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1.
J Infect Dis ; 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32572470

RESUMO

BACKGROUND: Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. METHODS: A phase I study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC, strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. RESULTS: 12 subjects received the challenge virus; 6 with 0.5 mL of 6.5 x 103 PFU/mL (low-dose group) and 6 with 0.5 mL of 6.5 x 104 PFU/mL (mid-dose group). All except one in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5 to 9 days) and mean time of viremia was 6.8 days (range 3 to 9 days). Mean peak for all subjects was 1.6 x 107 GE/mL (range 4.6 x 103 to 5 x 107 GE/mL). There were no serious adverse events or long-term safety signals noted. CONCLUSIONS: We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing.

2.
J Infect Dis ; 221(9): 1494-1498, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-31802120

RESUMO

BACKGROUND: The World Health Organization recommends intradermal (ID) administration of rabies vaccine for preexposure prophylaxis. METHODS: In a randomized trial in adults assigned to 1 of 6 treatment groups (ID vs intramuscular [IM], 2 vs 3 doses, and controls), rabies neutralizing antibody titers were measured to 1 year postvaccination. RESULTS: ID vaccination produced acceptable antibody levels in all subjects (2- and 3-dose groups). At day 365, acceptable levels were 40% for IM and 50% for ID 2-dose schedule, and 70% for IM and 60% for ID 3-dose schedule. CONCLUSIONS: ID rabies vaccination induces acceptable antibody titers at a fraction of the dose. CLINICAL TRIALS REGISTRATION: NCT02374814.

3.
J Infect Dis ; 221(6): 927-933, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31743394

RESUMO

BACKGROUND: Chloroquine can impair the immune responses to intradermal rabies vaccination. Current guidelines recommend an extra intramuscular dose be given for postexposure prophylaxis in previously unvaccinated persons taking any antimalarial drug. METHODS: We conducted a randomized, open-label, single-site study in 103 previously unvaccinated healthy adults age ≥18 to ≤60 years old to evaluate the effects of chloroquine, atovaquone/proguanil (Malarone), and doxycycline on the antibody response to a purified chick embryo cell vaccine, given on a postexposure prophylaxis schedule. All treatment groups received antimalarials 14 days prior to and during vaccination. RESULTS: All subjects achieved accepted neutralizing antibody titers of ≥0.5 IU/mL following the second rabies vaccination dose and maintained this protection through the duration of the study. We observed a reduction in rabies antibody geometric mean titer in the chloroquine versus control groups 28 days after vaccination: 2.3 versus 6.87 IU/mL, respectively (P < .001, t test). A significant difference was not observed for those taking Malarone or doxycycline. CONCLUSIONS: We conclude that there is no reduction of rabies antibody response in subjects taking Malarone or doxycycline, but a significant reduction in those taking chloroquine; however, accepted antibody levels were achieved for all 3 antimalarials. CLINICAL TRIALS REGISTRATION: NCT02564471.


Assuntos
Anticorpos Antivirais/sangue , Antimaláricos/farmacologia , Vacinas Antirrábicas/imunologia , Raiva/prevenção & controle , Adolescente , Adulto , Anticorpos Neutralizantes , Antimaláricos/administração & dosagem , Interações Medicamentosas , Feminino , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Profilaxia Pós-Exposição , Vacinas Antirrábicas/administração & dosagem , Vírus da Raiva/imunologia , Vacinação , Adulto Jovem
4.
PLoS Negl Trop Dis ; 11(12): e0006150, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29253873

