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2.
Lancet ; 395(10233): 1361-1373, 2020 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334702

RESUMO

BACKGROUND: In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia). METHODS: We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400. FINDINGS: Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported. INTERPRETATION: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria. FUNDING: Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.


Assuntos
Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Malária Falciparum/prevenção & controle , Administração Massiva de Medicamentos/métodos , Controle de Mosquitos , Antimaláricos/administração & dosagem , Combinação Arteméter e Lumefantrina/administração & dosagem , Análise por Conglomerados , Humanos , Malária Falciparum/epidemiologia , Controle de Mosquitos/métodos , Namíbia/epidemiologia , Plasmodium falciparum , Estudos Soroepidemiológicos
3.
Infect Dis Poverty ; 9(1): 18, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32036792

RESUMO

BACKGROUND: The National Plan for Malaria Elimination (NPME) in Myanmar (2016-2030) aims to eliminate indigenous Plasmodium falciparum malaria in six states/regions of low endemicity by 2020 and countrywide by 2030. To achieve this goal, in 2016 the National Malaria Control Program (NMCP) implemented the "1-3-7" surveillance and response strategy. This study aims to identify the barriers to successful implementation of the NPME which emerged during the early phase of the "1-3-7" approach deployment. METHODS: A mixed-methods study was conducted with basic health staff (BHS) and Vector Born Disease Control Program (VBDC) staff between 2017 and 2018 in six townships of six states/regions targeted for sub-national elimination by 2020. A self-administered questionnaire, designed to assess the knowledge required to implement the "1-3-7" approach, was completed by 544 respondents. Bivariate analysis was performed for quantitative findings and thematic analysis was conducted for qualitative findings using Atals.ti software. RESULTS: Although 83% of participants reported performing the key activities in the "1-3-7" surveillance and response approach, less than half could report performing those activities within 3 days and 7 days (40 and 43%, respectively). Low proportion of BHS correctly identified six categories of malaria cases and three types of foci (22 and 26%, respectively). In contrast, nearly 80% of respondents correctly named three types of case detection methods. Most cited challenges included 'low community knowledge on health' (43%), 'inadequate supplies' (22%), and 'transportation difficulty' (21%). Qualitative data identified poor knowledge of key surveillance activities, delays in reporting, and differences in reporting systems as the primary challenges. The dominant perceived barrier to success was inability to control the influx of migrant workers into target jurisdictions especially in hard-to-reach areas. Interviews with township medical officers and the NMCP team leaders further highlighted the necessity of refresher training for every step in the "1-3-7" surveillance and response approach. CONCLUSIONS: The performance of the "1-3-7" surveillance and response approach in Myanmar delivers promising results. However, numerous challenges are likely to slow down malaria elimination progress in accordance with the NPME. Multi-stakeholder engagement and health system readiness is critical for malaria elimination at the sub-national level.


Assuntos
Antimaláricos/uso terapêutico , Agentes Comunitários de Saúde/psicologia , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Vigilância de Evento Sentinela , Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Mianmar/epidemiologia , Plasmodium falciparum , Inquéritos e Questionários , Migrantes
4.
PLoS One ; 15(2): e0224718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32097407

