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.

项目概要 登革热病毒比任何其他虫媒病毒造成更多的人类发病率，强调了公共卫生 与 NIAID 保持一致，迫切需要在流行地区提供安全有效的登革热疫苗 这一关键需求将通过测试 NIAID 的先导物质的安全性和保护功效来解决。 四价登革热减毒候选疫苗 TV005，用于登革热流行的孟加拉国成年人 通过基于登革热控制人类感染模型（D-CHIM）的疫苗挑战试验。 中心假设是，接种 TV005 疫苗可以预防活重组登革热感染 2攻击病毒（DENV-2），攻击后的DENV-2病毒血症作为主要疗效终点。 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方法 疫苗挑战设计旨在评估 TV005 在未接触过登革热的美国成年人中的安全性和有效性， 耐受性良好，预防病毒血症的效率 >99%，这是 NIAID 有希望的疫苗的下一个关键步骤。 目的是测试其在登革热流行环境中的安全性和有效性。在这项研究中，有 224 名健康成年志愿者参与。 曾接触过登革热且未接触过登革热的患者，将按 1:1（疫苗：安慰剂）的比例进行登记和随机分组，然后接受 TV005 为了检验我们的中心假设，我们将在疫苗接种后 6 或 24 个月通过住院患者使用 DENV-2 进行攻击。 追求以下具体目标： 目标 1A) 确定登革热流行人群的保护措施 TV005 疫苗对抗活重组 DENV-2 攻击病毒诱导的登革热感染的功效 (rDEN2Δ30-7169) 疫苗接种后 6 或 24 个月施用；目标 1B) 评估 TV005 的安全性和 登革热流行人群中的 DEN-2 病毒挑战；以及 目标 2) 使用预测模型来识别 基线和疫苗接种后免疫表型可更好地预测 TV005 的功效和安全性 了解对疫苗接种和保护性免疫的反应，并为未来的登革热研究设计提供信息 与大规模实地试验相比，D-CHIM 将提供早期疫苗开发。 疫苗功效和安全信号，同时招募最少数量的志愿者，并为我们做出贡献 通过以下方式了解流行环境中对疫苗接种和攻击的免疫反应 疫苗影响的统计模型。