A Phase II Evaluation of the Safety and Protective Efficacy of the Live Attenuated Tetravalent Dengue Vaccine TetraVax-DV with Challenge by the Recombinant DENV-2 Virus in a Dengue Endemic Population

对登革热流行人群中重组 DENV-2 病毒攻击的四价登革热减毒活疫苗 TetraVax-DV 的安全性和保护效果进行 II 期评估

• 批准号: 10219920
• 负责人: Beth Diane Kirkpatrick
• 金额: $ 123.98万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219920
• 关键词: Achievement; Address; Adult; Adverse event; Age; Arboviruses; Area; Asia; Attenuated; Attenuated Vaccines; Bangladesh; CD8-Positive T-Lymphocytes; Child; Clinical; Clinical Markers; Country; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Disease; Dose; Enrollment; Evaluation; Frequencies; Future; Hospitalization; Human; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Individual; Infection; Inpatients; Investigation; Latin America; Lead; Licensure; Marketing; Measures; Memory B-Lymphocyte; Modeling; National Institute of Allergy and Infectious Disease; Persons; Phase I/II Trial; Phenotype; Placebos; Polymerase Chain Reaction; Population; Public Health; Randomized; Recombinants; Reporting; Reproducibility; Research Design; Reverse Transcription; Risk; Safety; Serotyping; Serum; Signal Transduction; Statistical Models; Testing; United States National Institutes of Health; Vaccination; Vaccinee; Vaccines; Viremia; Virus; base; cytokine; design; efficacy trial; human morbidity; innovation; neutralizing antibody; phase 2 testing; predictive modeling; prevent; product development; protective efficacy; response; safety assessment; safety testing; transmission process; trial design; vaccine access; vaccine candidate; vaccine development; vaccine efficacy; vaccine safety; vaccine trial; volunteer

PROJECT SUMMARY Dengue viruses cause more human morbidity than any other arbovirus, underscoring the public health urgency of making safe and effective dengue vaccines available in endemic settings, in alignment with NIAID priorities. This critical need will be addressed by testing the safety and protective efficacy of NIAID's lead tetravalent, live attenuated dengue vaccine candidate, TV005, in adults in dengue-endemic Bangladesh through a vaccine-challenge trial based on the Dengue Controlled Human Infection Model (D-CHIM). Our central hypothesis is that vaccination with TV005 will protect against infection with a live, recombinant dengue 2 challenge virus (DENV-2), with DENV-2 viremia following challenge as the primary efficacy endpoint. In addition to extensive Phase I and II trials leading to the development of TV005, our team has used a similar vaccine-challenge design to evaluate the safety and efficacy of TV005 in dengue-naïve U.S. adults, which was well-tolerated and >99% efficacious in preventing viremia. The next critical step for NIAID's promising vaccine is to test its safety and efficacy in a dengue-endemic setting. In this study, 224 healthy adult volunteers, both dengue-exposed and -naïve, will be enrolled and randomized 1:1 (vaccine: placebo) to receive TV005 followed by inpatient challenge with DENV-2 at 6 or 24 months post-vaccination. To test our central hypothesis, we will pursue the following Specific Aims: Aim 1A) Determine, in a dengue endemic population, the protective efficacy of TV005 vaccine against dengue infection induced by a live, recombinant DENV-2 challenge virus (rDEN2∆30-7169) administered 6 or 24 months after vaccination; Aim 1B) Evaluate the safety of TV005 and the DEN-2 challenge virus in a dengue endemic population; and Aim 2) Use predictive modeling to identify baseline and post-vaccination immune phenotype(s) that predict TV005 efficacy and safety to better understand response to vaccination and protective immunity, and to inform future study design for dengue vaccine development in endemic settings. In contrast to large-scale field trails, the D-CHIM will provide early vaccine efficacy and safety signals while enrolling a minimal number of volunteers, and contribute to our understanding of the immune response to both vaccination and challenge in an endemic setting through statistical modeling of vaccine impact.

项目总结 登革热病毒导致的人类发病率比任何其他虫媒病毒都高，这突显了公共卫生 迫切需要在流行环境中提供安全有效的登革热疫苗，与NIAID保持一致 优先事项。这一迫切需要将通过测试NIAID的铅的安全性和保护效力来解决 登革热流行孟加拉国成人四价减毒活疫苗候选TV005 通过基于登革热控制的人类感染模型(D-CHIM)的疫苗挑战试验。我们的 中心假设是接种TV005疫苗将防止感染活的重组登革热 2攻击病毒(DENV-2)，以攻击后DENV-2病毒血症为主要疗效终点。在……里面 除了导致TV005开发的广泛的I期和II期试验外，我们的团队还使用了类似的 疫苗挑战设计，以评估TV005在登革热天真的美国成年人中的安全性和有效性，这是 耐受性好，预防病毒血症有效率达99%。NIAID前景看好的疫苗的下一步关键 是在登革热流行的环境中测试其安全性和有效性。在这项研究中，224名健康的成年志愿者， 登革热暴露者和幼稚者将被纳入并随机1：1(疫苗：安慰剂)接种TV005 在接种后6个月或24个月用DENV-2进行住院挑战。为了检验我们的中心假设，我们将 追求以下具体目标：目标1A)在登革热流行人群中确定保护性 TV005疫苗对重组登革2型登革热病毒感染的免疫效果 (rDEN2TV30-7169)在接种后6个月或24个月给药；目的1B)评估∆005和 登革热流行人群中登革2型挑战病毒；以及目的2)使用预测建模来识别 基线和接种后免疫表型(S)对TV005疗效和安全性的预测更好 了解对疫苗接种和保护性免疫的反应，并为未来登革热研究设计提供信息 流行环境中的疫苗开发。与大规模野外试验相比，D-Chim将提供更早的 疫苗效力和安全信号，同时招募最低数量的志愿者，并为我们的 了解在流行环境下对接种疫苗和挑战的免疫反应 疫苗影响的统计建模。