RESUMO

BACKGROUND: Understanding the interactions between increased insecticide resistance and resting behaviour patterns of malaria mosquitoes is important for planning of adequate vector control. This study was designed to investigate the resting behavior, host preference and rates of Plasmodium falciparum infection in relation to insecticide resistance of malaria vectors in different ecologies of western Kenya. METHODS: Anopheles mosquito collections were carried out during the dry and rainy seasons in Kisian (lowland site) and Bungoma (highland site), both in western Kenya using pyrethrum spray catches (PSC), mechanical aspiration (Prokopack) for indoor collections, clay pots, pit shelter and Prokopack for outdoor collections. WHO tube bioassay was used to determine levels of phenotypic resistance of indoor and outdoor collected mosquitoes to deltamethrin. PCR-based molecular diagnostics were used for mosquito speciation, genotype for knockdown resistance mutations (1014S and 1014F) and to determine specific host blood meal origins. Enzyme-linked Immunosorbent Assay (ELISA) was used to determine mosquito sporozoite infections. RESULTS: Anopheles gambiae s.l. was the most predominant species (75%, n = 2706) followed by An. funestus s.l. (25%, n = 860). An. gambiae s.s hereafter (An. gambiae) accounted for 91% (95% CI: 89-93) and An. arabiensis 8% (95% CI: 6-9) in Bungoma, while in Kisian, An. arabiensis composition was 60% (95% CI: 55-66) and An. gambiae 39% (95% CI: 34-44). The resting densities of An. gambiae s.l and An. funestus were higher indoors than outdoor in both sites (An. gambiae s.l; F1, 655 = 41.928, p < 0.0001, An. funestus; F1, 655 = 36.555, p < 0.0001). The mortality rate for indoor and outdoor resting An. gambiae s.l F1 progeny was 37% (95% CI: 34-39) vs 67% (95% CI: 62-69) respectively in Bungoma. In Kisian, the mortality rate was 67% (95% CI: 61-73) vs 76% (95% CI: 71-80) respectively. The mortality rate for F1 progeny of An. funestus resting indoors in Bungoma was 32% (95% CI: 28-35). The 1014S mutation was only detected in indoor resitng An. arabiensis. Similarly, the 1014F mutation was present only in indoor resting An. gambiae. The sporozoite rates were highest in An. funestus followed by An. gambiae, and An. arabiensis resting indoors at 11% (34/311), 8% (47/618) and 4% (1/27) respectively in Bungoma. Overall, in Bungoma, the sporozoite rate for indoor resting mosquitoes was 9% (82/956) and 4% (8/190) for outdoors. In Kisian, the sporozoite rate was 1% (1/112) for indoor resting An. gambiae. None of the outdoor collected mosquitoes in Kisian tested positive for sporozoite infections (n = 73). CONCLUSION: The study reports high indoor resting densities of An. gambiae and An. funestus, insecticide resistance, and persistence of malaria transmission indoors regardless of the use of long-lasting insecticidal nets (LLINs). These findings underline the difficulties of controlling malaria vectors resting and biting indoors using the current interventions. Supplemental vector control tools and implementation of sustainable insecticide resistance management strategies are needed in western Kenya.


Assuntos
Anopheles/genética , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Controle de Mosquitos/métodos , Mosquitos Vetores/fisiologia , Plasmodium falciparum/imunologia , Descanso/fisiologia , Animais , Anopheles/classificação , Anopheles/parasitologia , Ensaio de Imunoadsorção Enzimática , Comportamento Alimentar/efeitos dos fármacos , Feminino , Genótipo , Comportamento de Busca por Hospedeiro/efeitos dos fármacos , Resistência a Inseticidas/genética , Mosquiteiros Tratados com Inseticida , Inseticidas/farmacologia , Quênia/epidemiologia , Malária Falciparum/transmissão , Nitrilos/farmacologia , Reação em Cadeia da Polimerase , Piretrinas/farmacologia , Esporozoítos/imunologia
5.
PLoS One ; 15(2): e0228177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040522

RESUMO

BACKGROUND: Sterile protection against malaria, most likely mediated by parasite-specific CD8+ T cells, has been achieved by attenuated sporozoite vaccination of animals as well as malaria-naïve and malaria-exposed subjects. The circumsporozoite protein (CSP)-based vaccine, RTS,S, shows low efficacy partly due to limited CD8+ T cell induction, and inclusion of such epitopes could improve RTS,S. This study assessed 8-10mer CSP peptide epitopes, present in predicted or previously positive P. falciparum 3D7 CSP 15mer overlapping peptide pools, for their ability to induce CD8+ T cell IFN-γ responses in natural malaria-exposed subjects. METHODS: Cryopreserved PBMCs from nine HLA-typed subjects were stimulated with 23 8-10mer CSP peptides from the 3D7 parasite in IFN-É£ ELISpot assays. The CD8+ T cell specificity of IFN-γ responses was confirmed in ELISpot assays using CD8+ T cell-enriched PBMC fractions after CD4+ cell depletion. RESULTS: Ten of 23 peptide epitopes elicited responses in whole PBMCs from five of the nine subjects. Four peptides tested positive in CD8+ T cell-enriched PBMCs from two previously positive responders and one new subject. All four immunodominant peptides are restricted by globally common HLA supertypes (A02, A03, B07) and mapped to regions of the CSP antigen with limited or no reported polymorphism. Association of these peptide-specific responses with anti-malarial protection remains to be confirmed. CONCLUSIONS: The relatively conserved nature of the four identified epitopes and their binding to globally common HLA supertypes makes them good candidates for inclusion in potential multi-epitope malaria vaccines.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Epitopos de Linfócito T/química , Epitopos de Linfócito T/efeitos dos fármacos , Interferon gama/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia
6.
Biochim Biophys Acta Proteins Proteom ; 1868(3): 140362, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31927030

