RESUMO
BACKGROUND: The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652â673 children had received at least one dose of RTS,S and 494â745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26â285 children aged 1-59 months were admitted to sentinel hospitals and 13â198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.
Assuntos
Estudos de Viabilidade , Programas de Imunização , Vacinas Antimaláricas , Malária Cerebral , Humanos , Gana/epidemiologia , Malaui/epidemiologia , Lactente , Feminino , Quênia/epidemiologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Masculino , Pré-Escolar , Malária Cerebral/epidemiologia , Malária Cerebral/mortalidade , Estudos Prospectivos , Malária Falciparum/prevenção & controle , Malária Falciparum/epidemiologia , Meningite/epidemiologia , Meningite/prevenção & controleRESUMO
BACKGROUND: Over the last two decades, the scale-up of vector control and changes in the first-line anti-malarial, from chloroquine (CQ) to sulfadoxine-pyrimethamine (SP) and then to artemether-lumefantrine (AL), have resulted in significant decreases in malaria burden in western Kenya. This study evaluated the long-term effects of control interventions on molecular markers of Plasmodium falciparum drug resistance using parasites obtained from humans and mosquitoes at discrete time points. METHODS: Dried blood spot samples collected in 2012 and 2017 community surveys in Asembo, Kenya were genotyped by Sanger sequencing for markers associated with resistance to SP (Pfdhfr, Pfdhps), CQ, AQ, lumefantrine (Pfcrt, Pfmdr1) and artemisinin (Pfk13). Temporal trends in the prevalence of these markers, including data from 2012 to 2017 as well as published data from 1996, 2001, 2007 from same area, were analysed. The same markers from mosquito oocysts collected in 2012 were compared with results from human blood samples. RESULTS: The prevalence of SP dhfr/dhps quintuple mutant haplotype C50I51R59N108I164/S436G437E540A581A613 increased from 19.7% in 1996 to 86.0% in 2012, while an increase in the sextuple mutant haplotype C50I51R59N108I164/H436G437E540A581A613 containing Pfdhps-436H was found from 10.5% in 2012 to 34.6% in 2017. Resistant Pfcrt-76 T declined from 94.6% in 2007 to 18.3% in 2012 and 0.9% in 2017. Mutant Pfmdr1-86Y decreased across years from 74.8% in 1996 to zero in 2017, mutant Pfmdr1-184F and wild Pfmdr1-D1246 increased from 17.9% to 58.9% in 2007 to 55.9% and 90.1% in 2017, respectively. Pfmdr1 haplotype N86F184S1034N1042D1246 increased from 11.0% in 2007 to 49.6% in 2017. No resistant mutations in Pfk13 were found. Prevalence of Pfdhps-436H was lower while prevalence of Pfcrt-76 T was higher in mosquitoes than in human blood samples. CONCLUSION: This study showed an increased prevalence of dhfr/dhps resistant markers over 20 years with the emergence of Pfdhps-436H mutant a decade ago in Asembo. The reversal of Pfcrt from CQ-resistant to CQ-sensitive genotype occurred following 19 years of CQ withdrawal. No Pfk13 markers associated with artemisinin resistance were detected, but the increased haplotype of Pfmdr1 N86F184S1034N1042D1246 was observed. The differences in prevalence of Pfdhps-436H and Pfcrt-76 T SNPs between two hosts and the role of mosquitoes in the transmission of drug resistant parasites require further investigation.
