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1.
PLoS Comput Biol ; 16(10): e1008292, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33075052

RESUMEN

The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control-the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.


Asunto(s)
Control de Enfermedades Transmisibles/métodos , Enfermedades Endémicas/prevención & control , Programas de Inmunización , Animales , Número Básico de Reproducción , Infecciones por Coronavirus/prevención & control , Culicidae , Vacunas contra el Dengue/uso terapéutico , Política de Salud , Humanos , Insectos Vectores , Modelos Teóricos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Salud Pública , Rubéola (Sarampión Alemán)/prevención & control , Vacuna contra la Rubéola/uso terapéutico , Estaciones del Año , Dengue Grave/prevención & control , Vacunas Virales/uso terapéutico
2.
Arch Virol ; 165(3): 671-681, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31942645

RESUMEN

Dengue virus (DENV) is the most common mosquito-borne viral disease. The World Health Organization estimates that 400 million new cases of dengue fever occur every year. Approximately 500,000 individuals develop severe and life-threatening complications from dengue fever, such as dengue shock syndrome (DSS) and dengue hemorrhagic fever (DHF), which cause 22,000 deaths yearly. Currently, there are no specific licensed therapeutics to treat DENV illness. We have previously shown that the MEK/ERK inhibitor U0126 inhibits the replication of the flavivirus yellow fever virus. In this study, we demonstrate that the MEK/ERK inhibitor AZD6244 has potent antiviral efficacy in vitro against DENV-2, DENV-3, and Saint Louis encephalitis virus (SLEV). We also show that it is able to protect AG129 mice from a lethal challenge with DENV-2 (D2S20). The molecule is currently undergoing phase III clinical trials for the treatment of non-small-cell lung cancer. The effect of AZD6244 on the DENV life cycle was attributed to a blockade of morphogenesis. Treatment of AG129 mice twice daily with oral doses of AZD6244 (100 mg/kg/day) prevented the animals from contracting dengue hemorrhagic fever (DHF)-like lethal disease upon intravenous infection with 1 × 105 PFU of D2S20. The effectiveness of AZD6244 was observed even when the treatment of infected animals was initiated 1-2 days postinfection. This was also followed by a reduction in viral copy number in both the serum and the spleen. There was also an increase in IL-1ß and TNF-α levels in mice that were infected with D2S20 and treated with AZD6244 in comparison to infected mice that were treated with the vehicle only. These data demonstrate the potential of AZD6244 as a new therapeutic agent to treat DENV infection and possibly other flavivirus diseases.


Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Virus del Dengue/crecimiento & desarrollo , Dengue Grave/prevención & control , Animales , Línea Celular , Cricetinae , Virus del Dengue/efectos de los fármacos , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Interleucina-1beta/sangre , Ratones , Dengue Grave/virología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/sangre
3.
Viruses ; 11(9)2019 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-31450611

RESUMEN

Following the Ebola outbreak in Western Africa in 2013-16, a global effort has taken place for preparedness for future outbreaks. As part of this response, the development of vaccines, treatments and diagnostic tools has been accelerated, especially towards pathogens listed as likely to cause an epidemic and for which there are no current treatments. Several of the priority pathogens identified by the World Health Organisation are haemorrhagic fever viruses. This review provides information on the role of reference materials as an enabling tool for the development and evaluation of assays, and ultimately vaccines and treatments. The types of standards available are described, along with how they can be applied for assay harmonisation through calibration as a relative potency to a common arbitrary unitage system (WHO International Unit). This assures that assay metrology is accurate and robust. We describe reference materials that have been or are being developed for haemorrhagic fever viruses and consider the issues surrounding their production, particularly that of biosafety where the viruses require specialised containment facilities. Finally, we advocate the use of reference materials at early stages, including research and development, as this helps produce reliable assays and can smooth the path to regulatory approval.


