RESUMEN
BACKGROUNDDisease due to dengue viruses is a growing global health threat, causing 100-400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus.METHODSTwo randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain.RESULTSTV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype.CONCLUSIONSTV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model.TRIAL REGISTRATIONClinicalTrials.gov NCT02317900 and NCT02873260.FUNDINGIntramural Research Program, NIH (contract HHSN272200900010C).
Asunto(s)
Vacunas contra el Dengue , Virus del Dengue , Dengue , Exantema , Humanos , Vacunas contra el Dengue/efectos adversos , Serogrupo , Viremia , Vacunas Atenuadas , Exantema/inducido químicamente , Anticuerpos AntiviralesRESUMEN
New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in Flavivirus-naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted (N = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) (N = 8), or placebo (N = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.
Asunto(s)
Vacunas contra el Dengue/uso terapéutico , Dengue/prevención & control , Inmunización Secundaria , Adyuvantes Inmunológicos/uso terapéutico , Adulto , Hidróxido de Aluminio/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Virus del Dengue/inmunología , Método Doble Ciego , Femenino , Humanos , Inmunogenicidad Vacunal , Reacción en el Punto de Inyección , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Vacunas Atenuadas/uso terapéutico , Vacunas de Subunidad/uso terapéutico , Vacunas Sintéticas/uso terapéutico , Proteínas del Envoltorio Viral/inmunología , Adulto JovenRESUMEN
A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2Δ30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2Δ30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2Δ30 were protected from infection with rDEN2Δ30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2Δ30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2Δ30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials.
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Vacunas contra el Dengue/inmunología , Dengue/inmunología , Dengue/prevención & control , Modelos Biológicos , Vacunas Atenuadas/inmunología , Adulto , Vacunas contra el Dengue/administración & dosificación , Femenino , Humanos , Masculino , Vacunación , Vacunas Atenuadas/administración & dosificación , Viremia/inmunología , Viremia/virologíaRESUMEN
UNLABELLED: The ideal dengue vaccine will provide protection against all serotypes of dengue virus and will be economical and uncomplicated in its administration. To determine the ability of a single dose of the live attenuated tetravalent dengue vaccine TV003 to induce a suitable neutralizing antibody response, a placebo-controlled clinical trial was performed in 48 healthy adults who received 2 doses of vaccine or placebo administered 12 months apart. Evaluation of safety, vaccine viremia, and neutralizing antibody response after each dose indicated that the first dose of vaccine was capable of preventing infection with the second dose, thus indicating that multiple doses are unnecessary. CLINICAL TRIALS REGISTRATION: NCT01782300.
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Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacunas contra el Dengue/inmunología , Dengue/prevención & control , Adulto , Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/efectos adversos , Método Doble Ciego , Humanos , Esquemas de Inmunización , National Institute of Allergy and Infectious Diseases (U.S.) , Placebos/administración & dosificación , Estados Unidos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunologíaRESUMEN
BACKGROUND: The 4 serotypes of dengue virus, DENV-1-4, are the leading cause of arboviral disease globally. The ideal dengue vaccine would provide protection against all serotypes after a single dose. METHODS: Two randomized, placebo-controlled trials were performed with 168 flavivirus-naive adults to demonstrate the safety and immunogenicity of a live attenuated tetravalent dengue vaccine (TV003), compared with those of a second tetravalent vaccine with an enhanced DENV-2 component (TV005), and to evaluate the benefit of a booster dose at 6 months. Safety data, viremia, and neutralizing antibody titers were evaluated. RESULTS: A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. Compared with TV003, the higher-dose DENV-2 component increased the observed frequency of immunogenicity to DENV-2 in the TV005 trial. Both the first and second doses were well tolerated. Neither vaccine viremia, rash, nor a significant antibody boost were observed following a second dose. CONCLUSIONS: A single subcutaneous dose of TV005 dengue vaccine is safe and induces a tetravalent antibody response at an unprecedented frequency among vaccinees. A second dose has limited benefit and appears to be unnecessary. Studies to confirm these findings and assess vaccine efficacy will now move to populations in regions where DENV transmission is endemic. CLINICAL TRIALS REGISTRATION: NCT01072786 and NCT01436422.
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Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Vacunación/métodos , Adolescente , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Voluntarios Sanos , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunología , Viremia , Adulto JovenRESUMEN
BACKGROUND: Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue serotypes exist, and previous infection with one serotype increases the likelihood of severe disease with a second, heterotypic DENV infection. METHODS: In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180. RESULTS: A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%-90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P < .0001). Black race was significantly associated with a reduced incidence of vaccine viremia. CONCLUSIONS: TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection.