Assuntos
Antimaláricos , Artemisininas , Culicidae , Malária Falciparum , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Biomarcadores , Cloroquina/farmacologia , Resistência a Medicamentos/genética , Humanos , Quênia/epidemiologia , Malária Falciparum/parasitologia , Mosquitos Vetores , Oocistos , Plasmodium falciparum/genética , Tetra-Hidrofolato Desidrogenase/genéticaRESUMO
BACKGROUND: Global gains toward malaria elimination have been heterogeneous and have recently stalled. Interventions targeting afebrile malaria infections may be needed to address residual transmission. We studied the efficacy of repeated rounds of community-based mass testing and treatment (MTaT) on malaria infection prevalence in western Kenya. METHODS: Twenty clusters were randomly assigned to 3 rounds of MTaT per year for 2 years or control (standard of care for testing and treatment at public health facilities along with government-sponsored mass long-lasting insecticidal net [LLIN] distributions). During rounds, community health volunteers visited all households in intervention clusters and tested all consenting individuals with a rapid diagnostic test. Those positive were treated with dihydroartemisinin-piperaquine. Cross-sectional community infection prevalence surveys were performed in both study arms at baseline and each year after 3 rounds of MTaT. The primary outcome was the effect size of MTaT on parasite prevalence by microscopy between arms by year, adjusted for age, reported LLIN use, enhanced vegetative index, and socioeconomic status. RESULTS: Demographic and behavioral characteristics, including LLIN usage, were similar between arms at each survey. MTaT coverage across the 3 annual rounds ranged between 75.0% and 77.5% in year 1, and between 81.9% and 94.3% in year 2. The adjusted effect size of MTaT on the prevalence of parasitemia between arms was 0.93 (95% confidence interval [CI], .79-1.08) and 0.92 (95% CI, .76-1.10) after year 1 and year 2, respectively. CONCLUSIONS: MTaT performed 3 times per year over 2 years did not reduce malaria parasite prevalence in this high-transmission area. CLINICAL TRIALS REGISTRATION: NCT02987270.
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Malária , Estudos Transversais , Humanos , Quênia/epidemiologia , Malária/diagnóstico , Malária/tratamento farmacológico , Malária/epidemiologia , Parasitemia/tratamento farmacológico , Parasitemia/epidemiologia , PrevalênciaRESUMO
BACKGROUND: Simultaneous infection with multiple malaria parasite strains is common in high transmission areas. Quantifying the number of strains per host, or the multiplicity of infection (MOI), provides additional parasite indices for assessing transmission levels but it is challenging to measure accurately with current tools. This paper presents new laboratory and analytical methods for estimating the MOI of Plasmodium falciparum. METHODS: Based on 24 single nucleotide polymorphisms (SNPs) previously identified as stable, unlinked targets across 12 of the 14 chromosomes within P. falciparum genome, three multiplex PCRs of short target regions and subsequent next generation sequencing (NGS) of the amplicons were developed. A bioinformatics pipeline including B4Screening pathway removed spurious amplicons to ensure consistent frequency calls at each SNP location, compiled amplicons by SNP site diversity, and performed algorithmic haplotype and strain reconstruction. The pipeline was validated by 108 samples generated from cultured-laboratory strain mixtures in different proportions and concentrations, with and without pre-amplification, and using whole blood and dried blood spots (DBS). The pipeline was applied to 273 smear-positive samples from surveys conducted in western Kenya, then providing results into StrainRecon Thresholding for Infection Multiplicity (STIM), a novel MOI estimator. RESULTS: The 24 barcode SNPs were successfully identified uniformly across the 12 chromosomes of P. falciparum in a sample using the pipeline. Pre-amplification and parasite concentration, while non-linearly associated with SNP read depth, did not influence the SNP frequency calls. Based on consistent SNP frequency calls at targeted locations, the algorithmic strain reconstruction for each laboratory-mixed sample had 98.5% accuracy in dominant strains. STIM detected up to 5 strains in field samples from western Kenya and showed declining MOI over time (q < 0.02), from 4.32 strains per infected person in 1996 to 4.01, 3.56 and 3.35 in 2001, 2007 and 2012, and a reduction in the proportion of samples with 5 strains from 57% in 1996 to 18% in 2012. CONCLUSION: The combined approach of new multiplex PCRs and NGS, the unique bioinformatics pipeline and STIM could identify 24 barcode SNPs of P. falciparum correctly and consistently. The methodology could be applied to field samples to reliably measure temporal changes in MOI.