RESUMO

BACKGROUND: The malaria parasite Plasmodium falciparum expresses four related papain-family cysteine proteases known as falcipains. These proteases play critical roles in the parasite life cycle, and as such are potential targets for new modes of antimalarial chemotherapy, as discussed in this review. SCOPE OF REVIEW: This review summarizes available knowledge describing falcipain cysteine proteases of malaria parasites. MAJOR CONCLUSIONS: Based on available data the falcipains can be broken into two sub-families, the falcipain-1 and the falcipain-2/3 sub-families. Falcipain-1 has been difficult to study; it appears to play its most important roles in nonerythrocytic parasites, but not the erythrocytic stage responsible for human disease. Falcipain-2 and falcipain-3 have similar biochemical features, and are expressed sequentially during the erythrocytic cycle. Inhibition of either of these enzymes blocks hemoglobin hydrolysis and completion of the parasite developmental cycle. Knockout of falcipain-2 blocks hemoglobin hydrolysis, but parasites recover, presumably due to subsequent expression of falcipain-3. Knockout of falcipain-3 has not been possible, suggesting that the protease is essential for erythrocytic parasites. Determination of structures of falcipains and extensive chemistry efforts have facilitated identification of numerous small molecule falcipain inhibitors as potential new antimalarial agents. Other malaria parasites express close homologs of falcipain-1 and falcipain-2/3 proteases, suggesting that agents that target the falcipains will also be active against other human malaria parasites. GENERAL SIGNIFICANCE: Falcipain-2 and falcipain-3 play vital roles during the erythrocytic stage of infection with P. falciparum and thus are promising targets for new agents to treat malaria.


Assuntos
Cisteína Proteases/fisiologia , Plasmodium falciparum/enzimologia , Antimaláricos/uso terapêutico , Cisteína Proteases/química , Cisteína Proteases/genética , Cisteína Proteases/metabolismo , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Plasmodium/enzimologia , Plasmodium falciparum/genética
7.
Malar J ; 18(1): 428, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852499

RESUMO

BACKGROUND: Sample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters. METHODS: Data on uPCR-detected Plasmodium falciparum and Plasmodium vivax infections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence of Plasmodium infections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized. RESULTS: The ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 for P. falciparum and P. vivax respectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up. CONCLUSION: ICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogeneity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references for trials designed around prevalence and incidence of clinical outcomes. Adequately powered trials are critical to estimate the benefit of interventions to malaria in a reliable and reproducible fashion. TRIAL REGISTRATION: ClinicalTrials.govNCT01872702. Registered 7 June 2013. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT01872702.


Assuntos
Antimaláricos/administração & dosagem , Malária Falciparum/prevenção & controle , Malária Vivax/prevenção & controle , Administração Massiva de Medicamentos/estatística & dados numéricos , Camboja/epidemiologia , Humanos , Incidência , Laos/epidemiologia , Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Mianmar/epidemiologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Vietnã/epidemiologia
8.
Turkiye Parazitol Derg ; 43(4): 170-174, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31865651

RESUMO

Objective: Malaria is an infection disease caused by plamodium parasite. Sporadic cases have not been observed since 2011, but imported cases still present owing to travel. In this study, we aimed to evaluate labotauary and clinical findings patients with malaria who were hospitalized and treated in our hospital. Methods: Between January 2012-November 2018, a total of 31 adult patients was evaluated retrospectively, in terms of their epidemiological, physical examination and laboratory findings, complaints, countries they traveled to, prophylaxis and treatment that they received. Data of the patients were taken from the hospital's database. Results: A total of 31 cases were diagnosed as having malaria. The causative microorganism was P. falciparum in 54.83% (17/31) of the patients, P. vivax in 32.25% (10/31), and P. falciparum-P. vivax co-infection in 12.9% (4/31) of the patients. Co-infections were excluded from the study. None of the cases had used prophylactic drugs for prevention of malaria. All of the cases suffered from chills with fever. The most frequently encountered pathologic laboratory findings were thrombocytopenia and leucopenia. Antibiotics had been initiated in 51.85% (14/27) of the patients with non-specific diagnoses. Rapid antigen test was used in 8148% (22/27) of cases. None of cases needed intensive care. Conclusion: It is important to inform persons who plan to visit malaria endemic areas about malaria and to make them take appropriate prophylaxis against malaria. Although P. falciparum which has a high mortality rate may be considered in the first plan, P. vivax, treatment of which is different due to risk of relapse, should not be overlooked.


