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Mpox , Vacuna contra Viruela , Viruela , Vacunas , Virus de la Viruela , Humanos , Mpox/prevención & control , Viruela/prevención & controlRESUMEN
Streptococcus pyogenes (Strep A) infections result in a vastly underestimated burden of acute and chronic disease globally. The Strep A Vaccine Global Consortium's (SAVAC's) mission is to accelerate the development of safe, effective, and affordable S. pyogenes vaccines. The safety of vaccine recipients is of paramount importance. A single S. pyogenes vaccine clinical trial conducted in the 1960s raised important safety concerns. A SAVAC Safety Working Group was established to review the safety assessment methodology and results of more recent early-phase clinical trials and to consider future challenges for vaccine safety assessments across all phases of vaccine development. No clinical or biological safety signals were detected in any of these early-phase trials in the modern era. Improvements in vaccine safety assessments need further consideration, particularly for pediatric clinical trials, large-scale efficacy trials, and preparation for post-marketing pharmacovigilance.
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Infecciones Estreptocócicas , Vacunas Estreptocócicas , Niño , Humanos , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus pyogenes , Ensayos Clínicos como AsuntoRESUMEN
Dr. Emanuel Papper, the founding chairman of the Department of Anesthesiology at Columbia University, was passionate about research, training, and innovation. At an event held in his honor on March 20, 2021, experts came together to discuss the coronavirus disease 2019 (COVID-19) pandemic and its myriad challenges. Dr. Wellington Sun, MD, of Vaxcellerant LLC, an expert in infectious disease and vaccine research and development, presented a "Primer of COVID-19 vaccines for the perioperative physician." Operation Warp Speed was successful in producing multiple efficacious and safe vaccines for use in the United States and around the globe. Their development and authorization for emergency use occurred in an unprecedented timespan of <1 year. Technology such as V-SAFE has helped to accrue extensive postdevelopment safety data that will be utilized for licensure of these vaccines. The COVID-19 vaccine success is tempered by the knowledge that severe acute respiratory syndrome coronavirus 2 continues its natural selection of variants that threaten the efficacy of vaccines. Important questions remain regarding the future of the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 variants, successful vaccination strategies, and preparedness for future pandemics.
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COVID-19 , Médicos , Vacunas contra la COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 µg, 100 µg, or 250 µg. There were 15 participants in each dose group. RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-µg group, 109,209 in the 100-µg group, and 213,526 in the 250-µg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-µg dose group reported one or more severe adverse events. CONCLUSIONS: The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).
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Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/prevención & control , ARN Mensajero/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas Virales/uso terapéutico , Vacuna nCoV-2019 mRNA-1273 , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Betacoronavirus , COVID-19 , Vacunas contra la COVID-19 , Femenino , Humanos , Inmunización Secundaria , Masculino , SARS-CoV-2 , Linfocitos T/inmunología , Vacunas Virales/efectos adversos , Adulto JovenRESUMEN
Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.
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Vacunas contra el Dengue/administración & dosificación , Dengue/prevención & control , Política de Salud , Guías de Práctica Clínica como Asunto , Vacunación , Ensayos Clínicos Fase III como Asunto , Dengue/inmunología , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Humanos , Esquemas de Inmunización , Pruebas de Neutralización , Seguridad del Paciente , Transferencia de Tecnología , Vacunas Atenuadas , Organización Mundial de la SaludRESUMEN
Many healthcare providers are not familiar with the Food and Drug Administration (FDA) vaccine licensure process, the Advisory Committee on Immunization Practices (ACIP) vaccine recommendation process, and how FDA vaccine licensure and ACIP recommendations are related. Vaccines for use in the United States military and civilian populations are licensed by the FDA by several potential pathways but use of licensed vaccines in the civilian population should be based on recommendations made by the ACIP. In performing these distinct activities, FDA and ACIP function under different mandates. In this article, we discuss whether the FDA licensure pathways used to approve a vaccine impacts ACIP recommendation categories for vaccines licensed from 2006 to 2016.
