Institute standards and guidelines. The clinical laboratory passed the College of American Pathologists inspection in April 2010, and received full accreditation in June 2010. Our efforts to implement high-quality standards have been valuable for evaluating safety and immunogenicity of malaria vaccine candidates in Mali. Other disease-specific research groups in resource-limited settings may benefit by incorporating similar training initiatives, QMS methods, and continual improvement practices to ensure best practices.
The American journal of tropical medicine and hygiene 04/2012; 86(4):573-9. · 2.59 Impact Factor
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ABSTRACT: We examined malaria infection in asymptomatic blood donors from Mali, analyzing allelic diversity of Plasmodium falciparum (Pf) merozoite surface proteins (msp) -1 and -2 as well as the distribution of sulphadoxine-pyrimethamine (SP) resistance genes. A total of 140 genomic DNA samples were screened. Allele-specific nested polymerase chain reaction (PCR) analysis of Pfmsp-1 and Pfmsp-2 was performed, plus fragment analysis of the polymorphic regions to identify allelic diversity of the parasite population. We found parasite positivity due to Pf alone in 20.7% of these donors. Diverse allelic polymorphism of Pfmsp-1 and Pfmsp-2 was identified, with a high rate of multiplicity of infection (1.84 and 1.82 for Pfmsp-1 and Pfmsp-2, respectively). In addition, we found a high degree of SP resistance, with mutations at several dhfr and dhps codons. We conclude that there is an extensive diversity of Pfmsp-1 and Pfmsp-2 allelic types and SP drug resistance in Pf-infected donors from Mali.
Infectious Diseases: Research and Treatment 01/2012; 6:49-57.
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ABSTRACT: Complement receptor one (CR1) is essential for removing circulating immune complexes (CIC), with malaria infection contributing to the formation of large amounts of CIC. We investigated CIC levels in children with malaria, of varying severity and seasonality. Two hundred age and sex-matched severe and mild malaria cases were studied during and after active disease. Pediatric controls had increased CIC levels (mean = 32 μg mEq/mL) compared to adult controls (mean = 26.9 μg mEq/mL). The highest levels of CIC were reported in severe malaria (mean = 39 μg mEq/mL). Higher levels of CIC were recorded in younger children and those with low E-CR1 copy numbers. Our data suggest that low levels of E-CR1 copy numbers, found in children with severe malaria, may adversely affect the ability to remove IC. Furthermore, the high background for circulating immune complex imply that Malian children are under constant assault by other pathogens that evoke a strong immune response.
Biomarker insights 01/2012; 7:81-6.
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Mahamadou A Thera,
Ogobara K Doumbo,
Drissa Coulibaly,
Matthew B Laurens,
Amed Ouattara,
Abdoulaye K Kone,
Ando B Guindo,
Karim Traore,
Idrissa Traore,
Bourema Kouriba, [......],
Joe Cohen,
Darby Thompson,
Tina Dube,
Lorraine Soisson,
Carter L Diggs,
Brent House,
David E Lanar,
Sheetij Dutta,
D Gray Heppner,
Christopher V Plowe
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ABSTRACT: Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children.
In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain.
The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine.
On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00460525.).
New England Journal of Medicine 09/2011; 365(11):1004-13. · 53.30 Impact Factor
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ABSTRACT: Breast cancer is the second most frequent cancer in Sub-Saharan African women with an incidence of 15-53 per 100,000 women. Using PubMed, we reviewed all the articles published on this topic between 1989 and 2009. Breast cancer is usually diagnosed in women younger than in developed countries (mean age: 42-53 years), with later stages (III or IV, i.e. with axillary nodes and distant metastases). Reported tumors are mostly invasive ductal carcinomas with aggressive characteristics: grade III histoprognosis, absence of hormonal receptors or HER2 expression. According to the new breast cancer classification, nearly half of these tumors should be classified as triple negative. However, studies are rare and require confirmation. In conclusion, data on epidemiology and biology of breast cancer in Sub-Saharan African women are still scarce and need more extensive studies. In these countries, the pattern of breast cancer will likely change in the future, according to the evolution of lifestyle namely urbanisation. There is a great need for commitment of research and clinical resources in Sub-Saharan Africa in order to develop specific strategies.