Assuntos
Malária Falciparum , Malária Vivax , Viagem , Adolescente , Adulto , Antimaláricos/uso terapêutico , Calafrios , Doenças Endêmicas/prevenção & controle , Feminino , Febre , Humanos , Leucopenia/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombocitopenia/diagnóstico , Adulto Jovem
9.
Malar J ; 18(1): 350, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619258

RESUMO

BACKGROUND: Malaria elimination requires diagnostic methods able to detect parasite levels well below what is currently possible with microscopy and rapid diagnostic tests. This is particularly true in surveillance of malaria at the population level that includes so-called "asymptomatic" individuals. METHODS: The development of the first ultrasensitive loop mediated amplification method capable of detecting malaria from both whole blood and dried blood spots (DBS) is described. The 18S rRNA and corresponding genes that remain stable on DBS for up to 5 months are targeted. RESULTS: In the case of Plasmodium falciparum, lower limits of detection of 25 parasite/mL and 50-100 parasite/mL from whole blood and DBS were obtained, respectively. A sensitivity of 97.0% (95% CI 82.5-99.8) and specificity of 99.1% (95% CI 97.6-99.7) was obtained for the detection of all species in asymptomatic individuals from Africa and Asia (n = 494). CONCLUSION: This tool is ideally suited for low middle-income countries where malaria is endemic and ultrasensitive surveillance of malaria is highly desirable for elimination.


Assuntos
Teste em Amostras de Sangue Seco , Técnicas de Amplificação de Ácido Nucleico/métodos , Plasmodium falciparum/isolamento & purificação , Testes Diagnósticos de Rotina , Malária Falciparum/prevenção & controle , RNA de Protozoário/análise , RNA Ribossômico 18S/análise , Fatores de Tempo
10.
BMC Infect Dis ; 19(1): 920, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664924

RESUMO

BACKGROUND: The only licensed malaria vaccine, RTS,S/AS01, has been developed for morbidity-control in young children. The potential impact on transmission of deploying such anti-infective vaccines to wider age ranges, possibly with co-administration of antimalarial treatment, is unknown. Combinations of existing malaria interventions is becoming increasingly important as evidence mounts that progress on reducing malaria incidence is stalling and threatened by resistance. METHODS: Malaria transmission and intervention dynamics were simulated using OpenMalaria, an individual-based simulation model of malaria transmission, by considering a seasonal transmission setting and by varying epidemiological and setting parameters such as transmission intensity, case management, intervention types and intervention coverages. Chemopreventive drugs and anti-infective vaccine efficacy profiles were based on previous studies in which model parameters were fitted to clinical trial data. These intervention properties were used to evaluate the potential of seasonal mass applications of preventative anti-infective malaria vaccines, alone or in combination with chemoprevention, to reduce malaria transmission, prevent resurgence, and/or reach transmission interruption. RESULTS: Deploying a vaccine to all ages on its own is a less effective intervention strategy compared to chemoprevention alone. However, vaccines combined with drugs are likely to achieve dramatic prevalence reductions and in few settings, transmission interruption. The combined mass intervention will result in lower prevalence following the intervention compared to chemoprevention alone and will increase chances of interruption of transmission resulting from a synergistic effect between both interventions. The combination of vaccine and drug increases the time before transmission resurges after mass interventions cease compared to mass treatment alone. Deploying vaccines and drugs together requires fewer rounds of mass intervention and fewer years of intervention to achieve the same public health impact as chemoprevention alone. CONCLUSIONS: Through simulations we identified a previously unidentified value of deploying vaccines with drugs, namely the greatest benefit will be in preventing and delaying transmission resurgence for longer periods than with other human targeted interventions. This is suggesting a potential role for deploying vaccines alongside drugs in transmission foci as part of surveillance-response strategies.