RESUMO

BACKGROUND: In Ecuador, dengue virus (DENV) infections transmitted by the Aedes aegypti mosquito are among the greatest public health concerns in urban coastal communities. Community- and household-level vector control is the principal means of controlling disease outbreaks. This study aimed to assess the impact of knowledge, attitudes, and practices (KAPs) and social-ecological factors on the presence or absence of DENV infections in the household. METHODS: In 2014 and 2015, individuals with DENV infections from sentinel clinics in Machala, Ecuador, were invited to participate in the study, as well as members of their household and members of four neighboring households located within 200 meters. We conducted diagnostic testing for DENV on all study participants; we surveyed heads of households (HOHs) regarding demographics, housing conditions and KAPs. We compared KAPs and social-ecological factors between households with (n = 139) versus without (n = 80) DENV infections, using bivariate analyses and multivariate logistic regression models with and without interactions. RESULTS: Significant risk factors in multivariate models included proximity to abandoned properties, interruptions in piped water, and shaded patios (p<0.05). Significant protective factors included the use of mosquito bed nets, fumigation inside the home, and piped water inside the home (p<0.05). In bivariate analyses (but not multivariate modeling), DENV infections were positively associated with HOHs who were male, employed, and of younger age than households without infections (p<0.05). DENV infections were not associated with knowledge, attitude, or reported barriers to prevention activities. DISCUSSION: Specific actions that can be considered to decrease the risk of DENV infections in the household include targeting vector control in highly shaded properties, fumigating inside the home, and use of mosquito bed nets. Community-level interventions include cleanup of abandoned properties, daily garbage collection, and reliable piped water inside houses. These findings can inform interventions to reduce the risk of other diseases transmitted by the Ae. aegypti mosquito, such as chikungunya and Zika fever.


Assuntos
Aedes/virologia , Vírus da Dengue/fisiologia , Dengue/prevenção & controle , Insetos Vetores/virologia , Controle de Mosquitos , Adulto , Animais , Dengue/epidemiologia , Dengue/virologia , Surtos de Doenças , Equador/epidemiologia , Monitoramento Epidemiológico , Características da Família , Feminino , Habitação , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Meio Social
5.
Am J Trop Med Hyg ; 97(2): 514-525, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28722611

RESUMO

Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).


Assuntos
Aminoquinolinas/uso terapêutico , Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Quimioterapia Combinada , Compostos Ferrosos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artesunato , Relação Dose-Resposta a Droga , Gabão , Humanos , Quênia , Masculino , Metalocenos , Pessoa de Meia-Idade
6.
Malar J ; 15(1): 573, 2016 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-27894320

RESUMO

BACKGROUND: In recent years, malaria (Plasmodium vivax and Plasmodium falciparum) has been successfully controlled in the Ecuador-Peru coastal border region. The aim of this study was to document this control effort and to identify the best practices and lessons learned that are applicable to malaria control and to other vector-borne diseases. A proximal outcome evaluation was conducted of the robust elimination programme in El Oro Province, Ecuador, and the Tumbes Region, Peru. Data collection efforts included a series of workshops with local public health experts who played central roles in the elimination effort, review of epidemiological records from Ministries of Health, and a review of national policy documents. Key programmatic and external factors are identified that determined the success of this eradication effort. CASE DESCRIPTION: From the mid 1980s until the early 2000s, the region experienced a surge in malaria transmission, which experts attributed to a combination of ineffective anti-malarial treatment, social-ecological factors (e.g., El Niño, increasing rice farming, construction of a reservoir), and political factors (e.g., reduction in resources and changes in management). In response to the malaria crisis, local public health practitioners from El Oro and Tumbes joined together in the mid-1990s to forge an unofficial binational collaboration for malaria control. Over the next 20 years, they effectively eradicated malaria in the region, by strengthening surveillance and treatment strategies, sharing of resources, operational research to inform policy, and novel interventions. DISCUSSION AND EVALUATION: The binational collaboration at the operational level was the fundamental component of the successful malaria elimination programme. This unique relationship created a trusting, open environment that allowed for flexibility, rapid response, innovation and resilience in times of crisis, and ultimately a sustainable control programme. Strong community involvement, an extensive microscopy network and ongoing epidemiologic investigations at the local level were also identified as crucial programmatic strategies. CONCLUSION: The results of this study provide key principles of a successful malaria elimination programme that can inform the next generation of public health professionals in the region, and serve as a guide to ongoing and future control efforts of other emerging vector borne diseases globally.