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Código de Barras de DNA Taxonômico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Malária Falciparum/diagnóstico , Reação em Cadeia da Polimerase Multiplex/métodos , Plasmodium falciparum/isolamento & purificação , Malária Falciparum/parasitologia , Plasmodium falciparum/classificaçãoRESUMO
BACKGROUND: The whole Plasmodium falciparum sporozoite (PfSPZ) vaccine is being evaluated for malaria prevention. The vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. METHODS: We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumsporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. RESULTS: Rates of AEs were similar in vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). CONCLUSIONS: PfSPZ vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. CLINICAL TRIALS REGISTRATION: NCT02687373.
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Vacinas Antimaláricas , Malária Falciparum , Adulto , Animais , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Imunogenicidade da Vacina , Lactente , Quênia , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/prevenção & controle , Plasmodium falciparum , Esporozoítos , VacinaçãoAssuntos
Vacinas Antimaláricas , Malária Falciparum , Malária , Criança , Humanos , Malária/prevenção & controleRESUMO
BACKGROUND: Parasite prevalence has been used widely as a measure of malaria transmission, especially in malaria endemic areas. However, its contribution and relationship to malaria mortality across different age groups has not been well investigated. Previous studies in a health and demographic surveillance systems (HDSS) platform in western Kenya quantified the contribution of incidence and entomological inoculation rates (EIR) to mortality. The study assessed the relationship between outcomes of malaria parasitaemia surveys and mortality across age groups. METHODS: Parasitological data from annual cross-sectional surveys from the Kisumu HDSS between 2007 and 2015 were used to determine malaria parasite prevalence (PP) and clinical malaria (parasites plus reported fever within 24 h or temperature above 37.5 °C). Household surveys and verbal autopsy (VA) were used to obtain data on all-cause and malaria-specific mortality. Bayesian negative binomial geo-statistical regression models were used to investigate the association of PP/clinical malaria with mortality across different age groups. Estimates based on yearly data were compared with those from aggregated data over 4 to 5-year periods, which is the typical period that mortality data are available from national demographic and health surveys. RESULTS: Using 5-year aggregated data, associations were established between parasite prevalence and malaria-specific mortality in the whole population (RRmalaria = 1.66; 95% Bayesian Credible Intervals: 1.07-2.54) and children 1-4 years (RRmalaria = 2.29; 1.17-4.29). While clinical malaria was associated with both all-cause and malaria-specific mortality in combined ages (RRall-cause = 1.32; 1.01-1.74); (RRmalaria = 2.50; 1.27-4.81), children 1-4 years (RRall-cause = 1.89; 1.00-3.51); (RRmalaria = 3.37; 1.23-8.93) and in older children 5-14 years (RRall-cause = 3.94; 1.34-11.10); (RRmalaria = 7.56; 1.20-39.54), no association was found among neonates, adults (15-59 years) and the elderly (60+ years). Distance to health facilities, socioeconomic status, elevation and survey year were important factors for all-cause and malaria-specific mortality. CONCLUSION: Malaria parasitaemia from cross-sectional surveys was associated with mortality across age groups over 4 to 5 year periods with clinical malaria more strongly associated with mortality than parasite prevalence. This effect was stronger in children 5-14 years compared to other age-groups. Further analyses of data from other HDSS sites or similar platforms would be useful in investigating the relationship between malaria and mortality across different endemicity levels.
Assuntos
Malária/epidemiologia , Parasitemia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Criança , Pré-Escolar , Estudos Transversais , Humanos , Incidência , Lactente , Recém-Nascido , Quênia/epidemiologia , Malária/mortalidade , Malária/transmissão , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
BACKGROUND: Malaria transmission is high in western Kenya and the asymptomatic infected population plays a significant role in driving the transmission. Mathematical modelling and simulation programs suggest that interventions targeting asymptomatic infections through mass testing and treatment (MTaT) or mass drug administration (MDA) have the potential to reduce malaria transmission when combined with existing interventions. OBJECTIVE: This paper describes the study site, capacity development efforts required, and lessons learned for implementing a multi-year community-based cluster-randomized controlled trial to evaluate the impact of MTaT for malaria transmission reduction in an area of high transmission in western Kenya. METHODS: The study partnered with Kenya's Ministry of Health (MOH) and other organizations on community sensitization and engagement to mobilize, train and deploy community health volunteers (CHVs) to deliver MTaT in the community. Within the health facilities, the study availed staff, medical and laboratory supplies and strengthened health information management system to monitor progress and evaluate impact of intervention. RESULTS: More than 80 Kenya MOH CHVs, 13 clinical officers, field workers, data and logistical staff were trained to carry out MTaT three times a year for 2 years in a population of approximately 90,000 individuals. A supply chain management was adapted to meet daily demands for large volumes of commodities despite the limitation of few MOH facilities having ideal storage conditions. Modern technology was adapted more to meet the needs of the high daily volume of collected data. CONCLUSIONS: In resource-constrained settings, large interventions require capacity building and logistical planning. This study found that investing in relationships with the communities, local governments, and other partners, and identifying and equipping the appropriate staff with the skills and technology to perform tasks are important factors for success in delivering an intervention like MTaT.