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Vacunación/legislación & jurisprudencia , Comités Consultivos/legislación & jurisprudencia , Comités Consultivos/normas , Humanos , Inmunización/legislación & jurisprudencia , Inmunización/normas , Programas de Inmunización/legislación & jurisprudencia , Programas de Inmunización/normas , Esquemas de Inmunización , Concesión de Licencias/legislación & jurisprudencia , Concesión de Licencias/normas , Estados Unidos , United States Food and Drug Administration , Vacunación/normasAsunto(s)
Antivirales/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Aprobación de Drogas/métodos , Vacunas contra el Virus del Ébola , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/prevención & control , United States Food and Drug Administration , África Occidental/epidemiología , Ensayos Clínicos como Asunto/normas , Aprobación de Drogas/organización & administración , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Proyectos de Investigación , Estados UnidosRESUMEN
This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1-50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENV) type. Baseline seropositivity prevalence increased with age (10% [< 2 years], 26% [2-4 years], 60% [5-20 years], and 93% [21-50 years]). Safety profiles of TDEN vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. ClinicalTrials.gov: NCT00468858.
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Vacunas contra el Dengue/uso terapéutico , Virus del Dengue/inmunología , Dengue/prevención & control , Adolescente , Adulto , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Niño , Preescolar , Dengue/inmunología , Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/inmunología , Método Doble Ciego , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Puerto Rico/epidemiología , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/uso terapéutico , Adulto JovenRESUMEN
Dengue is a potentially fatal acute febrile illness caused by the mosquito-borne dengue viruses (DENV-1 to -4). To estimate DENV seroincidence in school-aged children, a 1-year prospective cohort study was conducted in Patillas, Puerto Rico; 10- to 18-year-olds (N = 345) were randomly selected from 13 public schools. At enrollment, 49.8% of the entire cohort had DENV immunoglobulin G (IgG) anti-DENV antibodies, and there were individuals with neutralizing antibodies specific to each of the four DENV. The mean age of participants with incident DENV infection was 13.4 years. The 1-year seroincidence rate was 5.6%, and 61.1% of infections were inapparent. Having IgG anti-DENV at enrollment was associated with seroincidence (risk ratio = 6.8). Acute febrile illnesses during the study period were captured by a fever diary and an enhanced and passive surveillance system in the municipios of Patillas and Guayama. In summary, at enrollment, nearly one-half of the participants had a prior DENV infection, with the highest incidence in the 10- to 11-year-olds, of which most were inapparent infections, and symptomatic infections were considered mild.
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Virus del Dengue , Dengue/epidemiología , Adolescente , Anticuerpos Antivirales/sangre , Niño , Dengue/sangre , Dengue/virología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Puerto Rico/epidemiología , Estudios SeroepidemiológicosRESUMEN
Dengue is a major cause of morbidity in Puerto Rico and is well-known to its physicians. Early case identification and timely initiation of treatment for patients with severe dengue can reduce medical complications and mortality. To determine clinical management and reporting practices, and assess knowledge of dengue and its management, a survey was sent to 2,512 physicians with a medical license in Puerto Rico. Of the 2,313 physicians who received the survey, 817 (35%) completed the questionnaire. Of the respondents, 708 were currently practicing medicine; 138 were board certified (Group 1), 282 were board eligible (Group 2), and 288 had not finished residency (Group 3). Although respondents clinically diagnosed, on average, 12 cases of dengue in the preceding three months, 31% did not report any suspected cases to public health officials while about half (56%) reported all cases. Overall, 29% of respondents correctly identified early signs of shock and 48% identified severe abdominal pain and persistent vomiting as warning signs for severe dengue with the proportion of correct respondents highest in Group 1. Reportedly about sixty percent (57%) appropriately never give corticosteroids or prophylactic platelet transfusions to dengue patients. One third (30%) of respondents correctly identified administration of intravenous colloid solution as the best treatment option for dengue patients with refractory shock and elevated hematocrit after an initial trial of intravenous crystalloids, and nearly one half (46%) correctly identified administration of a blood transfusion as the best option for dengue patients with refractory shock and decreased hematocrit after a trial of intravenous crystalloids. Even though dengue has been endemic in Puerto Rico for nearly 4 decades, knowledge of dengue management is still limited, compliance with WHO treatment guidelines is suboptimal, and underreporting is significant. These findings were used to design a post graduate training course to improve the clinical management of dengue.