Asunto(s)
Técnicas y Procedimientos Diagnósticos , Fiebre Hemorrágica Ebola , Servicios de Información , Infecciones por Virus ARN , Vacunas/normas , África Occidental/epidemiología , Animales , Antígenos Virales/sangre , Virus del Dengue/inmunología , Virus del Dengue/aislamiento & purificación , Virus del Dengue/patogenicidad , Brotes de Enfermedades/prevención & control , Ebolavirus/inmunología , Ebolavirus/aislamiento & purificación , Ebolavirus/patogenicidad , Epidemias/prevención & control , Virus de la Fiebre Hemorrágica de Crimea-Congo/inmunología , Virus de la Fiebre Hemorrágica de Crimea-Congo/aislamiento & purificación , Virus de la Fiebre Hemorrágica de Crimea-Congo/patogenicidad , Fiebre Hemorrágica de Crimea/diagnóstico , Fiebre Hemorrágica de Crimea/inmunología , Fiebre Hemorrágica de Crimea/prevención & control , Fiebre Hemorrágica Ebola/diagnóstico , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Fiebre de Lassa/diagnóstico , Fiebre de Lassa/inmunología , Fiebre de Lassa/prevención & control , Virus Lassa/inmunología , Virus Lassa/aislamiento & purificación , Virus Lassa/patogenicidad , Enfermedad del Virus de Marburg/diagnóstico , Enfermedad del Virus de Marburg/inmunología , Enfermedad del Virus de Marburg/prevención & control , Marburgvirus/inmunología , Marburgvirus/aislamiento & purificación , Marburgvirus/patogenicidad , Infecciones por Virus ARN/diagnóstico , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/prevención & control , Virus ARN/inmunología , Virus ARN/aislamiento & purificación , Virus ARN/patogenicidad , ARN Viral/aislamiento & purificación , Fiebre del Valle del Rift/diagnóstico , Fiebre del Valle del Rift/inmunología , Fiebre del Valle del Rift/prevención & control , Virus de la Fiebre del Valle del Rift/inmunología , Virus de la Fiebre del Valle del Rift/aislamiento & purificación , Virus de la Fiebre del Valle del Rift/patogenicidad , Dengue Grave/diagnóstico , Dengue Grave/inmunología , Dengue Grave/prevención & control , Organización Mundial de la Salud
4.
Enferm. clín. (Ed. impr.) ; 29(supl.1): 30-33, mar. 2019.
Artículo en Inglés | IBECS | ID: ibc-184764

RESUMEN

Objective: This study aims to determine the effectiveness of health education through audiovisual media on improving family knowledge in the prevention of dengue fever (DHF). Method: This study used a Quasi Experiment research design with a research design of Non-Equivalent Control Group. The study was conducted in the community with a sample of 40 people, consisting of 20 for experimental group and 20 for control group. The samples were selected using purposive sample collection method. The measuring instrument used is a questionnaire that has been tested for validity and reliability. The analysis was done through univariate analysis and bivariate analysis using t-independent test. Result: This study found that the showed a significant increase in changes in the level of attitudes and actions of families in the prevention of dengue fever by using audiovisual media, (p = 0.000), (p = 0.000). Conclusion: It is recommended that the health workers should provide health education by using audiovisual media in the prevention of dengue fever


No disponible


Asunto(s)
Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Recursos Audiovisuales , Salud de la Familia , Conductas Relacionadas con la Salud , Educación en Salud/métodos , Conocimientos, Actitudes y Práctica en Salud , Dengue Grave/prevención & control
5.
Enferm Clin ; 29 Suppl 1: 30-33, 2019 03.
Artículo en Inglés, Español | MEDLINE | ID: mdl-30745163

RESUMEN

OBJECTIVE: This study aims to determine the effectiveness of health education through audiovisual media on improving family knowledge in the prevention of dengue fever (DHF). METHOD: This study used a Quasi Experiment research design with a research design of Non-Equivalent Control Group. The study was conducted in the community with a sample of 40 people, consisting of 20 for experimental group and 20 for control group. The samples were selected using purposive sample collection method. The measuring instrument used is a questionnaire that has been tested for validity and reliability. The analysis was done through univariate analysis and bivariate analysis using t-independent test. RESULT: This study found that the showed a significant increase in changes in the level of attitudes and actions of families in the prevention of dengue fever by using audiovisual media, (p=0.000), (p=0.000). CONCLUSION: It is recommended that the health workers should provide health education by using audiovisual media in the prevention of dengue fever.


Asunto(s)
Recursos Audiovisuales , Salud de la Familia , Conductas Relacionadas con la Salud , Educación en Salud/métodos , Conocimientos, Actitudes y Práctica en Salud , Dengue Grave/prevención & control , Adolescente , Adulto , Anciano , Humanos , Persona de Mediana Edad , Adulto Joven
6.
Lancet Infect Dis ; 19(1): e31-e38, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30195995

RESUMEN

The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE's working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses.