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Anticuerpos Antivirales/sangre , Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Adulto , Indio Americano o Nativo de Alaska , Población Negra , Dengue/prevención & control , Vacunas contra el Dengue/administración & dosificación , Método Doble Ciego , Exantema/virología , Femenino , Humanos , Masculino , Nativos de Hawái y Otras Islas del Pacífico , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunología , Viremia/virología , Población Blanca , Adulto JovenRESUMEN
Suppressed IL-12 production and maladaptive immune activation, both of which are ameliorated by successful highly active antiretroviral therapy (HAART), are thought to play important roles in the immunopathogenesis of chronic HIV infection. Despite the important effects of the immunological and virological events of early HIV infection on subsequent disease progression, IL-12 production and immune activation in early infection remain under-defined. To quantify IL-12 production and immune activation during acute/early HIV infection, in the presence and absence of HAART, we performed a prospective, longitudinal study of participants in the Baltimore site of the Acute Infection and Early Disease Research Program, with cross-sectional comparison to healthy control subjects. PBMC cytokine productive capacity and plasma immune activation markers [soluble CD8 (sCD8), sCD4, granzyme B, neopterin, beta2-microglobulin, sIL-2R, sTNFRI, sTNFRII, and IL-12p70] were quantified by ELISA. Notably, PBMC from patients with acute/early HIV infection exhibited in vivo IL-12p70 production along with increased, maximal in vitro IL-12 production. Further, despite evidence from plasma markers of generalized immune activation, no elevation in plasma levels of sCD4 was observed, suggesting relative blunting of in vivo CD4+ T cell activation from the beginning of HIV infection. Finally, despite successful virological responses to HAART, heightened in vivo CD8+ T cell activation, IL-12 production, and IFN activity were sustained for at least 6 months during primary HIV infection. These data underscore the need for comparative mechanistic analysis of the immunobiology of early and chronic HIV infection.
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Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Interleucina-12/metabolismo , Activación de Linfocitos/inmunología , Enfermedad Aguda , Adulto , Baltimore/epidemiología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Infecciones por VIH/terapia , Humanos , Interferón gamma/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/genética , ARN Viral/inmunología , Carga ViralRESUMEN
BACKGROUND: Although information technology (IT) plays an increasingly important role in the delivery of healthcare, specific guidelines to assist human immunodeficiency virus (HIV) care settings in adopting IT are lacking. METHODS: Through the experiences of six Special Projects of National Significance - (SPNS) funded HIV-specific IT interventions, key considerations prior to adoption and evaluation of IT are presented. The purpose of this article is to provide guidelines to consider prior to adoption and evaluation of IT in HIV care settings. RESULTS: Six sites conducted comprehensive evaluations of IT interventions between 2002 and 2005, encompassing care delivered to 24,232 clients by 700 providers. Six key considerations prior to adoption of IT in HIV care delivery were identified, including IT and programmatic capacity, expectations, participation, organizational models, end-user types, and challenges. Specific evaluation techniques included implementation assessment, formative evaluation, cost studies, outcomes evaluation, and performance indicators. Grantee experiences are used to illustrate key considerations. DISCUSSION: With proper preparation, even resource-poor HIV care delivery programs can successfully adopt IT.
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Guías como Asunto , Seropositividad para VIH , Informática Médica/organización & administración , Integración de Sistemas , Seropositividad para VIH/tratamiento farmacológico , Humanos , Estados UnidosRESUMEN
STUDY OBJECTIVES: To examine the frequency of highly active antiretroviral therapy (HAART) modifications, the reasons for these modifications, and toxicities of these drugs in patients receiving their first HAART regimen after a diagnosis of acute (< 2 mo from infection) or early (2-12 mo) human immunodeficiency virus (HIV) infection. PATIENTS: Fifty-one patients who were enrolled in the Acute Infection and Early Disease Research Program at a Baltimore, Maryland, site between January 1, 1998, and April 30, 2002, and who chose to start HAART. MEASUREMENTS AND MAIN RESULTS: Time from initiation of therapy to first modification-defined as change in any HAART drug without an interruption in therapy or as simultaneous discontinuation of all drugs within the regimen-and time from initiation of therapy to reinitiation of therapy were recorded, as well as reasons for modification and reinitiation. With a median follow-up of 1,549 days, 21 (41%) of 51 patients received HAART continuously, but only 10 (20%) continued to receive their original regimen without any modification. Among the 41 patients (80%) who received modified therapy, the main reasons for the first modification were toxicity (16 patients), nonadherence (8), and new data on treatment efficacy or safety (8). Of 30 patients who stopped HAART, 18 restarted HAART at a later time. CONCLUSION: The high frequency of treatment modification among patients treated after acute or early HIV infection underscores the importance of determining the usefulness of antiretroviral therapy early in HIV infection, and the need for more tolerable regimens if HAART is to be started at this stage.