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Dengue/diagnóstico , Dengue/terapia , Notificación de Enfermedades/métodos , Adulto , Recolección de Datos , Dengue/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puerto Rico/epidemiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Adenovirus (ADV) types 4 (ADV-4) and 7 (ADV-7) are presently the major cause of febrile acute respiratory disease (ARD) in U.S. military recruits. We conducted a multi-center, randomized, double-blind, placebo-controlled phase 3 study of the new vaccine to assess its safety and efficacy. Healthy adults at two basic training sites were randomly assigned to receive either vaccine (two enteric-coated tablets consisting of no less than 4.5 log10 TCID50 of live ADV-4 or ADV-7) or placebo in a 3:1 ratio. Volunteers were observed throughout the approximate eight weeks of their basic training and also returned for four scheduled visits. The primary endpoints were prevention of febrile ARD due to ADV-4 and seroconversion of neutralizing serum antibodies to ADV-7, which was not expected to circulate in the study population during the course of the trial. A total of 4151 volunteers were enrolled and 4040 (97%) were randomized and included in the primary analysis (110 were removed prior to randomization and one was removed after randomization due to inability to swallow tablets). A total of 49 ADV-4 febrile ARD cases were identified with 48 in the placebo group and 1 in the vaccine group (attack rates of 4.76% and 0.03%, respectively). Vaccine efficacy was 99.3% (95% CI, 96.0-99.9; P<0.001). Seroconversion rates for vaccine recipients for ADV-4 and ADV-7 were 94.5% (95% CI, 93.4-95.5%) and 93.8% (95% CI: 93.4-95.2%), respectively. The vaccine was well tolerated as compared to placebo. We conclude that the new live, oral ADV-4 and ADV-7 vaccine is safe and effective for use in groups represented by the study population.
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Infecciones por Adenovirus Humanos/prevención & control , Vacunas contra el Adenovirus/inmunología , Adenovirus Humanos/inmunología , Infecciones del Sistema Respiratorio/prevención & control , Enfermedad Aguda , Infecciones por Adenovirus Humanos/inmunología , Vacunas contra el Adenovirus/administración & dosificación , Vacunas contra el Adenovirus/efectos adversos , Administración Oral , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Personal Militar , Infecciones del Sistema Respiratorio/inmunología , Adulto JovenRESUMEN
In June of 2007, West Nile virus (WNV) was detected in sentinel chickens and blood donors in Puerto Rico, where dengue virus (DENV) is hyperendemic. Enhanced human surveillance for acute febrile illness (AFI) began in eastern Puerto Rico on July 1, 2007. Healthcare providers submitted specimens from AFI cases for WNV and DENV virology and serology testing. Over 6 months, 385 specimens were received from 282 cases; 115 (41%) specimens were DENV laboratory-positive, 86 (31%) specimens were laboratory-indeterminate, and 32 (11%) specimens were laboratory-negative for WNV and DENV. One WNV infection was detected by anti-WNV immunoglobulin M (IgM) antibody and confirmed by a plaque reduction neutralization test. DENV and WNV infections could not be differentiated in 27 cases (10%). During a period of active WNV transmission, enhanced human surveillance identified one case of symptomatic WNV infection. Improved diagnostic methods are needed to allow differentiation of WNV and DENV in dengue-endemic regions.
