Novel DNA-Launched Attenuated Vaccine for VEE Virus SBIR Phase II

新型 DNA 启动的 VEE 病毒减毒疫苗 SBIR II 期

• 批准号: 9048095
• 负责人: Peter M. Pushko
• 金额: $ 81.16万
• 依托单位: MEDIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9048095
• 关键词: Adjuvant; Advanced Development; Adverse effects; Alphavirus; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Biological; Bioterrorism; Categories; Cell Culture Techniques; Central America; Chikungunya virus; Classification; Cold Chains; Collaborations; Combined Vaccines; Communicable Diseases; Cyclic GMP; DNA; DNA Vaccines; Data; Development; Disease Outbreaks; Dose; Electroporation; Engineering; Epidemic; Equilibrium; Evaluation; Flavivirus; Flushield; Formulation; Funding; Future; Gene Rearrangement; Genetic; Goals; Grant; Health Personnel; Human; Human Resources; Hybrids; Immune response; Immunity; Immunization; Inbred BALB C Mice; Individual; Infection; Injection of therapeutic agent; Investigational Drugs; Laboratories; Lead; Left; Legal patent; Licensing; Life; Macaca mulatta; Mediating; Mediation; Medical; Medical Research; Methods; Modeling; Molecular Cloning; Mus; Mutagenesis; Mutation; National Institute of Allergy and Infectious Disease; Oryctolagus cuniculus; Patients; Phase; Phase I Clinical Trials; Phenotype; Plasmids; Population; Populations at Risk; Procedures; Process; Production; Protocols documentation; Recombinant DNA; Research Institute; Research Personnel; Resistance; Risk; Route; Safety; Secure; Signal Pathway; Small Business Innovation Research Grant; Subunit Vaccines; Technology; Testing; Texas; Toxicology; Transportation; United States; United States National Institutes of Health; Universities; Untranslated Regions; Vaccination; Vaccine Design; Vaccines; Venezuelan Equine Encephalitis Virus; Virus; Virus Diseases; Yellow Fever; base; biodefense; cGMP production; chemokine; cost; cytokine; design; epizootic; experience; immunogenic; immunogenicity; improved; in vivo; innovation; manufacturing process; meetings; neutralizing antibody; new technology; nonhuman primate; novel; novel vaccines; pathogen; preclinical evaluation; prototype; public health relevance; response; vaccine candidate; vaccine delivery; vaccine development; weapons

 DESCRIPTION (provided by applicant): Venezuelan Equine Encephalitis virus (VEEV) is a life-threatening, NIH/NIAID category B human pathogen and a potential bioterrorism threat. Outbreaks of VEEV occur in Central America and have previously spread into the United States. The potentially devastating effects of the virus reemergence in the U.S. demand an effective vaccine to protect population. Currently, live attenuated TC-83 vaccine is used under IND protocol for vaccination of medical personnel at risk. The vaccine causes adverse effects, and efforts to develop an improved VEEV vaccine are underway. However, because vaccine development is a lengthy process and the supply of TC-83 vaccine is limited, the U.S. may soon experience a shortage of the VEEV vaccine. This can leave both the U.S. population and at-risk personnel unprotected. Furthermore, in the absence of vaccine, VEEV may require re-classification as a BSL4 Select Agent. In Phase I SBIR, we developed a new technology for vaccination against VEEV and, potentially, other viral diseases. The proposed iDNA vaccination technology represents a unique combination of conventional DNA immunization with the high efficacy of live attenuated vaccines. The key feature of this technology is that live attenuated virus is launched in vivo from iDNA plasmid carrying a molecular clone of VEEV vaccine with enhanced safety and immunogenic features. In Phase I SBIR studies we have shown that injection in vivo of the prototype iDNA derived from the TC-83 vaccine has successfully launched live attenuated vaccine in mice. In this Phase II SBIR we propose advanced preclinical evaluation of iDNA VEEV vaccine based on the rational engineering of TC-83 clones and iDNA immunization technology. In Sp. Aim 1, we propose (i) optimization of iDNA vaccination in vivo including iDNA formulation and the route of administration with, and without, electroporation, and (ii) dose escalation study to determine the minimal amount of iDNA sufficient to launch the vaccine virus and to induce protection in BALB/c mice. The iDNA will be formulated to minimize the need for electroporation and cold chain. In summary, the goal of Sp. Aim 1 is the development of patient- and doctor-friendly procedure for iDNA vaccination. In Sp. Aim 2, in collaboration with the University of Louisville, KY (UofL) we propose evaluation of safety, immunogenicity and efficacy of experimental VEEV iDNA vaccines in mice, rabbits, as well as in rhesus non-human primates (NHP), which represent the best model for human VEEV infection. As a control, the standard TC-83 vaccine will be used. Following these studies, the lead VEEV iDNA vaccine will be selected for the cGMP production during Sp. Aim 3. In addition, we propose a pre-IND meeting with the FDA to seek input on the design of (i) GLP toxicology study and (ii) Phase I clinical trial. Our preliminary data suggest that the rational vaccine design and iDNA technology can provide a revolutionary solution for VEEV vaccine by improving safety, genetic stability, and immunogenicity, and by eliminating many costly steps of the conventional manufacturing process. Essentially, live attenuated vaccine will be "manufactured" within the immunized individuals. This technology also utilizes many advantages of DNA vaccines (genetic homogeneity and stability, low cost of manufacturing, storage, and transportation, no cold chain) and, more importantly, enhances immunogenicity. As any recombinant DNA, the iDNA activates cGAS-cGAMP-STING-dependent signaling pathways resulting in robust production of cyto- and chemokines, which induce strong priming effects and stimulate acquired virus-specific immune responses. The final iDNA VEEV vaccine will represent a novel class of vaccines combining the advantages of DNA and live attenuated vaccines. The iDNA technology can be easily adapted for the development of other vaccines including live attenuated vaccines for WEEV, EEEV, other alphaviruses, and flaviviruses. If successful, this technology can potentially transform the field of live attenuated vaccines for many viral diseases.