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Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Femenino , Infecciones por VIH/transmisión , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: Lymphocyte activation, associated with vaccination or infection, can be measured by positron emission tomography (PET). We investigated the ability of PET to detect and measure magnitude of lymph-node activation among asymptomatic HIV-1-infected individuals. METHODS: Initially we assessed PET response in eight HIV-1-uninfected individuals who had received licensed killed influenza vaccine. In an urban teaching hospital, we recruited 12 patients recently infected with HIV-1 (<18 months since seroconversion) and 11 chronic long-term HIV-1 patients who had stable viraemia by RT-PCR (non-progressors). After injection with fluorine-18-labelled fluorodeoxyglucose, patients underwent PET. We correlated summed PET signal from nodes with viral load by linear regression on log-transformed values. FINDINGS: Node activation was more localised after vaccination than after HIV-1 infection. In early and chronic HIV-1 disease, node activation was greater in cervical and axillary than in inguinal and iliac chains (p<0.0001), and summed PET signal correlated with viraemia across a 4 log range (r2=0.98, p<0.0001). Non-progressors had small numbers of persistently active nodes, most of which were surgically accessible. INTERPRETATION: The anatomical restriction we noted may reflect microenvironmental niche selection, and tight correlation of PET signal with viraemia suggests target-cell activation determines steady-state viral replication.
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Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1 , Ganglios Linfáticos/inmunología , Activación de Linfocitos/inmunología , Tomografía Computarizada de Emisión , Adolescente , Adulto , Femenino , Fluorodesoxiglucosa F18 , Infecciones por VIH/diagnóstico por imagen , Seropositividad para VIH/inmunología , VIH-1/inmunología , VIH-1/aislamiento & purificación , Humanos , Vacunas contra la Influenza/inmunología , Ganglios Linfáticos/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Viremia/diagnóstico por imagen , Viremia/inmunología , Replicación Viral/inmunologíaRESUMEN
OBJECTIVES: To evaluate the effectiveness of urine screening to detect HIV-infected individuals in high-prevalence communities. METHODS: Urine HIV testing was performed at 16 discrete events and four ongoing testing sites in Baltimore communities with a high incidence of HIV infection. When possible, positive urine test results were confirmed by blood testing. In addition, we attempted to obtain blood samples from subjects who reported a possible exposure to HIV but did not have a positive urine test. RESULTS: From February 1998 to August 2001, we screened 1718 persons. Overall, 210 persons (12%) were HIV-positive, of whom 169 (80%) had never previously tested positive; 87% of those who tested positive received their results, and most were referred for medical care. CONCLUSIONS: Urine-based screening for HIV infection in high-prevalence inner city communities can be an effective tool for identifying and treating infected persons who are unaware of their infection.
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Anticuerpos Anti-VIH/orina , Infecciones por VIH/diagnóstico , Tamizaje Masivo/métodos , Baltimore/epidemiología , Infecciones por VIH/epidemiología , Humanos , Incidencia , Tamizaje Masivo/organización & administración , Prevalencia , Derivación y Consulta , Reproducibilidad de los ResultadosRESUMEN
T lymphocyte responses to human immunodeficiency virus (HIV) type 1 Gag were measured in 9 patients by interferon-gamma enzyme-linked immunospot assay at 3 time points within 12 months of infection. Patients with early recognition of HIV-1 Gag had lower subsequent HIV-1 load set points, as measured during the first 2 years of infection, compared with those of patients with undetectable Gag-specific responses (median, 4.27 vs. 5.05 log(10) HIV-1 RNA copies/mL, respectively; P=.028). An inverse correlation existed between the magnitude of the Gag-specific responses and the HIV-1 load set point (r=-0.733; P=.025). Early sustained T lymphocyte responses to HIV-1 Gag may be important for the establishment of virus load set point.