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Anticuerpos Antivirales/sangre , Dengue/epidemiología , Enfermedades Endémicas , Vigilancia de Guardia , Fiebre del Nilo Occidental/diagnóstico , Virus del Nilo Occidental/inmunología , Adulto , Dengue/diagnóstico , Virus del Dengue/genética , Virus del Dengue/inmunología , Femenino , Humanos , Masculino , Pruebas de Neutralización , Puerto Rico/epidemiología , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/virología , Adulto JovenRESUMEN
Two formulations of a new live tetravalent dengue virus (DENV) vaccine produced using re-derived master seeds from a precursor vaccine and that same precursor vaccine as a control were compared in a placebo-controlled, randomized, observer-blind, phase II trial of 86 healthy adults. Two vaccine doses were administered 6 months apart; a third dose was offered to a subset. Symptoms and signs of dengue-like illness reported after vaccination were mild to moderate, transient, and occurred with similar frequency among recipients of the new DENV vaccine and placebo, except for rash. Neither dengue nor vaccine-related serious adverse events were reported. The first DENV vaccine dose was moderately immunogenic; the second dose increased the potency and breadth of the neutralizing antibody response. Tetravalent response rates to the new formulations were 60% and 66.7% in unprimed subjects. A third dose did not increase tetravalent antibody rates. The new DENV vaccine candidates merit additional evaluation.
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Vacunas contra el Dengue/uso terapéutico , Virus del Dengue/inmunología , Adulto , Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/inmunología , Humanos , PlacebosRESUMEN
BACKGROUND: Protection against dengue requires immunity against all 4 serotypes of dengue virus (DENV). Experimental challenge may be useful in evaluating vaccine-induced immunity. METHODS: Ten subjects previously vaccinated with a live attenuated tetravalent dengue vaccine (TDV) and 4 DENV-naive control subjects were challenged by subcutaneous inoculation of either 10(3) plaque-forming units (PFU) of DENV-1 or 10(5) PFU of DENV-3. Two additional subjects who did not develop DENV-3 neutralizing antibody (NAb) from TDV were revaccinated with 10(4) PFU of live attenuated DENV-3 vaccine to evaluate memory response. RESULTS: All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3, 2 were protected. All DENV-3-challenge subjects who developed viremia also developed elevated liver enzyme levels, and 2 had values that were >10 times greater than normal. Of the 2 subjects revaccinated with DENV-3 vaccine, 1 showed a secondary response to DENV-2, while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of NAb, although 1 subject was protected despite a lack of measurable NAb at the time of DENV-1 challenge. CONCLUSIONS: Vaccination with TDV induced variable protection against subcutaneous challenge. DENV-3 experimental challenge was associated with transient but marked elevations of transaminases.
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Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Dengue/prevención & control , Adulto , Análisis Químico de la Sangre , Dengue/patología , Femenino , Humanos , Hígado/enzimología , Pruebas de Función Hepática , Masculino , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Viremia/patología , Viremia/prevención & control , Adulto JovenRESUMEN
BACKGROUND: The incidence and severity of dengue in Latin America has increased substantially in recent decades and data from Puerto Rico suggests an increase in severe cases. Successful clinical management of severe dengue requires early recognition and supportive care. METHODS: Fatal cases were identified among suspected dengue cases reported to two disease surveillance systems and from death certificates. To be included, fatal cases had to have specimen submitted for dengue diagnostic testing including nucleic acid amplification for dengue virus (DENV) in serum or tissue, immunohistochemical testing of tissue, and immunoassay detection of anti-DENV IgM from serum. Medical records from laboratory-positive dengue fatal case-patients were reviewed to identify possible determinants for death. RESULTS: Among 10,576 reported dengue cases, 40 suspect fatal cases were identified, of which 11 were laboratory-positive, 14 were laboratory-negative, and 15 laboratory-indeterminate. The median age of laboratory-positive case-patients was 26 years (range 5 months to 78 years), including five children aged < 15 years; 7 sought medical care at least once prior to hospital admission, 9 were admitted to hospital and 2 died upon arrival. The nine hospitalized case-patients stayed a mean of 15 hours (range: 3-48 hours) in the emergency department (ED) before inpatient admission. Five of the nine case-patients received intravenous methylprednisolone and four received non-isotonic saline while in shock. Eight case-patients died in the hospital; five had their terminal event on the inpatient ward and six died during a weekend. Dengue was listed on the death certificate in only 5 instances. CONCLUSIONS: During a dengue epidemic in an endemic area, none of the 11 laboratory-positive case-patients who died were managed according to current WHO Guidelines. Management issues identified in this case-series included failure to recognize warning signs for severe dengue and shock, prolonged ED stays, and infrequent patient monitoring.