Assuntos
Controle de Doenças Transmissíveis/métodos , Controle de Doenças Transmissíveis/organização & administração , Erradicação de Doenças , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/epidemiologia , Malária Vivax/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Equador/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Adulto Jovem
7.
PLoS Negl Trop Dis ; 10(2): e0004423, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26919472

RESUMO

BACKGROUND: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. METHODS: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 µg, 30 µg, or 60 µg respectively of VMP001, all formulated in 500 µL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. RESULTS: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. SIGNIFICANCE: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.


Assuntos
Vacinas Antimaláricas/imunologia , Malária Vivax/prevenção & controle , Plasmodium vivax/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Anticorpos Antiprotozoários/imunologia , Feminino , Humanos , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Malária Vivax/imunologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/efeitos adversos , Vacinação , Adulto Jovem
8.
Acta Trop ; 149: 202-11, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26048558

RESUMO

Vibrio cholerae is a globally distributed water-borne pathogen that causes severe diarrheal disease and mortality, with current outbreaks as part of the seventh pandemic. Further understanding of the role of environmental factors in potential pathogen distribution and corresponding V. cholerae disease transmission over time and space is urgently needed to target surveillance of cholera and other climate and water-sensitive diseases. We used an ecological niche model (ENM) to identify environmental variables associated with V. cholerae presence in marine environments, to project a global model of V. cholerae distribution in ocean waters under current and future climate scenarios. We generated an ENM using published reports of V. cholerae in seawater and freely available remotely sensed imagery. Models indicated that factors associated with V. cholerae presence included chlorophyll-a, pH, and sea surface temperature (SST), with chlorophyll-a demonstrating the greatest explanatory power from variables selected for model calibration. We identified specific geographic areas for potential V. cholerae distribution. Coastal Bangladesh, where cholera is endemic, was found to be environmentally similar to coastal areas in Latin America. In a conservative climate change scenario, we observed a predicted increase in areas with environmental conditions suitable for V. cholerae. Findings highlight the potential for vulnerability maps to inform cholera surveillance, early warning systems, and disease prevention and control.


Assuntos
Cólera/epidemiologia , Mudança Climática , Clima , Surtos de Doenças , Oceanos e Mares , Vibrio cholerae , Bangladesh/epidemiologia , Clorofila , Clorofila A , Meio Ambiente , Humanos , América Latina/epidemiologia , Modelos Teóricos , Fatores de Risco , Temperatura
9.
Am J Trop Med Hyg ; 91(5): 1049-56, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25200269

RESUMO

Dengue virus infection is the most widespread mosquito-borne viral infection in humans and has emerged as a serious global health challenge. In the absence of effective treatment and vaccine, host factors including nutritional status, which may alter disease progression, need investigation. The interplay between nutrition and other infections is well-established, and modulation of nutritional status often presents a simple low-cost method of interrupting transmission, reducing susceptibility, and/or ameliorating disease severity. This review examines the evidence on the role of micronutrients in dengue virus infection. We found critical issues and often inconsistent results across studies; this finding along with the lack of sufficient literature in this field have limited our ability to make any recommendations. However, vitamins D and E have shown promise in small supplementation trials. In summary, the role of micronutrients in dengue virus infection is an exciting research area and needs to be examined in well-designed studies with larger samples.


Assuntos
Dengue/tratamento farmacológico , Dengue/prevenção & controle , Micronutrientes/administração & dosagem , Micronutrientes/deficiência , Cromo/administração & dosagem , Vírus da Dengue , Suplementos Nutricionais , Progressão da Doença , Humanos , Ferro na Dieta/administração & dosagem , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina A/administração & dosagem , Vitamina D/administração & dosagem , Vitamina E/administração & dosagem , Zinco/administração & dosagem
10.
Vaccine ; 30(22): 3311-9, 2012 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-22425788

