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: 10673589
• 负责人: Beth Diane Kirkpatrick
• 金额: $ 124.94万
• 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/10673589
• 关键词: Acceleration; 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; Latin America; Lead; Licensing; Licensure; Measures; Memory B-Lymphocyte; Modeling; National Institute of Allergy and Infectious Disease; Persons; Phase; Phenotype; Placebos; Polymerase Chain Reaction; Population; Probability; 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; cytokine; design; efficacy trial; human morbidity; innovation; neutralizing antibody; phase 2 testing; post-market; 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.

项目摘要 登革热病毒比任何其他虫媒病毒引起更多的人类发病率，强调公共卫生 迫切需要在地方性环境中提供安全有效的登革热疫苗，与NIAID保持一致 优先事项这一关键需求将通过测试NIAID铅的安全性和保护功效来解决 孟加拉国登革热流行区成人接种四价登革热减毒活疫苗候选物TV 005 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 中心假设是接种TV 005将保护免受活的重组登革病毒感染， 2攻毒病毒（DENV-2），攻毒后DENV-2病毒血症作为主要疗效终点。在 除了导致TV 005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 疫苗攻毒设计，以评价TV 005在美国登革热初治成人中的安全性和有效性， 耐受性良好，预防病毒血症的有效性>99%。NIAID有前途的疫苗的下一个关键步骤 是在登革热流行的环境中测试它的安全性和有效性。在这项研究中，224名健康的成年志愿者， 暴露于登革热且未经治疗的受试者将入组，并以1：1（疫苗：安慰剂）的比例随机接受TV 005，随后 通过在接种后6个月或24个月用DENV-2进行住院攻毒。为了验证我们的核心假设，我们将 追求以下具体目标：目标1A）确定在登革热流行人群中， TV 005疫苗对重组登革2型攻击病毒诱导登革感染的效力 （rDEN 2 β 30-7169）接种后6或24个月给药;目的1B）评价TV 005的安全性， 登革流行人群中的DEN-2攻击病毒;以及目标2）使用预测建模来识别 预测TV 005疗效和安全性的基线和接种后免疫表型 了解对疫苗接种和保护性免疫的反应，并为登革热的未来研究设计提供信息 在地方病流行的情况下开发疫苗。与大规模的野外试验相比，D-CHIM将提供早期的 疫苗的有效性和安全性信号，同时招募最少数量的志愿者，并有助于我们的 了解在地方性环境中对疫苗接种和攻毒的免疫反应， 疫苗影响的统计模型。