Clinical Trials of Biodefense Vaccines (Dengue)

生物防御疫苗（登革热）的临床试验

• 批准号: 9566648
• 负责人: Stephen Whitehead
• 金额: $ 128.22万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9566648
• 关键词: Admixture; Age; Agreement; Antibodies; Antibody Response; Area; Attenuated; Bangladesh; Brazil; CD8-Positive T-Lymphocytes; Child; Clinical Research; Clinical Trials; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Detection; Development; Disease; Dose; Elderly; Enrollment; Evaluation; Formulation; Frequencies; Goals; Immune response; Immunity; Immunization; India; Individual; Infection; Innate Immune Response; Knowledge; Licensing; Manufacturer Name; Measurable; Modeling; National Institute of Allergy and Infectious Disease; Natural Immunity; Phase; Preparation; Public Health; Regimen; Research Institute; Safety; Sampling; Serotyping; Sterility; Study Subject; T cell response; Taiwan; Thailand; United States; Vaccination; Vaccines; Vietnam; Virus; West Nile virus; age group; biodefense; clinically significant; cross reactivity; design; efficacy trial; immunogenic; immunogenicity; neutralizing antibody; phase 2 study; phase II trial; research clinical testing; response; safety testing; seroconversion; vaccination strategy; vaccine candidate; vaccine development

The development strategy for an effective tetravalent dengue vaccine has consisted of the clinical evaluation of monovalent vaccine candidates for each of the four serotypes with the goal of selecting suitable candidates for inclusion in a tetravalent formulation. Optimal admixtures (TV003 and TV005: DEN1del30, DEN2/4del30, DEN3del30/31, DEN4del30) have been selected and induce an unprecedented level of neutralizing antibody in sero-nave subjects that is both balanced among the serotypes and sufficient to provide sterile immunity against a second dose administered at six months. Following a single dose of TV005, the frequency of seroconversion in vaccinees to the individual serotypes 1 - 4 reached a remarkable 92%, 97%, 97%, and 97%, respectively, with 90% of vaccinees achieving a tetravalent antibody response. These data initially suggested that a single dose of vaccine may be sufficiently immunogenic and this has been demonstrated using challenge with safety-tested strains of DENV-2 and DENV-3. This points to a significant advantage of the LID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result and which require pre-vaccination dengue antibodies for full efficacy. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, Vietnam, Taiwan and the United States. Through on-going technological and scientific support, these licensees are making significant progress in the development of the vaccine and a Phase III is underway in Brazil. Through an Interagency Agreement initiated with the Walter Reed Army Institute of Research, a Phase II study has been designed to evaluate the tetravalent vaccine in subjects of decreasing age in Bangkok, Thailand. In addition, an NIAID-sponsored Phase II trial is underway in subjects of decreasing age in Dhaka, Bangladesh. At LID, several clinical evaluations are ongoing: Safety and immunogenicity of TV005 in older adults (age 50 70 years); safety and immunogenicity of a prime-boost vaccination regimen consisting of a TV005 prime vaccination followed by a dengue subunit boost (Merck); TV005 vaccination followed by challenge with DENV-3; TV005 vaccination followed by DENV-2 challenge after one month to investigate the use of the vaccine for travelers. We have also enrolled two clinical studies to investigate the immune response to DENV. In the first study, subjects received a trivalent preparation of vaccine viruses (lacking DENV-2) and were then challenged with DENV-2 to evaluate cross-protection from DENV-1, -3, and -4. In the second study, we sought to model natural sequential infections by administering a DENV-1 vaccine followed 9 months later by challenge with DENV-2. From this study, we are evaluating the repertoire of both cross-reactive and enhancing antibodies. We have also completed the evaluation of a live attenuated West Nile virus vaccine in older adults (age 50 - 65 years). This vaccine, rWN/DEN4del30, is constructed using the DEN4del30 vaccine background and is both safe and immunogenic in older adults. The development of effective vaccination strategies against dengue virus infection and clinically significant disease remains a task of high global public health value and significance, while also being a challenge of considerable complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes and enhancement of subsequent dengue disease in young children, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results have challenged the hypothesis that seroconversion is the only reliable correlate of protection. We have shown that CD4(+) and CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV.

有效的四卫登革热疫苗的开发策略包括对四种血清型中每种候选疫苗的临床评估，目的是选择合适的候选物，以纳入四含量的配方。已经选择了最佳混合物（TV003和TV005：DEN1DEL30，DEN2/4DEL30，DEN3DEL30/31，DEN4DEL30），并诱导了血清型型在血清型中的中和抗体的前所未有的中和抗体水平，这些抗体在血清型中都可以在六个月的时间内均能在六个月内抗衡。在单剂量的TV005之后，疫苗的血清转化频率分别为1-4，分别达到了92％，97％，97％和97％的频率，其中90％的疫苗可实现四抗抗体响应。这些数据最初表明，单剂量的疫苗可能具有足够的免疫原性，并且使用挑战证明了与DENV-2和DENV-3的安全性菌株的挑战。与其他需要两三剂的DENV疫苗相比，这表明了盖子疫苗的显着优势，这些疫苗需要两到三剂才能获得相似的结果，并且需要预疫苗接种登革热抗体才能获得完全疗效。选择最佳的四位化混合物已使位于巴西，印度，越南，台湾和美国的几家制造商对疫苗的进一步开发。通过持续的技术和科学支持，这些被许可人在疫苗的开发中取得了重大进展，在巴西正在进行III期。通过与沃尔特·里德（Walter Reed）陆军研究所发起的一项机构间协议，已设计了一项II阶段研究，以评估泰国曼谷年龄降低的受试者的四价疫苗。此外，在孟加拉国达卡年龄降低的受试者中，正在进行一项NIAID赞助的II期试验。在盖子上，正在进行一些临床评估：老年人TV005的安全性和免疫原性（50岁70岁）；促进疫苗接种方案的安全性和免疫原性，该方案由TV005原始疫苗接种，然后是登革热亚基增压（Merck）； TV005疫苗接种，然后是DENV-3的挑战； TV005疫苗接种，然后在一个月后进行DENV-2挑战，以调查旅行者使用疫苗的使用。 我们还招募了两项临床研究，以研究对DENV的免疫反应。 在第一项研究中，受试者接受了疫苗病毒的三价制备（缺乏DENV-2），然后受到DENV-2的挑战，以评估DENV-1，-3和-4的交叉保护。 在第二项研究中，我们试图通过施用DENV-1疫苗来对自然顺序感染进行建模，然后9个月后与DENV-2挑战。从这项研究中，我们正在评估交叉反应和增强抗体的曲目。我们还完成了对老年人（50-65岁）的西尼尼罗河病毒疫苗的评估。 该疫苗RWN/DEN4DEL30是使用DEN4DEL30疫苗背景构建的，在老年人中既安全又具有免疫原性。 针对登革热病毒感染和临床意义疾病的有效疫苗接种策略的发展仍然是全球公共健康价值和意义高的任务，同时也是相当复杂的挑战。尽管最先进的登革热疫苗候选者的最新疗效试验仅显示针对所有四种DENV血清型的部分保护以及在大多数受试者中对每种血清型的可测量中和抗体的可测量中和抗体的检测，但幼儿中随后的登革热疾病的增强。这些结果挑战了血清转化是唯一可靠的保护相关性的假设。我们已经表明，疫苗中的CD4（+）和CD8（+）T细胞反应很容易检测，并且与天然登革热病毒感染相当。对T细胞反应的详细知识可能进一步有助于鉴定自然免疫和对DENV的疫苗接种的鲁棒相关性。