Assuntos
Antimaláricos/administração & dosagem , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Administração Massiva de Medicamentos , Vacinação em Massa , Modelos Teóricos , Estações do Ano , Adulto , Quimioprevenção/métodos , Criança , Pré-Escolar , Transmissão de Doença Infecciosa/prevenção & controle , Quimioterapia Combinada , Humanos , Lactente , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/imunologia , Prevalência
11.
Malar J ; 18(1): 300, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477111

RESUMO

BACKGROUND: The ability to report vaccine-induced IgG responses in terms of µg/mL, as opposed arbitrary units (AU), enables a more informed interpretation of the magnitude of the immune response, and better comparison between vaccines targeting different antigens. However, these interpretations rely on the accuracy of the methodology, which is used to generate ELISA data in µg/mL. In a previous clinical trial of a vaccine targeting the apical membrane antigen 1 (AMA1) from Plasmodium falciparum, three laboratories (Oxford, NIH and WRAIR) reported ELISA data in µg/mL that were correlated but not concordant. This current study sought to harmonize the methodology used to generate a conversion factor (CF) for ELISA analysis of human anti-AMA1 IgG responses across the three laboratories. METHODS: Purified IgG was distributed to the three laboratories and, following a set protocol provided by NIH, AMA1-specific human IgG was affinity purified. A new "harmonized CF" was generated by each laboratory using their in-house ELISA, and the original clinical trial ELISA data were re-analysed accordingly. RESULTS: Statistical analysis showed that the data remained highly correlated across all three laboratories, although only Oxford and NIH were able to harmonize their CF for ELISA and generate concordant data. CONCLUSIONS: This study enabled two out of the three laboratories to harmonize their µg/mL readouts for the human anti-AMA1 IgG ELISA, but results reported from WRAIR are ~ twofold higher. Given the need to validate such information for each species and antigen of interest, it is important to bear in mind these likely differences when interpreting µg/mL ELISA data in the future.


Assuntos
Anticorpos Antiprotozoários/análise , Técnicas de Laboratório Clínico/normas , Ensaio de Imunoadsorção Enzimática/normas , Imunoglobulina G/análise , Vacinas Antimaláricas/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunoglobulina G/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Membrana/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia
12.
Malar J ; 18(1): 302, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477117

RESUMO

BACKGROUND: Infection during pregnancy with Plasmodium falciparum is associated with maternal anaemia and adverse birth outcomes including low birth weight (LBW). Studies using polymerase chain reaction (PCR) techniques indicate that at least half of all infections in maternal venous blood are missed by light microscopy or rapid diagnostic tests. The impact of these subpatent infections on maternal and birth outcomes remains unclear. METHODS: In a cohort of women co-enrolled in a clinical trial of intermittent treatment with sulfadoxine-pyrimethamine (SP) plus azithromycin for the prevention of LBW (< 2500 g) in Papua New Guinea (PNG), P. falciparum infection status at antenatal enrolment and delivery was assessed by routine light microscopy and real-time quantitative PCR. The impact of infection status at enrolment and delivery on adverse birth outcomes and maternal haemoglobin at delivery was assessed using logistic and linear regression models adjusting for potential confounders. Together with insecticide-treated bed nets, women had received up to 3 monthly intermittent preventive treatments with SP plus azithromycin or a single clearance treatment with SP plus chloroquine. RESULTS: A total of 9.8% (214/2190) of women had P. falciparum (mono-infection or mixed infection with Plasmodium vivax) detected in venous blood at antenatal enrolment at 14-26 weeks' gestation. 4.7% of women had microscopic, and 5.1% submicroscopic P. falciparum infection. At delivery (n = 1936), 1.5% and 2.0% of women had submicroscopic and microscopic P. falciparum detected in peripheral blood, respectively. Submicroscopic P. falciparum infections at enrolment or at delivery in peripheral or placental blood were not associated with maternal anaemia or adverse birth outcomes such as LBW. Microscopic P. falciparum infection at antenatal enrolment was associated with anaemia at delivery (adjusted odds ratio [aOR] 2.00, 95% confidence interval [CI] 1.09, 3.67; P = 0.025). Peripheral microscopic P. falciparum infection at delivery was associated with LBW (aOR 2.75, 95% CI 1.27; 5.94, P = 0.010) and preterm birth (aOR 6.58, 95% CI 2.46, 17.62; P < 0.001). CONCLUSIONS: A substantial proportion of P. falciparum infections in pregnant women in PNG were submicroscopic. Microscopic, but not submicroscopic, infections were associated with adverse outcomes in women receiving malaria preventive treatment and insecticide-treated bed nets. Current malaria prevention policies that combine insecticide-treated bed nets, intermittent preventive treatment and prompt treatment of symptomatic infections appear to be appropriate for the management of malaria in pregnancy in settings like PNG.