Bulletin du cancer 06/2011; 98(7):797-806. · 0.67 Impact Factor
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ABSTRACT: We investigated PfCRT 76T mutation in severe and non-severe malaria in Southern Mali. One hundred and ninety three severe malaria cases were each matched against two non-severe malaria cases. Patients with G6PD deficiency and any known hemoglobin abnormality were excluded. PfCRT 76T was present in 60.8% (n=386) non-severe malaria cases and in 77.2% (n=193) severe malaria cases (p<0.0001). In children 5 years or younger, these proportions were 62.9% (n=294) vs. 73.5% (n=147), respectively (p<0.01). PfCRT 76T was therefore associated with malaria severity in this setting of Mali.
Acta tropica 02/2011; 119(1):11-3. · 2.22 Impact Factor
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Ruth D Ellis,
Issaka Sagara,
Anna Durbin,
Alassane Dicko,
Donna Shaffer,
Louis Miller,
Mahamadoun H Assadou,
Mamady Kone,
Beh Kamate,
Ousmane Guindo,
Michael P Fay, Dapa A Diallo,
Ogobara K Doumbo,
Ezekiel J Emanuel,
Joseph Millum
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ABSTRACT: Initial responses to questionnaires used to assess participants' understanding of informed consent for malaria vaccine trials conducted in the United States and Mali were tallied. Total scores were analyzed by age, sex, literacy (if known), and location. Ninety-two percent (92%) of answers by United States participants and 85% of answers by Malian participants were correct. Questions more likely to be answered incorrectly in Mali related to risk, and to the type of vaccine. For adult participants, independent predictors of higher scores were younger age and female sex in the United States, and male sex in Mali. Scores in the United States were higher than in Mali (P = 0.005). Despite this difference participants at both sites were well informed overall. Although interpretation must be qualified because questionnaires were not intended as research tools and were not standardized among sites, these results do not support concerns about systematic low understanding among research participants in developing versus developed countries.
The American journal of tropical medicine and hygiene 10/2010; 83(4):868-72. · 2.59 Impact Factor
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Mahamadou A Thera,
Ogobara K Doumbo,
Drissa Coulibaly,
Matthew B Laurens,
Abdoulaye K Kone,
Ando B Guindo,
Karim Traore,
Mady Sissoko, Dapa A Diallo,
Issa Diarra, [......],
Tina Dube,
Lorraine Soisson,
Carter L Diggs,
Shannon L Takala,
Kirsten E Lyke,
Brent House,
David E Lanar,
Sheetij Dutta,
D Gray Heppner,
Christopher V Plowe
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ABSTRACT: The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02(A) in children exposed to seasonal falciparum malaria.
A Phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02(A) is a recombinant protein (FMP2.1) based on apical membrane antigen 1 (AMA1) from the 3D7 clone of P. falciparum, formulated in the Adjuvant System AS02(A). The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). One hundred healthy Malian children aged 1-6 years were recruited into 3 cohorts and randomized to receive either 10 microg FMP2.1 in 0.1 mL AS02(A), or 25 microg FMP2.1 in 0.25 mL AS02(A), or 50 microg FMP2.1 50 microg in 0.5 mL AS02(A), or rabies vaccine. Three doses of vaccine were given at 0, 1 and 2 months, and children were followed for 1 year. Solicited symptoms were assessed for 7 days and unsolicited symptoms for 30 days after each vaccination. Serious adverse events were assessed throughout the study. Transient local pain and swelling were common and more frequent in all malaria vaccine dosage groups than in the comparator group, but were acceptable to parents of participants. Levels of anti-AMA1 antibodies measured by ELISA increased significantly (at least 100-fold compared to baseline) in all 3 malaria vaccine groups, and remained high during the year of follow up.
The FMP2.1/AS02(A) vaccine had a good safety profile, was well-tolerated, and induced high and sustained antibody levels in malaria-exposed children. This malaria vaccine is being evaluated in a Phase 2 efficacy trial in children at this site.
ClinicalTrials.gov NCT00358332 [NCT00358332].
PLoS ONE 01/2010; 5(2):e9041. · 4.09 Impact Factor
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Yaya I Coulibaly,
Benoit Dembele,
Abdallah A Diallo,
Ettie M Lipner,
Salif S Doumbia,
Siaka Y Coulibaly,
Siaka Konate, Dapa A Diallo,
Daniel Yalcouye,
Joseph Kubofcik,
Ogobara K Doumbo,
Abdel K Traore,
Adama D Keita,
Michael P Fay,
Sekou F Traore,
Thomas B Nutman,
Amy D Klion
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ABSTRACT: Mansonella perstans infection is common in areas of Africa where Wuchereria bancrofti, a causative agent of lymphatic filariasis, is endemic. M. perstans is refractory to standard antifilarial therapies. The recent discovery of bacterial endosymbionts (e.g., wolbachia) in most filarial species, including M. perstans, provides new therapeutic options for reducing microfilaremia.
