The path of malaria vaccine development: challenges and perspectives.

Malaria is a life-threatening disease caused by parasites of the Plasmodium genus. In many parts of the world, the parasites have developed resistance to a number of antimalarial agents. Key interventions to control malaria include prompt and effective treatment with artemisinin-based combination therapies, use of insecticidal nets by individuals at risk and active research into malaria vaccines. Protection against malaria through vaccination was demonstrated more than 30 years ago when individuals were vaccinated via repeated bites by Plasmodium falciparum-infected and irradiated but still metabolically active mosquitoes. However, vaccination with high doses of irradiated sporozoites injected into humans has long been considered impractical. Yet, following recent success using whole-organism vaccines, the approach has received renewed interest; it was recently reported that repeated injections of irradiated sporozoites increased protection in 80 vaccinated individuals. Other approaches include subunit malaria vaccines, such as the current leading candidate RTS,S (consisting of fusion between a portion of the P. falciparum-derived circumsporozoite protein and the hepatitis B surface antigen), which has been demonstrated to induce reasonably good protection. Although results have been encouraging, the level of protection is generally considered to be too low to achieve eradication of malaria. There is great interest in developing new and better formulations and stable delivery systems to improve immunogenicity. In this review, we will discuss recent strategies to develop efficient malaria vaccines.

[Place of malaria among febrile illnesses in two ethnic tribes living in sympatry in Mali from 1998 to 2008]. / Place du paludisme dans les syndromes fébriles dans deux groupes ethniques vivant en sympatrie au Mali de 1998 à 2008.

In Africa, malaria is responsible for 25-40% of all outpatient visits and 20-50% of all hospitalizations. In malaria-endemic areas, individuals do not behave the same toward the outcome of clinical malaria. The aim of this study is to determine the prevalence of malaria in the locality among the different ethnic groups, evaluate the place of malaria among febrile illnesses, and assess the relationship between fever and parasite density of Plasmodium falciparum. Studies on susceptibility to malaria between the Fulani and Dogon groups in Mali were conducted in Mantéourou and the surrounding villages from 1998 to 2008. We carried out six cross-sectional studies during the malaria transmission and longitudinal surveys (July to December depending on the year) during the 10-year duration. In longitudinal studies, clinical data on malaria and other diseases frequently observed in the population were recorded. It appears from this work that malaria is the leading cause of febrile syndromes. We observed a significant reduction in malaria morbidity in the study population from 1998 to 2008. The pyrogenic threshold of parasitaemia was 1,000 parasites/mm(3) of blood in the Dogon and 5,000 parasites/mm(3) of blood in the Fulani.We have also found that high parasitical densities were not always associated with fever. Malaria morbidity was higher among the Dogon than in Fulani. The immunogenetic factors might account for this difference in susceptibility to malaria between Fulani and Dogon in the area under study. With regard to this study, it is important to take into account the ethnic origin of subjects when interpreting data of clinical and malarial vaccine trials.

[Humoral immune anti-Plasmodium falciparum AMA1 and MSP1 response in two ethnic groups living in sympatry in Mali]. / Réponse humorale anti-Plasmodium falciparum AMA1 et MSP1 dans deux groupes ethniques vivant en sympatrie au Mali.

Fulani of Mali are known for their lower susceptibility to Plasmodium falciparum malaria than their neighbours, the Dogon, despite similar transmission conditions. However, the mechanisms underlying these differences are poorly understood, particularly those concerning antigenspecific immune responses. The Apical Membrane Antigen 1 (AMA1) and the Merozoite Surface Antigen 1 (MSP1) are two malaria vaccine candidates, which play a pivotal role during the invasion of parasites into erythrocytes, and in the case of AMA1, of hepatocytes. Therefore, we analyzed the level of anti-AMA1 and anti-MSP1 antibodies (FVO and 3D7 alleles), by using ELISA (Enzyme Linked Immuno Sorbent Assay) to investigate whether there are differences between the two ethnic groups. Our results show that the splenic rate, the level of anti-AMA1 and anti-MSP1 were significantly higher in Fulani compared to Dogon; while the parasite rate was lower in Fulani group compared to Dogon. Our results suggest that the lower susceptibility of Fulani to malaria could be due to the higher specific humoral responses against AMA1 and MSP 1 in Fulani's ethnic group compared to Dogon.

[Relationship between malaria and anemia in two ethnic groups living in sympatry in Mali]. / Relation entre l'anémie et le paludisme dans deux groupes ethniques vivant en sympatrie au Mali.