Asunto(s)
Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Inmunización Secundaria , Dengue Grave/prevención & control , Vacunación , Vacunas Atenuadas/inmunología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Tamizaje Masivo , Estudios Seroepidemiológicos , Dengue Grave/virología , Resultado del Tratamiento , Organización Mundial de la Salud
7.
Proc Natl Acad Sci U S A ; 115(52): E12363-E12369, 2018 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-30530648

RESUMEN

Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here, we applied virus-inclusive single-cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls and to characterize distinct leukocyte subtypes that harbor viral RNA (vRNA). Multiple IFN response genes, particularly MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes, were up-regulated in a cell-specific manner before progression to SD. The majority of vRNA-containing cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and various antiviral genes, followed by monocytes. Bystander, non-vRNA-containing B cells also demonstrated immune activation, and IgG1 plasmablasts from two patients exhibited clonal expansions. Lastly, assembly of the DENV genome sequence revealed diversity at unexpected sites. This study presents a multifaceted molecular elucidation of natural dengue infection in humans with implications for any tissue and viral infection and proposes candidate biomarkers for prediction of SD.


Asunto(s)
Dengue/diagnóstico , Dengue/genética , Análisis de la Célula Individual/métodos , Adulto , Linfocitos B/metabolismo , Biomarcadores/sangre , Dengue/virología , Virus del Dengue/genética , Progresión de la Enfermedad , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Monocitos/metabolismo , Células Plasmáticas/metabolismo , Virus ARN/genética , ARN Viral/metabolismo , Análisis de Secuencia de ARN/métodos , Dengue Grave/prevención & control , Transcriptoma , Replicación Viral/inmunología
8.
PLoS Negl Trop Dis ; 12(12): e0006938, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30550569

RESUMEN

BACKGROUND: Given that dengue disease is growing and may progress to dengue hemorrhagic fever (DHF), data on economic cost and disease burden are important. However, data for Mexico are limited. METHODOLOGY/PRINCIPAL FINDINGS: Burden of dengue fever (DF) and DHF in Mexico was assessed using official databases for epidemiological information, disabilities weights from Shepard et al, the reported number of cases and deaths, and costs. Overall costs of dengue were summed from direct medical costs to the health system, cost of dengue to the patient (out-of-pocket expenses [medical and non-medical], indirect costs [loss of earnings, patient and/or caregiver]), and other government expenditures on prevention/surveillance. The first three components, calculated as costs per case by a micro-costing approach (PAATI; program, actions, activities, tasks, inputs), were scaled up to overall cost using epidemiology data from official databases. PAATI was used to calculate cost of vector control and prevention, education, and epidemiological surveillance, based on an expert consensus and normative construction of an ideal scenario. Disability-adjusted life years (DALYs) for Mexico in 2016 were calculated to be 2283.46 (1.87 per 100,000 inhabitants). Overall economic impact of dengue in Mexico for 2012 was US$144 million, of which US$44 million corresponded to direct medical costs and US$5 million to the costs from the patient's perspective. The estimated cost of prevention/surveillance was calculated with information provided by federal government to be US$95 million. The overall economic impact of DF and DHF showed an increase in 2013 to US$161 million and a decrease to US$133, US$131 and US$130 million in 2014, 2015 and 2016, respectively. CONCLUSIONS/SIGNIFICANCE: The medical and economic impact of dengue were in agreement with other international studies, and highlight the need to include governmental expenditure for prevention/surveillance in overall cost analyses given the high economic impact of these, increasing the necessity to evaluate its effectiveness.


Asunto(s)
Dengue/economía , Dengue Grave/economía , Adolescente , Adulto , Anciano , Cuidadores , Niño , Preescolar , Dengue/epidemiología , Dengue/prevención & control , Personas con Discapacidad , Programas de Gobierno , Costos de la Atención en Salud , Gastos en Salud , Humanos , Lactante , México/epidemiología , Persona de Mediana Edad , Años de Vida Ajustados por Calidad de Vida , Dengue Grave/epidemiología , Dengue Grave/prevención & control , Adulto Joven
9.
Antiviral Res ; 158: 1-7, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30071205