Assuntos
Antimaláricos/uso terapêutico , Participação da Comunidade/métodos , Malária/prevenção & controle , Administração Massiva de Medicamentos/métodos , Programas de Rastreamento/métodos , Agentes Comunitários de Saúde/estatística & dados numéricos , Quênia , Voluntários/estatística & dados numéricosRESUMO
Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/efeitos adversos , Epidemias , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Serra Leoa/epidemiologia , Análise de Sobrevida , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Adulto JovemRESUMO
Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti-malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices.
Assuntos
Antimaláricos/uso terapêutico , Malária/diagnóstico , Malária/tratamento farmacológico , Projetos de Pesquisa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise por Conglomerados , Estudos Transversais , Testes Diagnósticos de Rotina , Feminino , Humanos , Lactente , Quênia , Estudos Longitudinais , Malária/prevenção & controle , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto JovemRESUMO
BACKGROUND: Coverage with malaria in pregnancy interventions remains unacceptably low. Implementation research is needed to identify and quantify the bottlenecks for the delivery and use of these life-saving interventions through antenatal clinics (ANC). METHODS: A cross-sectional study was carried out in ANC across nine health facilities in western Kenya. Data were collected for an individual ANC visit through structured observations and exit interviews with the same ANC clients. The cumulative and intermediate systems effectiveness for the delivery of intermittent preventive treatment (IPTp) and insecticide-treated nets (ITNs) to eligible pregnant women on this one specific visit to ANC were estimated. RESULTS: Overall the ANC systems effectiveness for delivering malaria in pregnancy interventions was suboptimal. Only 40 and 53 % of eligible women received IPTp by directly observed therapy as per policy in hospitals and health centres/dispensaries respectively. The overall systems effectiveness for the receipt of IPTp disregarding directly observed therapy was 62 and 72 % for hospitals and lower level health facilities, respectively. The overall systems effectiveness for ITNs for first ANC visit was 63 and 67 % for hospitals and lower level facilities, respectively. CONCLUSION: This study found that delivery of IPTp and ITNs through ANC was ineffective and more so for higher-level facilities. This illustrates missed opportunities and provider level bottlenecks to the scale up and use of interventions to control malaria in pregnancy delivered through ANC. The high level of clustering within health facilities suggest that future studies should assess the feasibility of implementing interventions to improve systems effectiveness tailored to the health facility level.