Studies performed in Burkina Faso and Mali showed differences in susceptibility to malaria between the Fulani and other sympatric ethnic groups, the Mossi and Dogon. We carried out a longitudinal survey and three cross-sectional studies from 2003 to 2005 in order to assess the prevalence of anemia in Dogon and Fulani. The distribution of the study population by sex was comparable between the two ethnic groups (p = ns). The Fulani are mainly cattle breeders and the Dogons, farmers. They were exposed to similar entomological inoculation rates, and studies on "knowledge, attitude, and practices" showed no difference between the two ethnic groups. The cross-sectional studies were performed during the intense malaria transmission season (in September 2003 and 2005) and during the dry season (in March 2004). Longitudinal clinical follow-up studies were performed from August to December 2005 using the WHO 28 days in vivo test, after administration of a curative dose of antimalarial drugs to patients with mild malaria. During the cross-sectional studies, both Fulani men and women had significantly lower hemoglobin levels than their Dogon counterparts; this difference was most evident in the women (in 2005: 9.4 g/dl in Fulani vs 10.7 g/dl in Dogon, p = 0.0002). Clinical longitudinal follow-up data showed that Fulani children aged 10-14 years have lower hemoglobin levels than Dogon children. At day 0, the mean of hemoglobin level was 9.6 g/dl in Dogon children vs. 8.7 g/dl in Fulani children (p = 0.01). At day 28, after malaria treatment, we also observed a significant difference in hemoglobin levels in children (10.6 g/dl in Dogon vs 9.3 g/dl in Fulani, p < 0.001). A stronger association between anemia and spleen enlargement was found in the Fulani (53.2% with spleen enlargement) than in the Dogon (32.9%) [p = 0.005]. The Fulani suffer more from anemia than the Dogon, despite their lower susceptibility to malaria. The difference in anemia between Dogon and Fulani must be further investigated to determine possible factors involved in malaria susceptibility.

Spleen enlargement and genetic diversity of Plasmodium falciparum infection in two ethnic groups with different malaria susceptibility in Mali, West Africa.

The high resistance to malaria in the nomadic Fulani population needs further understanding. The ability to cope with multiclonal Plasmodium falciparum infections was assessed in a cross-sectional survey in the Fulani and the Dogon, their sympatric ethnic group in Mali. The Fulani had lower parasite prevalence and densities and more prominent spleen enlargement. Spleen rates in children aged 2-9 years were 75% in the Fulani and 44% in the Dogon (P<0.001). There was no difference in number of P. falciparum genotypes, defined by merozoite surface protein 2 polymorphism, with mean values of 2.25 and 2.11 (P=0.503) in the Dogon and Fulani, respectively. Spleen rate increased with parasite prevalence, density and number of co-infecting clones in asymptomatic Dogon. Moreover, splenomegaly was increased in individuals with clinical malaria in the Dogon, odds ratio 3.67 (95% CI 1.65-8.15, P=0.003), but not found in the Fulani, 1.36 (95% CI 0.53-3.48, P=0.633). The more susceptible Dogon population thus appear to respond with pronounced spleen enlargement to asymptomatic multiclonal infections and acute disease whereas the Fulani have generally enlarged spleens already functional for protection. The results emphasize the importance of spleen function in protective immunity to the polymorphic malaria parasite.

[Frequency of glucose-6-phosphate dehydrogenase deficiency (A-376/202) in three Malian ethnic groups]. / Fréquence du déficit en glucose-6-phosphate déshydrogénase (A-376/202) dans trois groupes ethniques vivant en zone d'endémie palustre au Mali.

Erythrocyte G6PD deficiency is the most common worldwide enzymopathy. The aim of this study was to determine erythrocyte G6PD deficiency in 3 ethnic groups of Mali and to investigate whether erythrocyte G6PD deficiency was associated to the observed protection against malaria seen in Fulani ethnic group. The study was conducted in two different areas of Mali: in the Sahel region of Mopti where Fulani and Dogon live as sympatric ethnic groups and in the Sudanese savannah area where lives mostly the Malinke ethnic group. The study was conducted in 2007 in Koro and in 2008 in Naguilabougou. It included a total 90 Dogon, 42 Fulani and 80 Malinke ethnic groups. Malaria was diagnosed using microscopic examination after Giemsa-staining of thick and thin blood smear. G6PD deficiency (A-(376/202)) samples were identified using RFLP (Restriction Fragment Length Polymorphism) assay and analysis of PCR-amplified DNA amplicon. G6PD deficiency (A-(376/202)) rate was 11.1%, 2.4%, and 13.3% in Dogon, Fulani, and Malinke ethnic group respectively. Heterozygous state for G6PD (A-(376/202)) was found in 7.8% in Dogon; 2.4% in Fulani and 9.3% in Malinke ethnic groups while hemizygous state was found at the frequency of 2.2% in Dogon and 4% in Malinke. No homozygous state was found in our study population.We conclude that G6PD deficiency is not differing significantly between the three ethnic groups, Fulani, Dogon and Malinke.

[Study of the quality of life of hemodialysis patients at the University Hospital of Point G (CHU) in Bamako- the study of 30 cases]. / Etude de la qualite de vie des malades hemodialyses au CHU du Point G a Bamako (a propos de 30 observations).