RESUMEN

Dengue virus (DENV) currently circulates in more than 100 countries and causes an estimated 390 million infections per year. While most cases manifest as a self-resolving fever, ∼1.5% of infections develop into a more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which causes ∼20,000 deaths annually. The underlying pathological feature of DHF/DSS, also known as Severe Dengue, is an acute increase in vascular permeability leading to hypovolemia and shock. Angiogenic factors and cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF), have been implicated in the increased vascular permeability, suggesting a potential therapeutic strategy for Severe Dengue. Here, we employed a mouse model of antibody-dependent enhancement of DENV infection, which recapitulates the fatal capillary leakage and shock of human Severe Dengue, to investigate the effects of approved VEGF- and TNF-targeting drugs. DENV infection caused a significant increase in serum VEGF levels within 2 days and resulted in ∼80% mortality within 8 days of infection. Treatment of mice with sunitinib, a VEGF receptor tyrosine kinase inhibitor, once (day 2) or twice (days 1 and 2) post-infection reduced mortality by 50-80% compared with untreated mice. Notably, sunitinib treatment decreased serum TNF levels, white blood cell counts, and hematocrit levels relative to untreated mice, but had only marginal effects on tissue viral burden. Combination therapy with anti-TNF antibody and sunitinib significantly reduced vascular leakage and synergized to provide superior protection from lethal DENV infection compared with either agent alone. These data suggest that a two-pronged anti-angiogenic and anti-inflammatory approach may be useful for the rapid treatment of DHF/DSS.


Asunto(s)
Anticuerpos Antivirales/farmacología , Dengue/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sunitinib/farmacología , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Inductores de la Angiogénesis , Animales , Acrecentamiento Dependiente de Anticuerpo , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Culicidae , Dengue/virología , Virus del Dengue/patogenicidad , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Masculino , Ratones , ARN Viral/aislamiento & purificación , Dengue Grave/prevención & control , Tasa de Supervivencia , Factor A de Crecimiento Endotelial Vascular/sangre , Carga Viral
10.
Expert Rev Vaccines ; 17(8): 753-763, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30063839

RESUMEN

BACKGROUND: A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination. RESEARCH DESIGN AND METHODS: Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study. The model was used to assess vaccination outcomes for a range of transmission settings over 5-30 years, with or without indirect protection. MAIN OUTCOME MEASURES: Symptomatic dengue cases, dengue hospitalizations, and severe dengue cases. RESULTS: The model is consistent with previous results indicating a transitory period at increased risk for dengue-seronegative vaccine recipients (setting-dependent duration) and long-term benefits for dengue-seropositive recipients. At the population level, benefits to seropositive individuals over 10 years outweighed the risk to those seronegative in moderate to high transmission settings (≥50% seropositivity at age 9), especially in high transmission settings (no excess hospitalizations in dengue-seronegative for ≥80% seropositivity at age 9). Results were more favorable when longer time horizons or indirect protection were considered. CONCLUSIONS: Results indicate a public health benefit associated with dengue vaccination especially in high-transmission settings, even with the initial excess risks to dengue-seronegative patients which diminish over time.


Asunto(s)
Vacunas contra el Dengue/administración & dosificación , Dengue/prevención & control , Modelos Teóricos , Vacunación , Adolescente , Niño , Preescolar , Ensayos Clínicos como Asunto , Estudios de Cohortes , Dengue/epidemiología , Dengue/transmisión , Vacunas contra el Dengue/inmunología , Hospitalización/estadística & datos numéricos , Humanos , Salud Pública , Estudios Seroepidemiológicos , Dengue Grave/epidemiología , Dengue Grave/prevención & control , Dengue Grave/transmisión , Factores de Tiempo
11.
J Biomed Sci ; 25(1): 58, 2018 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-30037331

RESUMEN

Dengue virus (DENV) infection is the most common mosquito-transmitted viral infection. DENV infection can cause mild dengue fever or severe dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Hemorrhage and vascular leakage are two characteristic symptoms of DHF/DSS. However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat nor vaccine to prevent dengue infection are available, and the mortality of DHF/DSS is still high. DENV nonstructural protein 1 (NS1), which can be secreted in patients' sera, has been used as an early diagnostic marker for dengue infection for many years. However, the roles of NS1 in dengue-induced vascular leakage were described only recently. In this article, the pathogenic roles of DENV NS1 in hemorrhage and vascular leakage are reviewed, and the possibility of using NS1 as a therapeutic target and vaccine candidate is discussed.