Assuntos
Anemia/parasitologia , Recém-Nascido de Baixo Peso , Malária Falciparum/sangue , Malária Falciparum/complicações , Complicações Infecciosas na Gravidez/parasitologia , Adulto , Antibacterianos/administração & dosagem , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Infecções Assintomáticas , Azitromicina/administração & dosagem , Feminino , Hemoglobina A/análise , Humanos , Recém-Nascido , Malária Falciparum/prevenção & controle , Papua Nova Guiné , Plasmodium falciparum/genética , Gravidez , Resultado da Gravidez , Nascimento Prematuro , Estudos Prospectivos , Pirimetamina/administração & dosagem , Sulfadoxina/administração & dosagem , Adulto Jovem
13.
Malar J ; 18(1): 329, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551076

RESUMO

BACKGROUND: Distribution campaigns for insecticide-treated nets (ITN) have increased the use of ITNs in Malawi, but malaria prevalence remains high even among those using the nets. Previous studies have addressed ITN ownership, insecticide resistance, and frequency of ITN use as possible contributing factors to the high prevalence of malaria infection despite high ITN coverage, but have rarely considered whether the condition of the ITN, or how many people use it, impacts efficacy. This study assessed how ITN integrity, ITN age, and the number of persons sharing a net might mitigate or reduce protective efficacy among self-identified ITN users in Malawi. METHODS: From 2012 to 2014, six cross-sectional surveys were conducted in both the rainy and dry seasons in southern Malawi. Data were collected on ITN use, integrity (number and size of holes), and age. Blood samples for detecting Plasmodium falciparum infection were obtained from reported ITN users over 6 months of age. Generalized linear mixed models were used to account for clustering at the household and community level. The final model controlled for gender, household eaves, and community-level infection prevalence during the rainy season. RESULTS: There were 9646 ITN users with blood samples across six surveys, 15% of whom tested positive for P. falciparum infection. Among children under 5 years old, there was a 50% increased odds of P. falciparum infection among those sleeping under an ITN older than two years, compared to those using an ITN less than 2 years old (OR = 1.50; 95% CI 1.07-2.08). ITN integrity and number of individuals sharing an ITN were not associated with P. falciparum infection. CONCLUSIONS: Older ITNs were associated with higher rates of P. falciparum in young children, which may indicate that insecticide concentrations play a larger role in infection prevention than the physical barrier of an ITN. ITN use was self-reported and the integrity measures lacked the precision of newer methods, suggesting a need for objective measures of ITN use and more precise assessment of ITN integrity.


Assuntos
Mosquiteiros Tratados com Inseticida , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Controle de Mosquitos/instrumentação , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Malaui/epidemiologia , Masculino , Plasmodium falciparum , Prevalência , Estações do Ano , Inquéritos e Questionários
14.
Nat Commun ; 10(1): 4328, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551421

RESUMO

Transmission-blocking vaccines have the potential to be key contributors to malaria elimination. Such vaccines elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking the cycle of transmission. To date, characterization of humoral responses to Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted in pre-clinical models. Here, we present molecular analyses of human antibody responses generated in a clinical trial evaluating Pfs25 vaccination. From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544. The interactions of 2544 and three other antibodies with Pfs25 are analyzed by crystallography to understand structural requirements for elicitation of human transmission-blocking responses. Our analyses provide insights into Pfs25 immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. Our findings can be employed to guide the design of improved malaria transmission-blocking vaccines.


Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/prevenção & controle , Proteínas de Protozoários/imunologia , Anticorpos Antiprotozoários/química , Formação de Anticorpos , Sítios de Ligação de Anticorpos , Cristalografia por Raios X , Humanos , Malária Falciparum/transmissão , Proteínas de Protozoários/química
15.
Rev Inst Med Trop Sao Paulo ; 61: e52, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531630

