Clinical Trials of Biodefense Vaccines (Dengue)

生物防御疫苗（登革热）的临床试验

• 批准号: 10692095
• 负责人: Stephen Whitehead
• 金额: $ 45.58万
• 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/10692095
• 关键词: Admixture; Age; Antiviral Agents; Area; Attenuated; Attenuated Vaccines; Blinded; Brazil; CD8-Positive T-Lymphocytes; Child; Clinical; Clinical Research; Clinical Trials; Contracts; Cooperative Research and Development Agreement; Cyclic GMP; Dengue; Dengue Vaccine; Dengue Virus; Development; Dose; Elderly; Ensure; Evaluation; Exposure to; Flavivirus; Formulation; Goals; Human; Immune response; Immunization; India; Infant; Infection; Innate Immune Response; Institutes; Intention; Intervention; Licensing; Manufacturer; Medical; MicroRNAs; Modeling; National Institute of Allergy and Infectious Disease; Neurologic; Phase; Preparation; Publications; Research; Safety; Sampling; Serotyping; Serum; T cell response; Taiwan; Testing; Tissues; United States; Vaccination; Vaccines; Vietnam; Virus; Virus Replication; Zika Virus; Zika virus vaccine; age group; biodefense; clinical development; clinical research site; cross immunity; cross reactivity; effectiveness evaluation; immunogenic; immunogenicity; improved; neutralizing antibody; novel; panacea; pathogen; phase 3 testing; reproductive; research clinical testing; response; seropositive; vaccine candidate; vaccine development; vaccine evaluation; vaccine response

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 infectivity and neutralizing antibody in sero-naive subjects after a single dose. This vaccine response is well balanced among the serotypes and sufficient to provide protection against safety-tested challenge strains of DENV-2 and DENV-3. This indicates a significant advantage of the NIAID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result and which require the prior exposure to DENV to ensure safety and 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 ongoing technological and scientific support, these licensees are making significant progress in the development of the vaccine and a Phase III has been completed in Brazil. Phase I/II studies have been completed in India and are separately sponsored by Panacea Biotec and Serum Institute of India and plans are under development for Phase III evaluations by both companies. Through our intramural clinical contract with the JHU Center for Immunization Research, numerous clinical evaluations have been successfully completed and have demonstrated that the NIAID vaccine is fully immunogenic after a single dose, elicits a well-balanced immune response across all four serotypes in DENV-nave recipients, is capable of eliciting catch-up responses for missing serotypes in DENV sero-positive recipients, is safe and immunogenic in infants and children, and elicits a strong cross-reactive CD8+ T-cell response. We have recently completed several studies and they are undergoing final analysis and preparation for publication: Safety and immunogenicity of TV005 in older adults (age 50 70 years); 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 in travelers to DENV endemic areas; and a study in which 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. Through a CRADA with Janssen Pharmaceutica, we are using our DENV-3 controlled human infection model to evaluate the effectiveness of a novel antiviral drug at our clinical site at JHU. The development strategy for an effective live attenuated Zika virus vaccine consists of the clinical evaluation of attenuated vaccine candidates as monovalent presentations prior to their eventual combination with TV003 or TV005 tetravalent DENV vaccines to generate a pentavalent vaccine for both DENV and ZIKV. We completed our first clinical study to evaluate the safety and immunogenicity of a live-attenuated chimeric vaccine candidate rZIKV/D4del30. Although this candidate appears to be safe for use in humans, low infectivity was observed with limited immunogenicity. We have repeated the clinical trial using a higher dose inoculum, but we were unable to improve the overall infectivity and resulting immunogenicity. Additional ZIKV vaccine candidates containing microRNA targets to restrict virus replication in placental, reproductive, and neurological tissues have been produced under cGMP conditions and IND applications for their clinical evaluation are pending. After a protracted review period and clinical holds imposed by the FDA, the controlled human infection model for ZIKV has finally progressed to clinical safety evaluation at JHU. To date the safety profile is acceptable and the clinical endpoints look achievable (although the study is still blinded). This model will allow us to evaluate the protective capacity of a variety of ZIKV vaccines and interventions.

有效四价登革热疫苗的开发策略包括对四种血清型中每种血清型的单价候选疫苗进行临床评估，目的是选择合适的候选疫苗纳入四价制剂中。已选择最佳混合物（TV003 和 TV005：DEN1del30、DEN2/4del30、DEN3del30/31、DEN4del30），单次剂量后可在血清初治受试者中诱导前所未有的感染性和中和抗体水平。这种疫苗反应在血清型之间非常平衡，足以提供针对经过安全测试的 DENV-2 和 DENV-3 挑战株的保护。这表明与其他 DENV 减毒活疫苗相比，NIAID 疫苗具有显着优势，其他 DENV 减毒活疫苗需要两剂或三剂才能达到类似结果，并且需要事先接触 DENV 以确保安全性和充分效力。最佳四价混合物的选择使得位于巴西、印度、越南、台湾和美国的多家制造商能够进一步开发疫苗。通过持续的技术和科学支持，这些被许可方在疫苗的开发方面取得了重大进展，并且第三阶段已经在巴西完成。 I/II 期研究已在印度完成，由 Panacea Biotec 和印度血清研究所分别赞助，两家公司正在制定 III 期评估计划。通过我们与 JHU 免疫研究中心的校内临床合同，已成功完成大量临床评估，并证明 NIAID 疫苗在单剂量后具有完全免疫原性，在 DENV-nave 中的所有四种血清型中引发均衡的免疫反应接受者，能够对 DENV 血清阳性接受者中缺失的血清型引起追赶反应，对婴儿和儿童安全且具有免疫原性，并引起强烈的免疫反应。交叉反应 CD8+ T 细胞反应。 我们最近完成了几项研究，正在进行最终分析并准备发表： TV005 在老年人（50 至 70 岁）中的安全性和免疫原性； TV005 疫苗接种，然后用 DENV-3 攻击； TV005疫苗接种一个月后进行DENV-2攻击，以调查前往DENV流行地区的旅行者使用该疫苗的情况；在一项研究中，受试者接受了三价疫苗病毒制剂（缺乏 DENV-2），然后接受 DENV-2 攻击，以评估与 DENV-1、-3 和 -4 的交叉保护。通过与 Janssen Pharmaceutica 合作的 CRADA，我们正在使用 DENV-3 控制的人类感染模型来评估一种新型抗病毒药物在 JHU 临床中心的有效性。 有效的减毒寨卡病毒活疫苗的开发策略包括对候选减毒疫苗进行单价临床评估，然后最终与 TV003 或 TV005 四价 DENV 疫苗组合，产生针对 DENV 和 ZIKV 的五价疫苗。 我们完成了第一项临床研究，以评估减毒嵌合候选疫苗 rZIKV/D4del30 的安全性和免疫原性。 尽管该候选药物似乎可以安全地用于人类，但观察到低传染性和有限的免疫原性。 我们使用更高剂量的接种物重复了临床试验，但我们无法提高整体感染性和由此产生的免疫原性。 其他含有 microRNA 靶点的 ZIKV 候选疫苗已在 cGMP 条件下生产，其临床评估的 IND 申请正在等待中，以限制病毒在胎盘、生殖和神经组织中的复制。 经过 FDA 的长期审查和临床搁置，ZIKV 的受控人类感染模型终于在 JHU 进入临床安全性评估。 迄今为止，安全性是可以接受的，临床终点看起来是可以实现的（尽管该研究仍然是盲法）。 该模型将使我们能够评估各种 ZIKV 疫苗和干预措施的保护能力。