Asunto(s)
Virus del Dengue/genética , Dengue Grave/prevención & control , Vacunas/uso terapéutico , Proteínas no Estructurales Virales/genética , Anticuerpos Antivirales/uso terapéutico , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Humanos , Dengue Grave/inmunología , Dengue Grave/virología , Vacunas/inmunología , Proteínas no Estructurales Virales/inmunología , Proteínas no Estructurales Virales/uso terapéutico
12.
Arch Virol ; 163(7): 1717-1726, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29520688

RESUMEN

Dengue is the most prevalent arboviral disease in humans and leads to significant morbidity and socioeconomic burden in tropical and subtropical areas. Dengue is caused by infection with any of the four closely related serotypes of dengue virus (DENV1-4) and usually manifests as a mild febrile illness, but may develop into fatal dengue hemorrhagic fever and shock syndrome. There are no specific antiviral therapies against dengue because understanding of DENV biology is limited. A tetravalent chimeric dengue vaccine, Dengvaxia, has finally been licensed for use, but its efficacy was significantly lower against DENV-2 infections and in dengue-naïve individuals. The identification of mechanisms underlying the interactions between DENV and immune responses will help to determine efficient therapeutic and preventive options. It has been well established how the innate immune system responds to DENV infection and how DENV overcomes innate antiviral defenses, however further progress in this field remains hampered by the absence of appropriate experimental dengue models. Herein, we review the available in vitro and in vivo approaches to study the innate immune responses to DENV.


Asunto(s)
Virus del Dengue/inmunología , Dengue/inmunología , Inmunidad Innata , Dengue Grave/inmunología , Animales , Antivirales/uso terapéutico , Dengue/tratamiento farmacológico , Dengue/prevención & control , Dengue/virología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/inmunología , Virus del Dengue/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Ratones , Primates , Dengue Grave/tratamiento farmacológico , Dengue Grave/prevención & control , Dengue Grave/virología
13.
PLoS Negl Trop Dis ; 12(1): e0006191, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29309412

RESUMEN

BACKGROUND: Dengue is one of the fastest spreading vector-borne diseases, caused by four antigenically distinct dengue viruses (DENVs). Antibodies against DENVs are responsible for both protection as well as pathogenesis. A vaccine that is safe for and efficacious in all people irrespective of their age and domicile is still an unmet need. It is becoming increasingly apparent that vaccine design must eliminate epitopes implicated in the induction of infection-enhancing antibodies. METHODOLOGY/PRINCIPAL FINDINGS: We report a Pichia pastoris-expressed dengue immunogen, DSV4, based on DENV envelope protein domain III (EDIII), which contains well-characterized serotype-specific and cross-reactive epitopes. In natural infection, <10% of the total neutralizing antibody response is EDIII-directed. Yet, this is a functionally relevant domain which interacts with the host cell surface receptor. DSV4 was designed by in-frame fusion of EDIII of all four DENV serotypes and hepatitis B surface (S) antigen and co-expressed with unfused S antigen to form mosaic virus-like particles (VLPs). These VLPs displayed EDIIIs of all four DENV serotypes based on probing with a battery of serotype-specific anti-EDIII monoclonal antibodies. The DSV4 VLPs were highly immunogenic, inducing potent and durable neutralizing antibodies against all four DENV serotypes encompassing multiple genotypes, in mice and macaques. DSV4-induced murine antibodies suppressed viremia in AG129 mice and conferred protection against lethal DENV-4 virus challenge. Further, neither murine nor macaque anti-DSV4 antibodies promoted mortality or inflammatory cytokine production when passively transferred and tested in an in vivo dengue disease enhancement model of AG129 mice. CONCLUSIONS/SIGNIFICANCE: Directing the immune response to a non-immunodominant but functionally relevant serotype-specific dengue epitope of the four DENV serotypes, displayed on a VLP platform, can help minimize the risk of inducing disease-enhancing antibodies while eliciting effective tetravalent seroconversion. DSV4 has a significant potential to emerge as a safe, efficacious and inexpensive subunit dengue vaccine candidate.


Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Acrecentamiento Dependiente de Anticuerpo , Virus del Dengue/inmunología , Dengue Grave/prevención & control , Vacunas de Partículas Similares a Virus/inmunología , Proteínas del Envoltorio Viral/inmunología , Animales , Virus del Dengue/genética , Modelos Animales de Enfermedad , Macaca , Ratones , Pichia/genética , Pichia/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serogrupo , Dengue Grave/patología , Análisis de Supervivencia , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/genética , Proteínas del Envoltorio Viral/genética
14.
Rev. cuba. med. trop ; 69(3): 1-15, set.-dic. 2017.
Artículo en Español | LILACS, CUMED | ID: biblio-901256

RESUMEN

El dengue es una enfermedad viral transmitida por mosquitos que puede ser causa de gravedad y muerte. No existe droga antiviral reconocida como eficaz. Sin embargo, las regularidades de esta enfermedad han permitido la identificación de signos de alarma que anuncian extravasación de plasma e inminencia del choque. El inicio precoz del tratamiento de los pacientes mediante la reposición de líquidos cristaloides por vía intravenosa ha demostrado ser una medida efectiva y salvadora. Se necesita capacitación sistemática y acciones de reorganización de la atención médica en función de la epidemia. Se expone la contribución de los profesionales del Instituto de Medicina Tropical Pedro Kourí y otras instituciones cubanas a ese empeño(AU)


Dengue is a viral disease transmitted by mosquitoes which may be severe and cause death. No antiviral drug has been recognized as effective. However, the regularities of this condition have made it possible to identify warning signs announcing plasma leakage and the imminence of shock. Early start of treatment with intravenous crystalloid fluid replacement has proven to be an effective, life-saving measure. Systematic training actions and reorganization of medical care are required during an epidemic. The paper describes the contribution of professionals from Pedro Kouri Tropical Medicine Institute and other Cuban institutions to this effort(AU)


Asunto(s)
Humanos , Masculino , Femenino , Dengue Grave/prevención & control , Dengue/mortalidad , Dengue/terapia , Cuba , Dengue/diagnóstico , Cristales Líquidos/normas
15.
Vaccine ; 35(36): 4659-4669, 2017 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-28757058

RESUMEN

Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied extensively but are still not fully understood. Results from Phase 3 vaccine efficacy trials have recently become available for one vaccine candidate, now licensed for use in several countries, and more Phase 2 and 3 studies of additional vaccine candidates are ongoing, making these issues all the more urgent and timely. At the "Summit on Dengue Immune Correlates of Protection", held in Annecy, France, on March 8-9, 2016, dengue experts from diverse fields came together to discuss the current understanding of the immune response to and protection from DENV infection and disease, identify key unanswered questions, discuss data on immune correlates and plans for comparison of results across assays/consortia, and propose a research agenda for investigation of dengue immune correlates, all in the context of both natural infection studies and vaccine trials.


Asunto(s)
Anticuerpos Antivirales/inmunología , Virus del Dengue/inmunología , Dengue/inmunología , Dengue Grave/inmunología , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/inmunología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Congresos como Asunto , Dengue/prevención & control , Vacunas contra el Dengue , Virus del Dengue/genética , Humanos , Dengue Grave/prevención & control
16.
PLoS Negl Trop Dis ; 11(7): e0005721, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28686617

RESUMEN

Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are severe disease manifestations that can occur following sequential infection with different dengue virus serotypes (DENV1-4). At present, there are no licensed therapies to treat DENV-induced disease. DHF and DSS are thought to be mediated by serotype cross-reactive antibodies that facilitate antibody-dependent enhancement (ADE) by binding to viral antigens and then Fcγ receptors (FcγR) on target myeloid cells. Using genetically engineered DENV-specific antibodies, it has been shown that the interaction between the Fc portion of serotype cross-reactive antibodies and FcγR is required to induce ADE. Additionally, it was demonstrated that these antibodies were as neutralizing as their non-modified variants, were incapable of inducing ADE, and were therapeutic following a lethal, antibody-enhanced infection. Therefore, we hypothesized that avian IgY, which do not interact with mammalian FcγR, would provide a novel therapy for DENV-induced disease. We demonstrate here that goose-derived anti-DENV2 IgY neutralized DENV2 and did not induce ADE in vitro. Anti-DENV2 IgY was also protective in vivo when administered 24 hours following a lethal DENV2 infection. We were also able to demonstrate via epitope mapping that both full-length and alternatively spliced anti-DENV2 IgY recognized different epitopes, including epitopes that have not been previously identified. These observations provide evidence for the potential therapeutic applications of goose-derived anti-DENV2 IgY.