RESUMO

In 2018, Bhutan reported 54 cases of malaria, of which six were indigenous, 14 introduced and 34 imported. Considering the continuous reduction in the number of indigenous cases, Bhutan plans to eliminate malaria by 2025 under the Bhutan Malaria Elimination Strategy. The study was conducted to assess the presence of asymptomatic plasmodial infection in both, Bhutanese population living in malaria-risk areas and in migrant workers to guide the elimination strategies. A cross-sectional study was conducted from April to May 2016 in 750 Bhutanese people and 473 migrant workers. Plasmodium falciparum and Plasmodium vivax infections were investigated by using a rapid diagnostic test (RDT) and the polymerase chain reaction (PCR). Prevalence of asymptomatic plasmodial infection based on PCR was 0.27% (95% CI: 0.05-1.07%) among Bhutanese people with a mean age of 43 years old. The proportions of males and females were 45% and 55%, respectively. Among migrant workers, the prevalence of asymptomatic plasmodial infection was 0.42% (95% CI: 0.07-1.69%) with a mean age of 30 years old. The majority of migrant workers were from the neighboring Indian State of West Bengal (57.51%), followed by Assam (12.26%). RDT in both study groups did not detect any plasmodial infection. The presence of a low prevalence of asymptomatic plasmodial infection indicates that the current elimination strategies and interventions are effective.


Assuntos
Malária Falciparum/diagnóstico , Malária Vivax/diagnóstico , Infecções Assintomáticas , Butão/epidemiologia , Estudos Transversais , Feminino , Humanos , Índia , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Masculino , Reação em Cadeia da Polimerase , Prevalência , Migrantes
16.
Infect Dis Poverty ; 8(1): 69, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31383040

RESUMO

BACKGROUND: The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria. METHODS: At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005. RESULTS: Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015 (P = 0.002 and P <  0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% CI, 1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P <  0.0001 for each). Enrolment parasitaemia > 75 000 µl- 1, haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014-2015 independently predicted APPD1. In parallel, Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P <  0.0001). CONCLUSIONS: These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children. TRIAL REGISTRATION: Pan African Clinical Trial Registration PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015 PACTR201510001189370 , 3 July 2015; PACTR201709002064150 , 1 March 2017; https://www.pactr.samrca.ac.za.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Adolescente , Amodiaquina/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Lactente , Masculino , Nigéria
17.
BMC Med ; 17(1): 157, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31409398

RESUMO

BACKGROUND: Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity. METHODS: We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection. RESULTS: RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3-0.93], p = 0.03, for MSP1; 0.52 [0.26-0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses. CONCLUSIONS: Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines.


Assuntos
Anticorpos Antiprotozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Formação de Anticorpos , Antígenos de Protozoários/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Plasmodium falciparum/imunologia , Vacinação/métodos
18.
BMC Immunol ; 20(1): 25, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362695

RESUMO

BACKGROUND: In this study, seven adjuvants were compared for use with Plasmodium falciparum DiCo-Apical Membrane Antigen 1 (Pf-DiCo-AMA1), with the aim to identify an ideal adjuvant which yields high antibody titres and potentially broadens the responses in clinical trials. The following adjuvant formulations were evaluated: SE, SE-GLA, Liposomes, Liposomes-GLA, CoVaccine HT™, ImSaVac-P and ImSaVac-P o/w. The study was performed in rabbits, which were immunized with FVO-AMA1 in combination with one of the seven adjuvants. Antibody levels (humoral responses) and functional activity of the antibodies induced against malaria vaccine candidate AMA1 were evaluated. Thus, in this study the ideal adjuvant is expected to induce high functional antibody levels, a long-lived response, and a broad cross-strain activity. RESULTS: AMA1 formulated in all adjuvants was immunogenic. However, the magnitude of the immune responses differed between the seven adjuvants. The highest IgG levels were observed for the CoVaccine HT™ group, this was statistically significant for all four AMA1 variants versus all other adjuvant groups. No differences were observed in the breadth of the humoral response, i.e., increased recognition of AMA1 variants. Also, Growth Inhibition Activity (GIA) for both Plasmodium falciparum strains (FCR3 - homologous to FVO AMA1 protein and NF54 - heterologous to FVO AMA1 protein) were significantly higher in the CoVaccine HT™ group as compared to the other adjuvant groups. CONCLUSIONS: In brief, all seven vaccine - adjuvant formulations were immunogenic. The magnitude of the immune responses differed between the seven adjuvants. No statistically significant differences were observed in the breadth of the humoral response, nor in longevity of the response. Nevertheless, AMA1 formulated in CoVaccine HT™ appeared as the best adjuvant for use in clinical trials.