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Dengue/epidemiología , Dengue/mortalidad , Brotes de Enfermedades , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Antígenos Virales/análisis , Niño , Preescolar , Dengue/patología , Dengue/terapia , Virus del Dengue/aislamiento & purificación , Femenino , Humanos , Inmunoglobulina M/sangre , Lactante , Masculino , Persona de Mediana Edad , Puerto Rico/epidemiología , ARN Viral/genética , ARN Viral/aislamiento & purificación , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Live, multivalent vaccines have historically exhibited interference in humans; live dengue virus (DENV) vaccines have proven no exception. METHODS: To characterize interactions between DENV serotypes in a tetravalent live-attenuated virus vaccine candidate, we analyzed data from a factorial clinical trial in which all combinations of high- and low-dose DENV serotypes were combined in 16 live-attenuated tetravalent vaccine formulations (N = 64) and administered to flavivirus-naive adult volunteers. Regression models considered the outcomes of reactogenicity and seroconversion, controlling for all serotype doses simultaneously. Additionally, results were compared against earlier evaluations of the same viruses administered as monovalent formulations. RESULTS: DENV-1 was immunologically dominant in both monovalent and tetravalent formulations. In tetravalent formulations, DENV-1 and DENV-2 antagonized each other, with a high dose of one decreasing seroconversion to the other. However, high-dose DENV-1 significantly increased seroconversion against 3 or more serotypes, increasing seroconversion to DENV-1, DENV-3, and DENV-4. The highest reactogenicity occurred when DENV-1 was at high dose and all others were low; reactogenicity decreased with the incorporation of other high-dose serotypes. CONCLUSIONS: Interference and facilitation occurred between serotypes in the live vaccine candidate evaluated. These analyses suggest that it may be possible to exploit facilitation to increase overall seroconversion.
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Vacunas contra el Dengue/administración & dosificación , Virus del Dengue/clasificación , Anticuerpos Antivirales/sangre , Ensayos Clínicos como Asunto , Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/inmunología , Relación Dosis-Respuesta Inmunológica , Humanos , Modelos Logísticos , Serotipificación , Vacunación/efectos adversosRESUMEN
A live-attenuated dengue-2 virus strain S16803 vaccine candidate that is immunogenic and safe in humans was derived by 50 passages in primary dog kidney (PDK) cells. To identify mutations associated with attenuation of the dengue-2 PDK50 vaccine strain, we determined the nucleotide changes that arose during PDK passage of the dengue-2 virus. Thirteen mutations distinguished the PDK50 virus from low-passage parent resulting in amino acid substitutions in the premembrane (E89G), envelope (E202K, N203D), nonstructural proteins NS1 (A43T), NS2A (L181F), NS2B (I26V), and NS4B (I/T108T, L112F). In addition, the PDK50 virus contained a C to T change of nucleotide 57 in the 5' non-coding region and four silent mutations of nucleotides 591, 987, 6471, and 8907. An infectious PDK50 cDNA clone virus was produced and characterized for growth kinetics in monkey (LLC-MK(2), Vero) and mosquito (C6/36) cells. Identification of mutations in the vaccine strain and availability of an infectious clone will permit systematic analysis of the importance of individual or collective mutations on attenuation of dengue virus.