RESUMO

Plasmodium vivax is the major cause of malaria outside of sub-Saharan Africa and causes morbidity and results in significant economic impact in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study, groups of C57BL/6J mice were immunized subcutaneously three times with VMP001 emulsified with synthetic TLR4 (GLA) or TLR7/8 (R848) agonist in stable emulsion (SE), a combination of the TLR4 and TLR7/8 agonists, or SE alone. Sera and splenocytes were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of mice generated high titers of anti-P. vivax IgG antibodies as detected by ELISA and immunofluorescence assay. GLA-SE promoted a shift in the antibody response to a Th1 profile, as demonstrated by the change in IgG2c/IgG1 ratio. In addition, GLA-SE induced a strong cellular immune response characterized by multi-functional, antigen-specific CD4(+) T cells secreting IL-2, TNF and IFN-γ. In contrast, mice immunized with SE or R848-SE produced low numbers of antigen-specific CD4(+) T cells, and these T cells secreted IL-2 and TNF, but not IFN-γ. Finally, R848-SE did not enhance the immune response compared to GLA-SE alone. Based on these results, we conclude that the combination of VMP001 and GLA-SE is highly immunogenic in mice and may serve as a potential second-generation vaccine candidate against vivax malaria.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Antimaláricas/imunologia , Plasmodium vivax/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Antiprotozoários/sangue , Linfócitos T CD4-Positivos/imunologia , Emulsões/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Imunoglobulina G/sangue , Injeções Subcutâneas , Interferon gama/metabolismo , Interleucina-2/metabolismo , Vacinas Antimaláricas/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Protozoários/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
11.
PLoS One ; 7(2): e31472, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22328935

RESUMO

The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) "enveloped" by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.


Assuntos
Ácido Láctico/química , Vacinas Antimaláricas/administração & dosagem , Malária Vivax/prevenção & controle , Nanopartículas/química , Plasmodium vivax/imunologia , Ácido Poliglicólico/química , Animais , Vacinas Antimaláricas/química , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Esporozoítos/imunologia
12.
Am J Trop Med Hyg ; 85(1): 34-41, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21734121

RESUMO

In vitro drug sensitivity and molecular analyses of Plasmodium falciparum track drug resistance. DNA-binding fluorescent dyes like SYBR Green I may allow field laboratories, proximal to P. falciparum collection sites, to conduct drug assays. In 2007-2008, we assayed 121 P. falciparum field isolates from western Kenya for 50% inhibitory concentrations (IC(50)) against 6 antimalarial drugs using a SYBR Green I in vitro assay: 91 immediate ex vivo (IEV) and 30 culture-adapted, along with P. falciparum reference clones D6 (chloroquine [CQ] sensitive) and W2 (CQ resistant). We also assessed P. falciparum mdr1 (Pfmdr1) copy number and single nucleotide polymorphisms (SNPs) at four codons. The IC(50)s for IEV and culture-adapted P. falciparum isolates were similar, and approximated historical IC(50)s. For Pfmdr1, mean copy number was 1, with SNPs common at codons 86 and 184. The SYBR Green I assay adapted well to our field-based laboratory, for both IEV and culture-adapted P. falciparum, warranting continued use.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Seguimentos , Humanos , Lactente , Quênia
13.
Infect Immun ; 79(9): 3492-500, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21690242

RESUMO

Plasmodium vivax is the major cause of malaria outside sub-Saharan Africa and inflicts debilitating morbidity and consequent economic impacts in developing countries. In order to produce a P. vivax vaccine for global use, we have previously reported the development of a novel chimeric recombinant protein, VMP001, based on the circumsporozoite protein (CSP) of P. vivax. Very few adjuvant formulations are currently available for human use. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study rhesus monkeys were immunized intramuscularly three times with VMP001 in combination with a stable emulsion (SE) or a synthetic Toll-like receptor 4 (TLR4) agonist (glucopyranosyl lipid A [GLA]) in SE (GLA-SE). Sera and peripheral blood mononuclear cells (PBMCs) were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of monkeys generated high titers of anti-P. vivax IgG antibodies, as detected by enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence assays. In addition, all groups generated a cellular immune response characterized by antigen-specific CD4(+) T cells secreting predominantly interleukin-2 (IL-2) and lesser amounts of tumor necrosis factor (TNF). We conclude that the combination of VMP001 and GLA-SE is safe and immunogenic in monkeys and may serve as a potential second-generation vaccine candidate against P. vivax malaria.