In an open-label, randomized trial, we recruited subjects with M. perstans microfilaremia, with or without concomitant W. bancrofti infection, from four villages in Mali and randomly assigned them to receive doxycycline, at a dose of 200 mg daily for 6 weeks (106 subjects), or no treatment (110). At 6 months, subjects who were coinfected with W. bancrofti underwent a second random assignment, to treatment with a single dose of albendazole (400 mg) and ivermectin (150 microg per kilogram of body weight) or no treatment. Subjects were monitored daily during the first 6-week study period for adverse events. M. perstans and W. bancrofti microfilarial levels were assessed at 6, 12, and 36 months.
At 12 months, 67 of 69 subjects who had received treatment with doxycycline only (97%) had no detectable M. perstans microfilariae per 60 microl of blood, as compared with 10 of 63 subjects who had received no treatment (16%) (relative risk, 6.18; 95% confidence interval, 3.63 to 11.89; P<0.001). At 36 months, M. perstans microfilaremia remained suppressed in 48 of 64 subjects who had received treatment with doxycycline only (75%), a finding that was consistent with a macrofilaricidal effect of doxycycline. Vomiting was more frequent in the doxycycline-treated group than in the untreated group (17% vs. 4%).
These results are consistent with previous findings that M. perstans harbors the intracellular endosymbiont, wolbachia, and suggest that doxycycline is an effective therapy for M. perstans infection. (ClinicalTrials.gov number, NCT00340691.)
New England Journal of Medicine 10/2009; 361(15):1448-58. · 53.30 Impact Factor
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Issaka Sagara,
Ruth D Ellis,
Alassane Dicko,
Mohamed B Niambele,
Beh Kamate,
Ousmane Guindo,
Mahamadou S Sissoko,
Michael P Fay,
Merepen A Guindo,
Ousmane Kante, [......],
Kazutoyo Miura,
Carole Long,
Gregory E D Mullen,
Mark Pierce,
Laura B Martin,
Kelly Rausch,
Amagana Dolo, Dapa A Diallo,
Louis H Miller,
Ogobara K Doumbo
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ABSTRACT: A double blind, randomized and controlled Phase 1 clinical trial was conducted to assess the safety and immunogenicity in malaria-exposed adults of the Plasmodium falciparum blood stage vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with and without the novel adjuvant CPG 7909. Participants were healthy adults 18-45 years old living in the village of Donéguébougou, Mali. A total of 24 participants received 2 doses one month apart of either 80 microg AMA1-C1/Alhydrogel or 80 microg AMA1-C1/Alhydrogel + 564 microg CPG 7909. The study started in October 2007 and completed follow up in May 2008. Both vaccines were well tolerated, with only mild local adverse events and no systemic adverse events judged related to vaccination. The difference in antibody responses were over 2-fold higher in the group receiving CPG 7909 for all time points after second vaccination and the differences are statistically significant (all p<0.05). This is the first use of the novel adjuvant CPG 7909 in a malaria-exposed population.
Vaccine 10/2009; 27(52):7292-8. · 3.77 Impact Factor
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Issaka Sagara,
Alassane Dicko,
Ruth D Ellis,
Michael P Fay,
Sory I Diawara,
Mahamadoun H Assadou,
Mahamadou S Sissoko,
Mamady Kone,
Abdoulbaki I Diallo,
Renion Saye, [......],
Mohamed B Niambele,
Kazutoyo Miura,
Gregory E D Mullen,
Mark Pierce,
Laura B Martin,
Amagana Dolo, Dapa A Diallo,
Ogobara K Doumbo,
Louis H Miller,
Allan Saul
[show abstract]
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ABSTRACT: A double blind, randomized, controlled Phase 2 clinical trial was conducted to assess the safety, immunogenicity, and biologic impact of the vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1), adjuvanted with Alhydrogel. Participants were healthy children 2-3 years old living in or near the village of Bancoumana, Mali. A total of 300 children received either the study vaccine or the comparator. No impact of vaccination was seen on the primary endpoint, the frequency of parasitemia measured as episodes >3000/microL/day at risk. There was a negative impact of vaccination on the hemoglobin level during clinical malaria, and mean incidence of hemoglobin <8.5 g/dL, in the direction of lower hemoglobin in the children who received AMA1-C1, although these differences were not significant after correction for multiple tests. These differences were not seen in the second year of transmission.