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Vacunas contra el Dengue/genética , Virus del Dengue/genética , Virus del Dengue/patogenicidad , Mutación Puntual , Aedes , Sustitución de Aminoácidos/genética , Animales , Línea Celular , Virus del Dengue/crecimiento & desarrollo , Haplorrinos , Datos de Secuencia Molecular , ARN Viral/genética , Análisis de Secuencia de ADN , Pase Seriado , Vacunas Atenuadas/genética , Proteínas Virales/genética , Virulencia , Cultivo de VirusRESUMEN
BACKGROUND: As the incidence of dengue increases globally, US travelers to endemic areas may be at an increased risk of travel-associated dengue. METHODS: Data from the US Centers for Disease Control and Prevention's laboratory-based Passive Dengue Surveillance System (PDSS) were used to describe trends in travel-associated dengue reported from January 1, 1996 to December 31, 2005. The PDSS relies on provider-initiated requests for diagnostic testing of serum samples via state health departments. A case of travel-associated dengue was defined as a laboratory-positive dengue infection in a resident of the 50 US states and the District of Columbia who had been in a dengue-endemic area within 14 days before symptom onset. Dengue infection was confirmed by serologic and virologic techniques. RESULTS: One thousand one hundred and ninety-six suspected travel-associated dengue cases were reported-334 (28%) were laboratory-positive, 597 (50%) were laboratory-negative, and 265 (22%) were laboratory-indeterminate. The incidence of laboratory-positive cases varied from 1996 to 2005, but had an overall increase with no significant trend (53.5 to 121.3 per 10(8) US travelers, p = 0.36). The most commonly visited regions were the Caribbean, Mexico and Central America, and Asia. The median age of laboratory-positive cases was 37 years (range: <1 to 75 y) and 166 (50%) were male. Of the 334 laboratory-positive cases, 41 (12%) were hospitalized, and 2 (1%) died. CONCLUSIONS: Residents of the US traveling to dengue-endemic regions are at risk of dengue infection and need to be instructed on appropriate prevention measures prior to travel. Especially in light of the potential transmissibility of dengue virus via blood transfusion, consistent reporting of travel-associated dengue infections is essential.
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Dengue/epidemiología , Viaje , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Centers for Disease Control and Prevention, U.S. , Niño , Preescolar , Dengue/sangre , Dengue/diagnóstico , Virus del Dengue/inmunología , Virus del Dengue/aislamiento & purificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina M/análisis , Lactante , Masculino , Persona de Mediana Edad , Factores de Riesgo , Vigilancia de Guardia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Dengue 4 virus strain 341750 serially passaged 20 times in primary dog kidney (PDK) cells was shown to have reduced infectivity for rhesus monkeys but was immunogenic and protected the monkeys from challenge with low passage parent dengue 4 virus. The dengue 4 PDK20 virus was also shown to be attenuated for human volunteers. We compared the genomic nucleotide sequences of low passage parent and PDK20 attenuated vaccine strains and identified 11 nucleotide (nt) substitutions in the PDK20 genome. Five mutations caused amino acid changes in viral proteins E (N366N/S), NS1 (E146Q), NS4B (S/L112L and A240V), and NS5 (F/L790L). Silent mutations occurred in genes encoding NS1 (nt 2609), NS3 (nt 6113, 6230 and 6239) and NS5 (nt 8081 and 8588). A full-length cDNA clone of the dengue 4 strain 341750 PDK20 was constructed and RNA transcripts of the clone were infectious in monkey kidney (LLC-MK(2)) and Aedes albopictus (C6/36) cells. The sequence analysis and availability of an infectious clone provide molecular tools to investigate the basis for the attenuation of dengue 4 virus.