Application of geographically-weighted regression analysis to assess risk factors for malaria hotspots in Keur Soce health and demographic surveillance site.

BACKGROUND: In Senegal, considerable efforts have been made to reduce malaria morbidity and mortality during the last decade. This resulted in a marked decrease of malaria cases. With the decline of malaria cases, transmission has become sparse in most Senegalese health districts. This study investigated malaria hotspots in Keur Soce sites by using geographically-weighted regression. Because of the occurrence of hotspots, spatial modelling of malaria cases could have a considerable effect in disease surveillance. METHODS: This study explored and analysed the spatial relationships between malaria occurrence and socio-economic and environmental factors in small communities in Keur Soce, Senegal, using 6 months passive surveillance. Geographically-weighted regression was used to explore the spatial variability of relationships between malaria incidence or persistence and the selected socio-economic, and human predictors. A model comparison of between ordinary least square and geographically-weighted regression was also explored. Vector dataset (spatial) of the study area by village levels and statistical data (non-spatial) on malaria confirmed cases, socio-economic status (bed net use), population data (size of the household) and environmental factors (temperature, rain fall) were used in this exploratory analysis. ArcMap 10.2 and Stata 11 were used to perform malaria hotspots analysis. RESULTS: From Jun to December, a total of 408 confirmed malaria cases were notified. The explanatory variables-household size, housing materials, sleeping rooms, sheep and distance to breeding site returned significant t values of -0.25, 2.3, 4.39, 1.25 and 2.36, respectively. The OLS global model revealed that it explained about 70 % (adjusted R(2) = 0.70) of the variation in malaria occurrence with AIC = 756.23. The geographically-weighted regression of malaria hotspots resulted in coefficient intercept ranging from 1.89 to 6.22 with a median of 3.5. Large positive values are distributed mainly in the southeast of the district where hotspots are more accurate while low values are mainly found in the centre and in the north. CONCLUSION: Geographically-weighted regression and OLS showed important risks factors of malaria hotspots in Keur Soce. The outputs of such models can be a useful tool to understand occurrence of malaria hotspots in Senegal. An understanding of geographical variation and determination of the core areas of the disease may provide an explanation regarding possible proximal and distal contributors to malaria elimination in Senegal

The Tostan program: Evaluation of a community based education program in Senegal

This operations research project evaluated the effect and impact of a basic education program, developed by TOSTAN, a nongovernmental organization based at Thiès, Senegal. The basic education program consisted of four modules: hygiene, problem-solving, women’s health, and human rights. Through these four themes, emphasis was placed on enabling the participants, who were mostly women, to analyze their own situation more effectively and thus find the best solutions for themselves. The GTZ Supra Regional Project for the Elimination of Female Genital Cutting funded implementation of the program in 90 villages in Kolda Region, and the Population Council’s Frontiers in Reproductive Health Program, with funding from USAID, used this opportunity to evaluate the program in 20 villages. The program was able to bring about a social change within the community and to mobilize the villagers for better environmental hygiene, and respect for human rights and improvement of health, as well as specifically reducing support for and practice of FGC

Randomized Trial of Piperaquine with Sulfadoxine-Pyrimethamine or Dihydroartemisinin for Malaria Intermittent Preventive Treatment in Children

BACKGROUND: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal. METHODS: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events. RESULTS: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season. CONCLUSIONS: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00529620

Dynamics and role of antibodies to Plasmodium falciparum merozoite antigens in children living in two settings with differing malaria transmission intensity

AbstractBackgroundYoung infants have reduced susceptibility to febrile malaria compared with older children, but the mechanism for this remains unclear. There are conflicting data on the role of passively acquired antibodies. Here, we examine antibody titres to merozoite surface antigens in the protection of children in their first two years of life in two settings with differing malaria transmission intensity and compare these titres to previously established protective thresholds.MethodsTwo cohorts of children aged four to six weeks were recruited in Banfora, Burkina and Keur Soce, Senegal and followed up for two years. Malaria infections were detected by light microscopic examination of blood smears collected at active and passive case detection visits. The titres of antibodies to the Plasmodium falciparum recombinant merozoite proteins (AMA1-3D7, MSP1-19, MSP2-Dd2, and MSP3-3D7) were measured by enzyme-linked immunosorbent assay at 1–6, 9, 12, 15 and 18 months of age and compared with the protective thresholds established in Kenyan children.ResultsAntibody titres were below the protective thresholds throughout the study period and we did not find any association with protection against febrile malaria. Antibodies to AMA1 and MSP1-19 appeared to be markers of exposure in the univariate analysis (and so associated with increasing risk) and adjusting for exposure reduced the strength and significance of this association.ConclusionThe antibody levels we measured are unlikely to be responsible for the apparent protection against febrile malaria seen in young infants. Further work to identify protective antibody responses might include functional assays and a wider range of antigens

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.This study was supported by the Department of Defense Con- gressionally Directed Medical Research Programs (DOD CDMRP, CA120318 to Y. Huang), Elizabeth’s Hope (J. Greenfield), the Starr Foundation, the Paduano Foundation, the Champalimaud Foun- dation, the Malcolm Hewitt Wiener Foundation, the POETIC Foundation, the Sohn Foundation, the Hartwell Foundation, and the Children’s Cancer and Blood Foundation (all to D. Lyden). Address correspondence to: David Lyden, Department of Pediatrics, Weill Medical Medicine, 413 E. 69th Street, Box 284, New York, New York 10021, USA. Phone: 646.962.6238; E-mail: [email protected]. Or to: Jeffrey P. Greenfield, Department of Neurological Surgery, Weill Cornell Medicine, 525 E 68th Street, Box 99, New York, New York 10065, USA. Phone: 212.746.2363; E-mail: [email protected]. HP’s present address is: Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid, Spain.S

Safety, Immunogenicity and Efficacy of Prime-Boost Vaccination with ChAd63 and MVA Encoding ME-TRAP against Plasmodium falciparum Infection in Adults in Senegal.

Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin-related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress

Safety and Immunogenicity of Malaria Vectored Vaccines Given with Routine Expanded Program on Immunization Vaccines in Gambian Infants and Neonates: A Randomized Controlled Trial.

BACKGROUND: Heterologous prime-boost vaccination with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) encoding multiple epitope string thrombospondin-related adhesion protein (ME-TRAP) has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Program on Immunization (EPI) vaccines. METHODS: We enrolled 65 Gambian infants and neonates, aged 16, 8, or 1 week at first vaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPI vaccines only. Safety was assessed by the description of vaccine-related adverse events (AEs). Immunogenicity was evaluated using IFNγ enzyme-linked immunospot, whole-blood flow cytometry, and anti-TRAP IgG ELISA. Serology was performed to confirm all infants achieved protective titers to EPI vaccines. RESULTS: The vaccines were well tolerated in all age groups with no vaccine-related serious AEs. High-level TRAP-specific IgG and T cell responses were generated after boosting with MVA. CD8+ T cell responses, previously found to correlate with protection, were induced in all groups. Antibody responses to EPI vaccines were not altered significantly. CONCLUSION: Malaria vectored prime-boost vaccines co-administered with routine childhood immunizations were well tolerated. Potent humoral and cellular immunity induced by ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPI vaccines, supporting further evaluation of this regimen in infant populations. CLINICAL TRIAL REGISTRATION: The clinical trial was registered on http://Clinicaltrials.gov (NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217)