Vaccine 06/2009; 27(23):3090-8. · 3.77 Impact Factor
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Mahamadou A Thera,
Ogobara K Doumbo,
Drissa Coulibaly, Dapa A Diallo,
Abdoulaye K Kone,
Ando B Guindo,
Karim Traore,
Alassane Dicko,
Issaka Sagara,
Mahamadou S Sissoko, [......],
Carter L Diggs,
Amanda Leach,
Alex Owusu,
Marie-Claude Dubois,
Joe Cohen,
Jason N Nixon,
Aric Gregson,
Shannon L Takala,
Kirsten E Lyke,
Christopher V Plowe
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ABSTRACT: The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria.
A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen-1 (AMA-1) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). Sixty healthy, malaria-experienced adults aged 18-55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 microg/AS02A 0.25 mL or FMP2.1 50 microg/AS02A 0.5 mL) or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively.
The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site.
PLoS ONE 02/2008; 3(1):e1465. · 4.09 Impact Factor
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Alassane Dicko,
Issaka Sagara,
Ruth D Ellis,
Kazutoyo Miura,
Ousmane Guindo,
Beh Kamate,
Moussa Sogoba,
Mohamed Balla Niambelé,
Mady Sissoko,
Mounirou Baby,
Amagana Dolo,
Gregory E D Mullen,
Michael P Fay,
Mark Pierce, Dapa A Diallo,
Allan Saul,
Louis H Miller,
Ogobara K Doumbo
[show abstract]
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ABSTRACT: Apical Membrane Antigen-1 (AMA1) is one of the leading blood stage malaria vaccine candidates. AMA1-C1/Alhydrogel consists of an equal mixture of recombinant AMA1 from FVO and 3D7 clones of P. falciparum, adsorbed onto Alhydrogel. A Phase 1 study in semi-immune adults in Mali showed that the vaccine was safe and immunogenic, with higher antibody responses in those who received the 80 microg dose. The aim of this study was to assess the safety and immunogenicity of this vaccine in young children in a malaria endemic area.
This was a Phase 1 dose escalating study in 36 healthy children aged 2-3 years started in March 2006 in Donéguébougou, Mali. Eighteen children in the first cohort were randomized 2 ratio 1 to receive either 20 microg AMA1-C1/Alhydrogel or Haemophilus influenzae type b Hiberix vaccine. Two weeks later 18 children in the second cohort were randomized 2 ratio 1 to receive either 80 microg AMA1-C1/Alhydrogel or Haemophilus influenzae type b Hiberix vaccine. Vaccinations were administered on Days 0 and 28 and participants were examined on Days 1, 2, 3, 7, and 14 after vaccination and then about every two months. Results to Day 154 are reported in this manuscript.
Of 36 volunteers enrolled, 33 received both vaccinations. There were 9 adverse events related to the vaccination in subjects who received AMA1-C1 vaccine and 7 in those who received Hiberix. All were mild to moderate. No vaccine-related serious or grade 3 adverse events were observed. There was no increase in adverse events with increasing dose of vaccine or number of immunizations. In subjects who received the test vaccine, antibodies to AMA1 increased on Day 14 and peaked at Day 42, with changes from baseline significantly different from subjects who received control vaccine.
AMA-C1 vaccine is well tolerated and immunogenic in children in this endemic area although the antibody response was short lived.
Clinicaltrials.gov NCT00341250.