Assuntos
Antimaláricos/administração & dosagem , Mosquiteiros Tratados com Inseticida/estatística & dados numéricos , Malária/prevenção & controle , Complicações Parasitárias na Gravidez/prevenção & controle , Adolescente , Adulto , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Criança , Estudos Transversais , Feminino , Humanos , Quênia , Malária/tratamento farmacológico , Pessoa de Meia-Idade , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Cuidado Pré-Natal/estatística & dados numéricos , Adulto JovemRESUMO
BACKGROUND: Nontyphoidal Salmonella (NTS), mainly serotypes Typhimurium and Enteritidis, cause invasive infections with high mortality in children in sub-Saharan Africa. Multidrug resistance is common, and resistance to third-generation cephalosporins has emerged. METHODS: We reviewed clinical features, outcomes, and antimicrobial resistance patterns in invasive NTS infections among children aged 6 weeks to 5 years participating in malaria vaccine studies in an area of high malaria and human immunodeficiency virus (HIV) transmission in Siaya, western Kenya. Blood culture was performed in hospitalized children and pediatric outpatients with prolonged fever. RESULTS: From July 2009 to December 2013, 1696 children aged 6 weeks to 17 months were enrolled into vaccine trials and followed for up to 53 months. We obtained 1692 blood cultures from 847 children. Of 134 bacterial pathogens isolated, 102 (76.1%) were Salmonella serogroup B or D. Invasive NTS disease occurred in 94 (5.5%) children, with an incidence of 1870, 4134, and 6510 episodes per 100 000 person-years overall, in infants, and in HIV-infected children, respectively. Malaria infection within the past 2 weeks occurred in 18.8% (3/16) of invasive NTS episodes in HIV-infected and 66.2% (53/80) in HIV-uninfected children. Case fatality rate was 3.1%. Salmonella group B resistant to ceftriaxone emerged in 2009 and 2010 (6.2% [2/32 isolates]), rising to 56.5% (13/23 isolates) in 2012 and 2013. CONCLUSIONS: Incidence of invasive NTS disease was high in this area of high malaria and HIV transmission, especially in HIV-infected children. Rapidly emerging resistance against ceftriaxone requires urgent reevaluation of antibiotic recommendations and primary prevention of exposure to Salmonella.
Assuntos
Farmacorresistência Bacteriana Múltipla , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia , Salmonella enterica/efeitos dos fármacos , Antibacterianos/farmacologia , Bacteriemia/complicações , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Ceftriaxona/farmacologia , Pré-Escolar , Feminino , Infecções por HIV/complicações , Infecções por HIV/microbiologia , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Lactente , Quênia/epidemiologia , Malária , Masculino , Pacientes Ambulatoriais/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , População Rural/estatística & dados numéricos , Infecções por Salmonella/complicações , Infecções por Salmonella/mortalidade , Fatores de TempoRESUMO
BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
Assuntos
Vacinas Antimaláricas , Malária Falciparum/prevenção & controle , Vacinas Sintéticas , África , Feminino , Humanos , Esquemas de Imunização , Incidência , Lactente , Análise de Intenção de Tratamento , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/epidemiologia , Masculino , Plasmodium falciparum/imunologia , Modelos de Riscos Proporcionais , Resultado do Tratamento , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: An initial study of genetic diversity of Plasmodium falciparum in Asembo, western Kenya showed that the parasite maintained overall genetic stability 5 years after insecticide-treated bed net (ITN) introduction in 1997. This study investigates further the genetic diversity of P. falciparum 10 years after initial ITN introduction in the same study area and compares this with two other neighbouring areas, where ITNs were introduced in 1998 (Gem) and 2004 (Karemo). METHODS: From a cross-sectional survey conducted in 2007, 235 smear-positive blood samples collected from children ≤15-year-old in the original study area and two comparison areas were genotyped employing eight neutral microsatellites. Differences in multiple infections, allele frequency, parasite genetic diversity and parasite population structure between the three areas were assessed. Further, molecular data reported previously (1996 and 2001) were compared to the 2007 results in the original study area Asembo. RESULTS: Overall proportion of multiple infections (MA) declined with time in the original study area Asembo (from 95.9 %-2001 to 87.7 %-2007). In the neighbouring areas, MA was lower in the site where ITNs were introduced in 1998 (Gem 83.7 %) compared to where they were introduced in 2004 (Karemo 96.7 %) in 2007. Overall mean allele count (MAC ~ 2.65) and overall unbiased heterozygosity (H e ~ 0.77) remained unchanged in 1996, 2001 and 2007 in Asembo and was the same level across the two neighbouring areas in 2007. Overall parasite population differentiation remained low over time and in the three areas at FST < 0.04. Both pairwise and multilocus linkage disequilibrium showed limited to no significant association between alleles in Asembo (1996, 2001 and 2007) and between three areas. CONCLUSIONS: This study showed the P. falciparum high genetic diversity and parasite population resilience on samples collected 10 years apart and in different areas in western Kenya. The results highlight the need for long-term molecular monitoring after implementation and use of combined and intensive prevention and intervention measures in the region.