Assuntos
Vacinas Antimaláricas/imunologia , Malária Vivax/prevenção & controle , Plasmodium vivax/imunologia , Receptor 4 Toll-Like/agonistas , Adjuvantes Imunológicos , Animais , Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos , Emulsões , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Imunoglobulina G/sangue , Interferon gama/biossíntese , Interleucina-2/biossíntese , Interleucina-2/metabolismo , Lipídeo A/imunologia , Macaca mulatta , Malária Vivax/imunologia , Proteínas de Protozoários/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Vacinas Sintéticas/imunologia
14.
Trop Med Int Health ; 16(7): 786-93, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21447064

RESUMO

OBJECTIVES: To determine the malaria prevalence by microscopy, antigen detection and nucleic acid detection in a defined subpopulation in a Plasmodium falciparum-endemic region during the peak transmission season. METHODS: Blood specimens were collected in a cross-sectional study involving children aged 5-10 years (n = 195) presenting with acute fever to two clinics in Western Kenya. All specimens underwent microscopy, HRP2 and aldolase antigen detection by enzyme immunoassay (EIA), parasite-specific DNA and total nucleic acid (RNA and DNA) by real-time PCR (qPCR) and reverse-transcriptase PCR (qRT-PCR). RESULTS: Microscopy detected 65/195 cases of malaria infection [95% confidence interval (CI) 52-78]. HRP2 and aldolase EIA had similar sensitivity levels detecting antigen in 65/195 (95% CI, 52-78) and 57/195 (95% CI, 45-70) cases. Discordants in antigen detection vs. microscopy occurred at <470 parasites/µl and <4900 parasites/µl for HRP2 and aldolase, respectively. Detection of total nucleic acid allowed a 3 log lower limit of detection than just DNA detection by real-time PCR in vitro. In clinical specimens, 114/195 (95% CI, 100-127) were qPCR positive (DNA), and 187/195 (95% CI, 179-191) were qRT-PCR positive (DNA plus RNA). CONCLUSIONS: The prevalence of submicroscopic malaria infection was significantly higher when detecting total nucleic acid than just DNA in this outpatient population during the high transmission season. Defining standards for submicroscopic infection will be important for control programmes, diagnostics development efforts and molecular epidemiology studies.


Assuntos
Antígenos de Protozoários/isolamento & purificação , DNA de Protozoário/isolamento & purificação , Doenças Endêmicas , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Técnicas de Amplificação de Ácido Nucleico , Contagem de Ovos de Parasitas , Plasmodium falciparum/isolamento & purificação , Proteínas de Protozoários/isolamento & purificação , Criança , Pré-Escolar , Estudos Transversais , Feminino , Frutose-Bifosfato Aldolase/imunologia , Humanos , Técnicas Imunoenzimáticas , Quênia/epidemiologia , Malária Falciparum/transmissão , Masculino , Microscopia , Plasmodium falciparum/genética , Plasmodium falciparum/imunologia , Prevalência , RNA de Protozoário/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Am J Trop Med Hyg ; 83(5): 1010-3, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21036828

RESUMO

A cross-sectional study was performed in children 5 through 10 years of age presenting to outpatient clinics in Nyanza Province, Kenya, in which nasal swab and blood specimens were collected during the high malaria transmission season. Patients presenting with malaria-like symptoms within 4 days of fever onset were enrolled in the study. Plasmodium parasitemia was determined by blood smear microscopy. Nasal swabs were screened for a panel of respiratory viruses by polymerase chain reaction. Influenza A, rhinoviruses, and other respiratory viruses were detected in 18%, 26%, and 12% of 197 specimens, respectively. Four of 36 patients with influenza A had a positive malaria blood slide, compared with 20 of 52 patients with rhinovirus. A significant burden of disease caused by influenza A in febrile children during the study period was observed, highlighting the need for further research into the burden of influenza disease in regions where malaria is holoendemic.