Asunto(s)
Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Acrecentamiento Dependiente de Anticuerpo/inmunología , Inmunoglobulinas/administración & dosificación , Dengue Grave/prevención & control , Animales , Línea Celular , Reacciones Cruzadas , Virus del Dengue , Epítopos/inmunología , Femenino , Gansos , Humanos , Ratones , Ratones Noqueados , Dengue Grave/inmunología , Vacunación , Proteínas del Envoltorio Viral/inmunología
17.
Expert Rev Anti Infect Ther ; 15(6): 585-604, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28480779

RESUMEN

INTRODUCTION: Pooled human immunoglobulins (IGs) are prepared from plasma obtained from healthy donors as a concentrated antibody-containing solution. In addition, high-titer IGs (hyperimmune) against a specific pathogen can be obtained from vaccinated or convalescing donors. Currently, IGs can be used for the treatment of a variety of infections for which no specific therapy exists or that remain difficult to treat. Moreover, the recent pathogen outbreaks for which there is no approved treatment have renewed attention to the role of convalescent plasma and IGs. Areas covered: In this review, a historical perspective of the use of sera and IGs in humans as anti-infective agents (any viral, bacterial, parasitic infection), excluding immunodeficient patients, is presented from early development to the latest clinical studies. A Medline search was conducted to examine the peer-reviewed literature, with no date limits. Expert commentary: Human pooled plasma-derived IG products benefit from the polyclonal response of every individual donor and from the interindividual variability in such response. The trend to increased availability of vaccines for infectious diseases also opens new potential applications of hyperimmune IGs for emerging or re-emerging infectious diseases (e.g.: Ebola, Zika, Dengue), for the prevention and treatment in the general population, healthcare personnel and caregivers.


Asunto(s)
Enfermedades Transmisibles Emergentes/tratamiento farmacológico , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Sueros Inmunes/administración & dosificación , Inmunización Pasiva/métodos , Inmunoglobulinas/uso terapéutico , Dengue Grave/tratamiento farmacológico , Infección por el Virus Zika/tratamiento farmacológico , Ensayos Clínicos como Asunto , Enfermedades Transmisibles Emergentes/inmunología , Enfermedades Transmisibles Emergentes/prevención & control , Enfermedades Transmisibles Emergentes/virología , Convalecencia , Virus del Dengue/efectos de los fármacos , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Ebolavirus/efectos de los fármacos , Ebolavirus/inmunología , Ebolavirus/patogenicidad , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/virología , Humanos , Dengue Grave/inmunología , Dengue Grave/prevención & control , Dengue Grave/virología , Vacunación , Vacunas Virales/administración & dosificación , Vacunas Virales/biosíntesis , Virus Zika/efectos de los fármacos , Virus Zika/inmunología , Virus Zika/patogenicidad , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/prevención & control , Infección por el Virus Zika/virología
18.
Hum Vaccin Immunother ; 13(5): 1059-1072, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28281864

RESUMEN

Dengue has become a major global public health threat with almost half of the world's population living in at-risk areas. Vaccination would likely represent an effective strategy for the management of dengue disease in endemic regions, however to date there is only one licensed preventative vaccine for dengue infection. The development of a vaccine against dengue virus (DENV) has been hampered by an incomplete understanding of protective immune responses against DENV. The most clinically advanced dengue vaccine is the chimeric yellow fever-dengue vaccine (CYD) that employs the yellow fever virus 17D strain as the replication backbone (Chimerivax-DEN; CYD-TDV). This vaccine had an overall pooled protective efficacy of 65.6% but was substantially more effective against severe dengue and dengue hemorrhagic fever. Several other vaccine approaches have been developed including live attenuated chimeric dengue vaccines (DENVax and LAV Delta 30), DEN protein subunit V180 vaccine (DEN1-80E) and DENV DNA vaccines. These vaccines have been shown to be immunogenic in animals and also safe and immunogenic in humans. However, these vaccines are yet to progress to phase III trials to determine their protective efficacy against dengue. This review will summarize the details of vaccines that have progressed to clinical trials in humans.