PLoS ONE 02/2008; 3(2):e1563. · 4.09 Impact Factor
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Rushina Cholera,
Nathaniel J Brittain,
Mark R Gillrie,
Tatiana M Lopera-Mesa,
Séidina A S Diakité,
Takayuki Arie,
Michael A Krause,
Aldiouma Guindo,
Abby Tubman,
Hisashi Fujioka, Dapa A Diallo,
Ogobara K Doumbo,
May Ho,
Thomas E Wellems,
Rick M Fairhurst
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ABSTRACT: Sickle trait, the heterozygous state of normal hemoglobin A (HbA) and sickle hemoglobin S (HbS), confers protection against malaria in Africa. AS children infected with Plasmodium falciparum are less likely than AA children to suffer the symptoms or severe manifestations of malaria, and they often carry lower parasite densities than AA children. The mechanisms by which sickle trait might confer such malaria protection remain unclear. We have compared the cytoadherence properties of parasitized AS and AA erythrocytes, because it is by these properties that parasitized erythrocytes can sequester in postcapillary microvessels of critical tissues such as the brain and cause the life-threatening complications of malaria. Our results show that the binding of parasitized AS erythrocytes to microvascular endothelial cells and blood monocytes is significantly reduced relative to the binding of parasitized AA erythrocytes. Reduced binding correlates with the altered display of P. falciparum erythrocyte membrane protein-1 (PfEMP-1), the parasite's major cytoadherence ligand and virulence factor on the erythrocyte surface. These findings identify a mechanism of protection for HbS that has features in common with that of hemoglobin C (HbC). Coinherited hemoglobin polymorphisms and naturally acquired antibodies to PfEMP-1 may influence the degree of malaria protection in AS children by further weakening cytoadherence interactions.
Proceedings of the National Academy of Sciences 02/2008; 105(3):991-6. · 9.68 Impact Factor
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Alassane Dicko,
Issaka Sagara,
David Diemert,
Moussa Sogoba,
Mohamed B Niambele,
Adama Dao,
Guimogo Dolo,
Daniel Yalcouye, Dapa A Diallo,
Allan Saul,
Louis H Miller,
Yeya T Toure,
Amy D Klion,
Ogobara K Doumbo
[show abstract]
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ABSTRACT: To explore the feasibility of field sites for malaria vaccine trials, we conducted a prospective study of clinical malaria incidence during two consecutive transmission seasons in children and young adults living in two areas of Mali with different entomologic inoculation rates (EIRs). Approximately 200 subjects (3 months to 2 years of age) were enrolled per site and followed weekly. Malaria smears were performed monthly in all participants and when symptoms or signs of malaria were present. In Sotuba (annual EIR < 15 infective bites per person), the incidence of clinical malaria was comparable across all age groups but varied significantly between the 2 years. In contrast, in Donéguébougou (annual EIR > 100 infective bites per person), incidence rates decreased significantly with increasing age but remained stable between years. Our results suggest that, although the age distribution of clinical malaria depends on transmission intensity, the total burden of disease may be similar or higher in settings of low transmission.
The American journal of tropical medicine and hygiene 12/2007; 77(6):1028-33. · 2.59 Impact Factor
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J Alexandra Rowe,
Ian G Handel,
Mahamadou A Thera,
Anne-Marie Deans,
Kirsten E Lyke,
Abdoulaye Koné, Dapa A Diallo,
Ahmed Raza,
Oscar Kai,
Kevin Marsh,
Christopher V Plowe,
Ogobara K Doumbo,
Joann M Moulds
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ABSTRACT: Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe malaria, is reduced in blood group O erythrocytes compared with groups A, B, and AB, but the contribution of the ABO blood group system to protection against severe malaria has received little attention. We hypothesized that blood group O may confer resistance to severe falciparum malaria through the mechanism of reduced rosetting. In a matched case-control study of 567 Malian children, we found that group O was present in only 21% of severe malaria cases compared with 44-45% of uncomplicated malaria controls and healthy controls. Group O was associated with a 66% reduction in the odds of developing severe malaria compared with the non-O blood groups (odds ratio 0.34, 95% confidence interval 0.19-0.61, P < 0.0005, severe cases versus uncomplicated malaria controls). In the same sample set, P. falciparum rosetting was reduced in parasite isolates from group O children compared with isolates from the non-O blood groups (P = 0.003, Kruskal-Wallis test). Statistical analysis indicated a significant interaction between host ABO blood group and parasite rosette frequency that supports the hypothesis that the protective effect of group O operates through the mechanism of reduced P. falciparum rosetting. This work provides insights into malaria pathogenesis and suggests that the selective pressure imposed by malaria may contribute to the variable global distribution of ABO blood groups in the human population.
Proceedings of the National Academy of Sciences 10/2007; 104(44):17471-6. · 9.68 Impact Factor
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[show abstract]
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ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection.
We conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies.
The A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these conclusions are consistent with data from at least one previous study, they have not heretofore been realized to our knowledge, and they therefore give fresh perspectives on malaria protection by G6PD deficiency as an X-linked trait.