Assuntos
Malária/diagnóstico , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/virologia , Viroses/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Quênia/epidemiologia , Malária/complicações , Malária/epidemiologia , Masculino , Pacientes Ambulatoriais , Infecções Respiratórias/complicações , Infecções Respiratórias/epidemiologia , Viroses/epidemiologia , Viroses/virologia , Eliminação de Partículas Virais
16.
Am J Trop Med Hyg ; 83(3): 458-64, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20810804

RESUMO

From April 2005 to April 2006, a phase 2 malaria vaccine trial in Kenya enrolled 400 children aged 12-47 months. Each received mixed supervised and unsupervised artemether-lumefantrine for uncomplicated malaria, using a standard six-dose regimen, by weight. Children were followed for detection of parasitemia and clinical malaria. A median of two negative malaria blood films occurred during every recurrent parasitemia (RP) episode, suggesting reinfection over late recrudescence. Median time to RP after starting artemether-lumefantrine was 37 days (36-38). Of 2,020 evaluable artemether-lumefantrine treatments, there were no RPs in 99% by day 14, 71% by day 28, and 41% by day 42. By World Health Organization standards, 71% of treatment courses had adequate responses. Although recrudescence in some cannot be ruled out, our cohort had a shorter median time to RP compared with other artemether-lumefantrine treatment studies. This underscores patient counseling on completing all treatment doses for optimal protection from RP.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária/tratamento farmacológico , Animais , Antimaláricos/administração & dosagem , Combinação Arteméter e Lumefantrina , Pré-Escolar , Combinação de Medicamentos , Humanos , Lactente , Quênia , Malária/sangue , Malária/parasitologia , Vacinas Antimaláricas/administração & dosagem , Plasmodium/classificação , Plasmodium/isolamento & purificação , Recidiva
17.
PLoS Negl Trop Dis ; 4(3): e628, 2010 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-20231896

RESUMO

BACKGROUND: Cutaneous Leishmania major has affected many travelers including military personnel in Iraq and Afghanistan. Optimal treatment for this localized infection has not been defined, but interestingly the parasite is thermosensitive. METHODOLOGY/PRINCIPAL FINDINGS: Participants with parasitologically confirmed L. major infection were randomized to receive intravenous sodium stibogluconate (SSG) 20mg/kg/day for ten doses or localized ThermoMed (TM) device heat treatment (applied at 50 degrees C for 30 seconds) in one session. Those with facial lesions, infection with other species of Leishmania, or more than 20 lesions were excluded. Primary outcome was complete re-epithelialization or visual healing at two months without relapse over 12 months. Fifty-four/56 enrolled participants received intervention, 27 SSG and 27 TM. In an intent to treat analysis the per subject efficacy at two months with 12 months follow-up was 54% SSG and 48% TM (p = 0.78), and the per lesion efficacy was 59% SSG and 73% TM (p = 0.053). Reversible abdominal pain/pancreatitis, arthralgias, myalgias, headache, fatigue, mild cytopenias, and elevated transaminases were more commonly present in the SSG treated participants, whereas blistering, oozing, and erythema were more common in the TM arm. CONCLUSIONS/SIGNIFICANCE: Skin lesions due to L. major treated with heat delivered by the ThermoMed device healed at a similar rate and with less associated systemic toxicity than lesions treated with intravenous SSG. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT 00884377.