Assuntos
Adjuvantes Imunológicos , Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Membrana/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Formação de Anticorpos/imunologia , Modelos Animais de Doenças , Imunização , Imunoglobulina G/imunologia , Vacinas Antimaláricas/administração & dosagem , Coelhos
19.
Malar J ; 18(1): 259, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362768

RESUMO

BACKGROUND: As areas move closer to malaria elimination, a combination of limited resources and increasing heterogeneity in case distribution and transmission favour a shift to targeted reactive interventions. Reactive case detection (RCD), the following up of additional individuals surrounding an index case, has the potential to target transmission pockets and identify asymptomatic cases in them. Current RCD implementation strategies vary, and it is unclear which are most effective in achieving elimination. METHODS: OpenMalaria, an established individual-based stochastic model, was used to simulate RCD in a Zambia-like setting. The capacity to follow up index cases, the search radius, the initial transmission and the case management coverage were varied. Suitable settings were identified and probabilities of elimination and time to elimination estimated. The value of routinely collected prevalence and incidence data for predicting the success of RCD was assessed. RESULTS: The results indicate that RCD with the aim of transmission interruption is only appropriate in settings where initial transmission is very low (annual entomological inoculation rate (EIR) 1-2 or prevalence approx. < 7-19% depending on case management levels). Every index case needs to be followed up, up to a maximum case-incidence threshold which defines the suitability threshold of settings for elimination using RCD. Increasing the search radius around index cases is always beneficial. CONCLUSIONS: RCD is highly resource intensive, requiring testing and treating of 400-500 people every week for 5-10 years for a reasonable chance of elimination in a Zambia-like setting.


Assuntos
Erradicação de Doenças/métodos , Malária Falciparum/prevenção & controle , Humanos , Incidência , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Modelos Teóricos , Prevalência , Zâmbia/epidemiologia
20.
Malar J ; 18(1): 277, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429785

RESUMO

BACKGROUND: HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Dihydroartemisinin-piperaquine (DPQ) is recommended for treatment of Plasmodium falciparum malaria, but its efficacy and safety has not been evaluated in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events were assessed in HIV-infected individuals on non-nucleoside reverse transcriptase inhibitor-based ART (efavirenz and nevirapine) with uncomplicated P. falciparum malaria treated with dihydroartemisinin-piperaquine. METHODS: An open label single arm clinical trial was conducted in Malawi (Blantyre and Chikhwawa districts) and Mozambique (Manhiça district) involving patients aged 15-65 years with uncomplicated P. falciparum malaria who were on efavirenz-based or nevirapine-based ART. They received a directly-observed 3-day standard treatment of DPQ and were followed up until day 63 for malaria infection and adverse events. Day-42 PCR-corrected-ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat (ITT) population. RESULTS: The study enrolled 160 and 61 patients on efavirenz and nevirapine-based ART, with a baseline geometric mean (95% CI) parasite density of 2681 (1964-3661) and 9819 (6606-14,593) parasites/µL, respectively. The day-42 PCR-corrected ACPR (95% CI) was 99.4% (95.6-99.9%) in the efavirenz group and 100% in the nevirapine group. Serious adverse events occurred in 5.0% (8/160) and 3.3% (2/61) of the participants in the efavirenz and nevirapine group, respectively, but none were definitively attributable to DPQ. Cases of prolonged QT interval (> 60 ms from baseline) occurred in 31.2% (48/154) and 13.3% (8/60) of the patients on the efavirenz and nevirapine ART groups, respectively. These were not clinically significant and resolved spontaneously over time. As this study was not designed to compare the efficacy and safety of DPQ in the two ART groups, no formal statistical comparisons were made between the two ART groups. CONCLUSIONS: DPQ was highly efficacious and safe for the treatment of malaria in HIV-infected patients concurrently taking efavirenz- or nevirapine-based ART, despite known pharmacokinetic interactions between dihydroartemisinin-piperaquine and efavirenz- or nevirapine-based ART regimens. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013, https://pactr.samrc.ac.za/Search.aspx.


Assuntos
Antirretrovirais/uso terapêutico , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Malária Falciparum/prevenção & controle , Quinolinas/efeitos adversos , Adolescente , Adulto , Benzoxazinas/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Malaui , Masculino , Pessoa de Meia-Idade , Moçambique , Nevirapina/uso terapêutico , Plasmodium falciparum/fisiologia , Adulto Jovem
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