PLoS Medicine 04/2007; 4(3):e66. · 16.27 Impact Factor
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Shannon L Takala,
Drissa Coulibaly,
Mahamadou A Thera,
Alassane Dicko,
David L Smith,
Ando B Guindo,
Abdoulaye K Kone,
Karim Traore,
Amed Ouattara,
Abdoulaye A Djimde,
Paul S Sehdev,
Kirsten E Lyke, Dapa A Diallo,
Ogobara K Doumbo,
Christopher V Plowe
[show abstract]
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ABSTRACT: Malaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-1(19)) derived from the 3D7 strain of Plasmodium falciparum are being tested in clinical trials in Africa. Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection.
Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-1(19) were genotyped from 1,363 malaria infections experienced by 100 children who participated in a prospective cohort study in Mali from 1999 to 2001. The frequencies of 14 MSP-1(19) haplotypes were compared over the course of the malaria transmission season for all three years, in three age groups, and in consecutive infections within individuals. While the frequency of individual MSP-1(19) haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-1(19) haplotypes QKSNGL and EKSNGL, respectively) were most prevalent during three consecutive years and in all age groups with overall prevalences of 46% (95% confidence interval [CI] 44%-49%) and 36% (95% CI 34%-39%), respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%-18%). Multiplicity of infection based on MSP-1(19) was higher at the beginning of the transmission season and in the oldest individuals (aged > or =11 y). Three MSP-1(19) haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-1(19) polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701) as being particularly important in determining allele specificity of anti-MSP-1(19) immunity.
Parasites with MSP-1(19) haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial site. If immunity elicited by an MSP-1-based vaccine is allele-specific, a vaccine based on either the FVO or FUP strain might have better initial efficacy at this site. This study, to our knowledge the largest of its kind to date, provides molecular information needed to interpret population responses to MSP-1-based vaccines and suggests that certain MSP-1(19) polymorphisms may be relevant to cross-protective immunity.
PLoS Medicine 03/2007; 4(3):e93. · 16.27 Impact Factor
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Alassane Dicko,
David J Diemert,
Issaka Sagara,
Moussa Sogoba,
Mohamed B Niambele,
Mahamadoun H Assadou,
Ousmane Guindo,
Beh Kamate,
Mounirou Baby,
Mady Sissoko, [......],
Michael P Fay,
Mahamadou A Thera,
Kazutoyo Miura,
Amagana Dolo, Dapa A Diallo,
Gregory E Mullen,
Carole A Long,
Allan Saul,
Ogobara Doumbo,
Louis H Miller
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ABSTRACT: Apical Membrane Antigen 1 (AMA1) of Plasmodium falciparum merozoites is a leading blood-stage malaria vaccine candidate. Protection of Aotus monkeys after vaccination with AMA1 correlates with antibody responses. STUDY DESIGN/RESULTS: A randomized, controlled, double-blind phase 1 clinical trial was conducted in 54 healthy Malian adults living in an area of intense seasonal malaria transmission to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of yeast-expressed recombinant proteins based on sequences from the FVO and 3D7 clones of P. falciparum, adsorbed on Alhydrogel. The control vaccine was the hepatitis B vaccine (Recombivax). Participants were enrolled into 1 of 3 dose cohorts (n = 18 per cohort) and randomized 2:1 to receive either AMA1-C1 or Recombivax. Participants in the first, second, and third cohorts randomized to receive AMA1-C1 were vaccinated with 5, 20 and 80 microg of AMA1-C1, respectively. Vaccinations were administered on days 0, 28, and 360, and participants were followed until 6 months after the final vaccination. AMA1-C1 was well tolerated; no vaccine-related severe or serious adverse events were observed. AMA1 antibody responses to the 80 microg dose increased rapidly from baseline levels by days 14 and 28 after the first vaccination and continued to increase after the second vaccination. After a peak 14 days following the second vaccination, antibody levels decreased to baseline levels one year later at the time of the third vaccination that induced little or no increase in antibody levels.
Although the AMA1-C1 vaccine candidate was well-tolerated and induced antibody responses to both vaccine and non-vaccine alleles, the antibody response after a third dose given at one year was lower than the response to the initial vaccinations. Additionally, post-vaccination increases in anti-AMA1 antibody levels were not associated with significant changes in in vitro growth inhibition of P. falciparum.
ClinicalTrials.gov NCT00343005.
PLoS ONE 02/2007; 2(10):e1045. · 4.09 Impact Factor