Assuntos
Gluconato de Antimônio e Sódio/uso terapêutico , Hipertermia Induzida , Leishmania major/efeitos dos fármacos , Leishmania major/efeitos da radiação , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/terapia , Adolescente , Adulto , Animais , Gluconato de Antimônio e Sódio/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
18.
Vaccine ; 28(31): 5135-44, 2010 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-19737527

RESUMO

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed "LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10microg LSA-NRC/0.5ml AS01 (n=5), high dose (HD) LSA-NRC/AS01: 50microg LSA-NRC/0.5ml AS01 (n=13); LD LSA-NRC/AS02: 10microg LSA-NRC/0.5ml AS02 (n=5) and HD LSA-NRC/AS02: 50microg LSA-NRC/0.5ml AS02 (n=13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-gamma) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-gamma responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p=0.95). LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.


Assuntos
Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Adjuvantes Imunológicos/farmacologia , Adulto , Anticorpos Antiprotozoários/sangue , Formação de Anticorpos , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Esquemas de Imunização , Imunização Secundária , Interferon gama/imunologia , Interleucina-2/imunologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/imunologia , Masculino , Parasitemia/imunologia , Plasmodium falciparum/imunologia , Proteínas Recombinantes/imunologia , Esporozoítos/imunologia , Adulto Jovem
19.
PLoS One ; 4(11): e7849, 2009 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-19924281

RESUMO

OBJECTIVE: RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02(A) or AS01(B). A recent trial of the RTS,S/AS02(A) and RTS,S/AS01(B) vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02(A) and RTS,S/AS01(B) on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias. DESIGN: The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine. SETTING: The study was conducted in Kombewa District, western Kenya. PARTICIPANTS: Semi-immune adults from the three study arms provided isolates at baseline and during break-through infections. OUTCOME: Parasite isolates used for determining MOI and divergence of csp T cell-epitopes were 191 at baseline and 87 from break-through infections. RESULTS: Grouping recipients of RTS,S/AS01(A) and RTS,S/AS02(B) together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01(B) group, but not the RTS,S/AS02(A) group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups. CONCLUSIONS: It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct.


Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária/prevenção & controle , Malária/parasitologia , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Adolescente , Adulto , Alelos , Epitopos de Linfócito T/química , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Polimorfismo Genético , Análise de Sequência de DNA
20.
PLoS One ; 4(7): e6465, 2009 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-19649245

RESUMO

BACKGROUND: This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine. METHODOLOGY: A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1ratio1ratio1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (Rabipur; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination. PRINCIPAL FINDINGS: Both candidate vaccines had a good safety profile and were well tolerated. One grade 3 systemic AE occurred within 7 days of vaccination (RTS,S/AS01B group). No unsolicited AEs or SAEs were related to vaccine. A marked increase in anti-CS antibody GMTs was observed post Dose 2 of both RTS,S/AS01B (31.6 EU/mL [95% CI: 23.9 to 41.6]) and RTS,S/AS02A (16.7 EU/mL [95% CI: 12.9 to 21.7]). A further increase was observed post Dose 3 in both the RTS,S/AS01B (41.4 EU/mL [95% CI: 31.7 to 54.2]) and RTS,S/AS02A (21.4 EU/mL [95% CI: 16.0 to 28.7]) groups. Anti-CS antibody GMTs were significantly greater with RTS,S/AS01B compared to RTS,S/AS02A at all time points post Dose 2 and Dose 3. Both candidate vaccines produced strong anti-HBs responses. Vaccine efficacy in the RTS,S/AS01B group was 29.5% (95% CI: -15.4 to 56.9, p = 0.164) and in the RTS,S/AS02A group 31.7% (95% CI: -11.6 to 58.2, p = 0.128). CONCLUSIONS: Both candidate malaria vaccines were well tolerated over a 12 month surveillance period. A more favorable immunogenicity profile was observed with RTS,S/AS01B than with RTS,S/AS02A. TRIAL REGISTRATION: Clinicaltrials.gov NCT00197054.


Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária/prevenção & controle , Adulto , Método Duplo-Cego , Seguimentos , Humanos , Quênia/epidemiologia , Malária/epidemiologia , Vacinas Antimaláricas/efeitos adversos , Método Simples-Cego , Resultado do Tratamento
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