AIMS: To assess the social and psychological state development of our patients six months after their dialysis treatment. PATIENTS AND METHODS: It was about a prospective study within January to June 2006. The data collection was conducted on personal search records and a questionnaire "Choice Health Experience Questionnaire" (CHEQ). The CHEQ self managed assessed the mental health, the physical health, the sexual and social functioning, the concept of sleeping disorders, familial life, leisure's and education's level. The typing was done on Epi Info 6,0 and the analyse on SPSS10. RESULTS: They where 20 men and 10 women or a ratio sex of 2. The average age was 40.36 years ±13.08. Twenty three patients (76.7%) were satisfied of their life in general. Four patients (13.3%) were depressed, two had sleeping disorders. Fifteen men (75%) had erection disorders. CONCLUSION: Our patients' quality of life in iterative haemodialysis remains satisfactory. A better care taking of the anaemia is necessary because it plays an important role in the erection disorders.

[Tuberculosis in chronic hemodialysis patients at the Teaching Hospital of Point G (CHU) in Bamako]. / La tuberculose chez les hemodialyses chroniques au CHU du Point G a Bamako (a propos de 10 observations).

AIMS: To determine the frequency and the diagnostic difficulties of tuberculosis of haemodialysis patients. PATIENTS AND METHODS: The study was about a retrospective analyse of patients haemodialysis records treated for tuberculosis within January 2003 to April 2006. The tuberculosis check-up contained a questioning, a meticulous clinic examination, thorax radiography, a tuberculosis intra dermoreaction (IDR) and the search of Koch Bacillus (BK) in biological liquids. RESULTS: Tuberculosis was identified to 15.52% of haemodialysis patients (10/95). The average age of our patients was from 44.3 years, with a ratio sex of 2.5 in favour of men. Tuberculosis infection happened on average 27.4 months after the beginning of the haemodialysis. We found out 50% of extra pulmonary tuberculosis (three peritoneales and two pleurales); and 50% of pulmonary tuberculosis. The IDR was positive in two cases (2/6). The search of BK didn't succeed. We reported three deaths. CONCLUSION: The effect of tuberculosis to chronic haemodialysis patients is very high. The diagnostic is sometimes difficult and is based only on specific therapeutic test.

[Clinical aspects, paraclinics and therapeutics of uro-genital tuberculosis]. / Tuberculose uro-genitale a Bamako. Aspects cliniques, paracliniques et therapeutiques.

OBJECTIVE: To specify the clinical, paraclinic and therapeutic aspects of urogenital tuberculosis in the services of Urology and Nephrology of the CHU of the Point G. PATIENTS AND METHODS: From January 2005 to November 2006, six patients reached of urogenital tuberculosis were seen. The initial evaluation comprised an interrogation in the search of antecedents of urinary extra tuberculosis, a creatinemy, a urogenital echography and an intravenous urography. The research of the bacillus of Koch in the urines was made. A bacteriological examination cyto- of urines (ECBU) was carried out as well as the histological analysis of the fragment S biological and/or the part of exérèse. RESULTS: The incidence of urogenital tuberculosis was 0.3%. compared to the consulted patients. The principal clinical demonstrations were the lumbar pain (83.33%), the hématurie (33.33%), the pollakiurie (33.33%) and the burns mictionnell be (16.67%). 50% of the patients presented a fever and 33.33% an asthenia. Three (50%) were presented with a renal insufficiency (average creatinemy: 866.7 micromol/l). The bacilluria was present in 50% of the cases. Echography had shown anomalies in 100% of the cases of which most frequent was the urétéro hydronéphrose (2 cases, are 33.33%). The positive diagnosis was related to the bacteriological data (3 times) and histological (3 times). The treatment consisted of a bacillar anti chemotherapy among all patients in association with the surgery (4 cases) and/or of the endo-urologic operations (1 case). CONCLUSION: The diagnosis of urogenital tuberculosis remains difficult and often late in our context. A surgical or endo-urologic gesture is often necessary to preserve the renal function and to improve the quality of life.

La tuberculose chez les hemodialyses chroniques au CHU du Point G a Bamako (a propos de 10 observations)

Objectif : determiner la frequence et les difficultes du diagnostic de la tuberculose chez les patients Hemodialyses. Patients et Methodes : il s'agissait d'une analyse retrospective des dossiers de patients dialyses Traites pour tuberculose de janvier 2003 a avril 2006. Le bilan de tuberculose a comporte un Interrogatoire; un examen clinique minutieux; une radiographie du thorax; une intradermoreaction a la tuberculine (IDR); ainsi que la recherche de bacilles de Koch (BK) dans les liquides biologiques. Resultats : la tuberculose a ete notee chez dix patients soit 15;52des hemodialyses (10/95 Patients). L'age moyen de nos patients etait de 44;3 ans; avec un sexe ratio de 2;5 en faveur des hommes. L'infection tuberculeuse survenait en moyenne 27;4 mois apres le debut de l'hemodialyse. Nous avons retrouve 50de tuberculose extra pulmonaire (trois peritoneales et deux pleurales) et 50de tuberculose pulmonaire. L'IDR etait positive dans deux cas (2/6). La recherche de BK a ete Infructueuse. Nous avons recenses trois deces. Conclusion : l'incidence de la tuberculose chez les hemodialyses chroniques est tres elevee. Le diagnostic est tres souvent difficile et ne peut reposer que sur l'epreuve therapeutique specifique