RESUMO
BACKGROUND: The artemisinin anti-malarials are widely deployed as artemisinin-based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce. METHODS: This was a prospective cohort study of women of child-bearing age carried out in 2011-2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used. RESULTS: The risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (≥6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08-2.68) and HR = 1.61 (0.96-2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56-2.74) and HR = 0.73 (0.19-2.82) relative to unexposed women, and HR = 0.99 (0.12-8.33) and HR = 0.32 (0.03-3.61) relative to quinine exposure, but the numbers of quinine exposures were very small. CONCLUSION: ACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk.
Assuntos
Aborto Espontâneo/induzido quimicamente , Aborto Espontâneo/epidemiologia , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Primeiro Trimestre da Gravidez , Adolescente , Adulto , Feminino , Humanos , Quênia , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Medição de Risco , Adulto JovemRESUMO
BACKGROUND: An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries. METHODS: From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories. RESULTS: In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). CONCLUSIONS: The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).
Assuntos
Vacinas Antimaláricas , Malária Falciparum/prevenção & controle , Plasmodium falciparum , África , Fatores Etários , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Incidência , Lactente , Análise de Intenção de Tratamento , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Masculino , Meningite/epidemiologia , Meningite/etiologia , Carga Parasitária , Plasmodium falciparum/imunologia , Plasmodium falciparum/isolamento & purificação , Convulsões/epidemiologia , Convulsões/etiologia , Resultado do TratamentoRESUMO
Health care workers (HCWs) are at increased risk for infection in outbreaks of Ebola virus disease (Ebola). To characterize Ebola in HCWs in Sierra Leone and guide prevention efforts, surveillance data from the national Viral Hemorrhagic Fever database were analyzed. In addition, site visits and interviews with HCWs and health facility administrators were conducted. As of October 31, 2014, a total of 199 (5.2%) of the total of 3,854 laboratory-confirmed Ebola cases reported from Sierra Leone were in HCWs, representing a much higher estimated cumulative incidence of confirmed Ebola in HCWs than in non-HCWs, based on national data on the number of HCW. The peak number of confirmed Ebola cases in HCWs was reported in August (65 cases), and the highest number and percentage of confirmed Ebola cases in HCWs was in Kenema District (65 cases, 12.9% of cases in Kenema), mostly from Kenema General Hospital. Confirmed Ebola cases in HCWs continued to be reported through October and were from 12 of 14 districts in Sierra Leone. A broad range of challenges were reported in implementing infection prevention and control measures. In response, the Ministry of Health and Sanitation and partners are developing standard operating procedures for multiple aspects of infection prevention, including patient isolation and safe burials; recruiting and training staff in infection prevention and control; procuring needed commodities and equipment, including personal protective equipment and vehicles for safe transport of Ebola patients and corpses; renovating and constructing Ebola care facilities designed to reduce risk for nosocomial transmission; monitoring and evaluating infection prevention and control practices; and investigating new cases of Ebola in HCWs as sentinel public health events to identify and address ongoing prevention failures.