 描述(申请人提供)：委内瑞拉马脑炎病毒(VEEV)是一种危及生命的NIH/NIAID B类人类病原体和潜在的生物恐怖主义威胁。VEEV疫情发生在中美洲，此前已蔓延至美国。这种病毒在美国重新出现的潜在破坏性影响需要一种有效的疫苗来保护人口。目前，根据IND方案，TC-83减毒活疫苗用于高危医务人员的疫苗接种。该疫苗会产生不良反应，目前正在努力开发改进的VEEV疫苗。然而，由于疫苗开发是一个漫长的过程，而且TC-83疫苗的供应有限，美国可能很快就会经历VEEV疫苗的短缺。这可能会使美国人口和高危人员得不到保护。此外，在缺乏疫苗的情况下，VEEV可能需要重新分类为BSL4选择试剂。在第一阶段SBIR中，我们开发了一种新技术，用于预防VEEV和潜在的其他病毒疾病的疫苗接种。拟议的IDNA疫苗接种技术代表了传统DNA免疫与减毒活疫苗的高效力的独特结合。这项技术的关键特征是从携带VEEV疫苗分子克隆的IDNA质粒体内发射减毒活病毒，具有增强的安全性和免疫原性。在第一阶段的SBIR研究中，我们已经证明，从TC-83疫苗衍生的原型IDNA在体内注射已经成功地在小鼠身上推出了减毒活疫苗。在这个第二阶段的SBIR中，我们提出了基于TC-83克隆的合理工程和IDNA免疫技术的IDNA VEEV疫苗的高级临床前评估。在Sp.目的：(1)优化IDNA体内接种方法，包括IDNA配方和给药途径，包括电穿孔和不加电穿孔，以及(Ii)剂量递增研究，以确定足以在BALB/c小鼠体内发射疫苗病毒和诱导保护的最低IDNA剂量。将制定IDNA以最大限度地减少对电穿孔和冷链的需求。总之，Sp.目标1是开发对患者和医生友好的IDNA疫苗接种程序。在Sp.目的2，我们与肯塔基州路易斯维尔大学(UofL)合作，对实验性VEEV IDNA疫苗在小鼠、兔以及恒河猴非人类灵长类动物(NHP)中的安全性、免疫原性和有效性进行了评估，这是研究人类VEEV感染的最佳模型。作为对照，将使用标准的TC-83疫苗。在这些研究之后，将选择领先的VEEV IDNA疫苗在Sp期间生产cGMP。目的3.此外，我们建议与FDA召开IND前会议，以征求对(I)GLP毒理学研究和(II)I期临床试验设计的意见。我们的初步数据表明，合理的疫苗设计和 IDNA技术可以通过提高安全性、遗传稳定性和免疫原性，并通过消除传统生产过程中许多昂贵的步骤，为VEEV疫苗提供革命性的解决方案。从本质上讲，减毒活疫苗将在接种疫苗的个体体内“制造”。这项技术还利用了DNA疫苗的许多优势(遗传同质性和稳定性，低制造、储存和运输成本，没有冷链)，更重要的是，增强了免疫原性。与任何重组DNA一样，IDNA激活cGAS-cGAMP-STING依赖的信号通路，导致细胞和趋化因子的大量产生，从而诱导强大的启动效应和刺激获得性病毒特异性免疫反应。最终的IDNA VEEV疫苗将代表一种结合DNA和减毒活疫苗优点的新型疫苗。IDNA技术可以很容易地用于其他疫苗的开发，包括Weev、EEEV、其他甲型病毒和黄病毒的减毒活疫苗。如果成功，这项技术可能会改变许多病毒性疾病的减毒活疫苗领域。