Asunto(s)
Vacunas contra el Dengue/inmunología , Dengue/prevención & control , Dengue Grave/prevención & control , Animales , Ensayos Clínicos como Asunto , Dengue/virología , Virus del Dengue/inmunología , Humanos , Inmunogenicidad Vacunal , Concesión de Licencias , Ratones , Vacunas Atenuadas/inmunología , Vacunas Sintéticas/inmunología , Vacuna contra la Fiebre Amarilla/genética , Vacuna contra la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/genética , Virus de la Fiebre Amarilla/inmunología
19.
J Neurovirol ; 23(3): 347-357, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28116673

RESUMEN

The neuroteratogenic nature of Zika Virus (ZIKV) infection has converted what would have been a tropical disease into a global threat. Zika is transmitted vertically via infected placental cells especially in the first and second trimesters. In the developing central nervous system (CNS), ZIKV can infect and induce apoptosis of neural progenitor cells subsequently causing microcephaly as well as other neuronal complications in infants. Its ability to infect multiple cell types (placental, dermal, and neural) and increased environmental stability as compared to other flaviviruses (FVs) has broadened the transmission routes for ZIKV infection from vector-mediated to transmitted via body fluids. To further complicate the matters, it is genetically similar (about 40%) with the four serotypes of dengue virus (DENV), so much so that it can almost be called a fifth DENV serotype. This homology poses the risk of causing cross-reactive immune responses and subsequent antibody-dependent enhancement (ADE) of infection in case of secondary infections or for immunized individuals. All of these factors complicate the development of a single preventive vaccine candidate or a pharmacological intervention that will completely eliminate or cure ZIKV infection. We discuss all of these factors in detail in this review and conclude that a combinatorial approach including immunization and treatment might prove to be the winning strategy.


Asunto(s)
Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Microcefalia/prevención & control , Complicaciones Infecciosas del Embarazo/prevención & control , Dengue Grave/prevención & control , Vacunas Virales/administración & dosificación , Infección por el Virus Zika/prevención & control , Virus Zika/patogenicidad , Antivirales/uso terapéutico , Bacteriocinas/uso terapéutico , Terapia Combinada , Ciclohexilaminas/uso terapéutico , Virus del Dengue/efectos de los fármacos , Virus del Dengue/patogenicidad , Virus del Dengue/fisiología , Femenino , Feto , Humanos , Microcefalia/inmunología , Microcefalia/virología , Péptidos/uso terapéutico , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/virología , Dengue Grave/inmunología , Dengue Grave/transmisión , Dengue Grave/virología , Tiofenos/uso terapéutico , Vacunas Virales/biosíntesis , Virus Zika/efectos de los fármacos , Virus Zika/fisiología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/transmisión , Infección por el Virus Zika/virología
20.
PLoS Negl Trop Dis ; 10(12): e0005179, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-28002420

RESUMEN

BACKGROUND: With approximately 3 billion people at risk of acquiring the infection, dengue fever is now considered the most important mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year, of which 96 million manifest symptoms with any level of disease severity. Treatment of uncomplicated dengue cases is only supportive and severe dengue cases require hospital intensive care. A vaccine now licensed in several countries and developed by Sanofi Pasteur (CYD-TDV, named Dengvaxia), was able to protect, in the first 25 months of the two Phase III, 66% of a subset of 9-16 year old participants. However, a significantly lower efficacy (including negative vaccine efficacy) was noted for children younger than 9 years of age. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of year 3 results of phase III trials of Dengvaxia suggest high rates of protection of vaccinated partial dengue immunes but high rates of hospitalizations during breakthrough dengue infections of persons who were vaccinated when seronegative, with vaccine appearing to induce enhancing antibodies (ADE). An age structured model was developed based on Sanofi's recommendation to vaccinate persons age 945 years in dengue endemic countries. The model was used to explore the clinical burden of two vaccination strategies: 1) Vaccinate 4 or 20% of individuals, ages 9-45 years, seropositives and seronegatives, and 2) vaccinate 4 or 20% of individuals, ages 9-45 years, who are dengue immune only. CONCLUSIONS/SIGNIFICANCE: Our results show that vaccinating dengue monotypic immune individuals prevents dengue hospitalizations, but at the same time dengue infections of vaccine-sensitized persons increases hospitalizations. When the vaccine is given only to partial immune individuals, after immunological screening of the population, disease burden decreases considerably.


Asunto(s)
Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/inmunología , Dengue/inmunología , Dengue/prevención & control , Hospitalización/estadística & datos numéricos , Vacunación/estadística & datos numéricos , Adolescente , Adulto , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Niño , Ensayos Clínicos Fase III como Asunto , Dengue/epidemiología , Dengue/virología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/normas , Virus del Dengue/inmunología , Enfermedades Endémicas/prevención & control , Enfermedades Endémicas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dengue Grave/inmunología , Dengue Grave/prevención & control , Dengue Grave/virología , Vacunación/legislación & jurisprudencia , Vacunación/normas , Vacunas Atenuadas/inmunología , Adulto Joven
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