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Ebolavirus/isolamento & purificação , Pessoal de Saúde , Doença pelo Vírus Ebola/diagnóstico , Doenças Profissionais/diagnóstico , Adolescente , Adulto , Feminino , Pessoal de Saúde/estatística & dados numéricos , Doença pelo Vírus Ebola/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/epidemiologia , Serra Leoa/epidemiologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: At least 39 sub-Saharan African countries have policies on preventing malaria in pregnancy (MIP), including use of long-lasting insecticidal nets (LLINs), intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) and case management. However, coverage of LLINs and IPTp-SP remains below international targets in most countries. One factor contributing to low coverage may be that MIP policies typically are developed by national malaria control programmes (NMCPs), but are implemented through national reproductive health (RH) programmes. METHODS: National-level MIP policies, guidelines, and training documents from NMCPs and RH programmes in Kenya, Mali, Mozambique, mainland Tanzania and Uganda were reviewed to assess whether they reflected WHO guidelines for prevention and treatment of MIP, and how consistent MIP content was across documents from the same country. Documents were compared for adherence to WHO guidance concerning IPTp-SP timing and dose, directly observed therapy, promotion and distribution of LLINs, linkages to HIV programmes and MIP case management. RESULTS: The five countries reviewed had national documents promoting IPTp-SP, LLINs and MIP case management. WHO guidance from 2004 frequently was not reflected: four countries recommended the first dose of IPTp-SP at 20 weeks or later (instead of 16 weeks), and three countries restricted the first and second IPTp-SP doses to specific gestational weeks. Documents from four countries provided conflicting guidance on MIP prevention for HIV-positive women, and none provided complete guidance on management of uncomplicated and severe malaria during pregnancy. In all countries, inconsistencies between NMCPs and RH programmes on the timing or dose of IPTp-SP were documented, as was the mechanism for providing LLINs. Inconsistencies also were found in training documents from NMCPs and RH programmes in a given country. Outdated, inconsistent guidelines have the potential to cause confusion and lead to incorrect practices among health workers who implement MIP programmes, contributing to low coverage of IPTp-SP and LLINs. CONCLUSIONS: MIP policies, guidelines and training materials are outdated and/or inconsistent in the countries assessed. Updating and ensuring consistency among national MIP documents is needed, along with re-orientation and supervision of health workers to accelerate implementation of the 2012 WHO Global Malaria Programme policy recommendations for IPTp-SP.
Assuntos
Política de Saúde , Malária/tratamento farmacológico , Malária/prevenção & controle , Guias de Prática Clínica como Assunto , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/prevenção & controle , África , Antimaláricos/uso terapêutico , Quimioprevenção/métodos , Combinação de Medicamentos , Feminino , Pesquisa sobre Serviços de Saúde , Humanos , Mosquiteiros Tratados com Inseticida/estatística & dados numéricos , Malária/diagnóstico , Gravidez , Complicações na Gravidez/diagnóstico , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêuticoRESUMO
BACKGROUND: Monitoring local malaria transmission intensity is essential for planning evidence-based control strategies and evaluating their impact over time. Anti-malarial antibodies provide information on cumulative exposure and have proven useful, in areas where transmission has dropped to low sustained levels, for retrospectively reconstructing the timing and magnitude of transmission reduction. It is unclear whether serological markers are also informative in high transmission settings, where interventions may reduce transmission, but to a level where considerable exposure continues. METHODS: This study was conducted through ongoing KEMRI and CDC collaboration. Asembo, in Western Kenya, is an area where intense malaria transmission was drastically reduced during a 1997-1999 community-randomized, controlled insecticide-treated net (ITN) trial. Two approaches were taken to reconstruct malaria transmission history during the period from 1994 to 2009. First, point measurements were calculated for seroprevalence, mean antibody titre, and seroconversion rate (SCR) against three Plasmodium falciparum antigens (AMA-1, MSP-119, and CSP) at five time points for comparison against traditional malaria indices (parasite prevalence and entomological inoculation rate). Second, within individual post-ITN years, age-stratified seroprevalence data were analysed retrospectively for an abrupt drop in SCR by fitting alternative reversible catalytic conversion models that allowed for change in SCR. RESULTS: Generally, point measurements of seroprevalence, antibody titres and SCR produced consistent patterns indicating that a gradual but substantial drop in malaria transmission (46-70%) occurred from 1994 to 2007, followed by a marginal increase beginning in 2008 or 2009. In particular, proportionate changes in seroprevalence and SCR point estimates (relative to 1994 baseline values) for AMA-1 and CSP, but not MSP-119, correlated closely with trends in parasite prevalence throughout the entire 15-year study period. However, retrospective analyses using datasets from 2007, 2008 and 2009 failed to detect any abrupt drop in transmission coinciding with the timing of the 1997-1999 ITN trial. CONCLUSIONS: In this highly endemic area, serological markers were useful for generating accurate point estimates of malaria transmission intensity, but not for retrospective analysis of historical changes. Further investigation, including exploration of different malaria antigens and/or alternative models of population seroconversion, may yield serological tools that are more informative in high transmission settings.