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

基本信息

批准号：
9210584
负责人：
Peter M. Pushko
金额：
$ 81.26万
依托单位：
MEDIGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210584
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 FluMist Formulation Funding Future Gene Rearrangement Genetic Goals Grant Health Personnel Human Human Resources Hybrids Immune response Immunity Immunization Immunize Inbred BALB C Mice Individual Infection Injection of therapeutic agent Investigational Drugs Laboratories Lead Legal patent 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 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 design epizootic experience immunogenic immunogenicity improved in vivo innovation manufacturing process meetings neutralizing antibody new technology nonhuman primate novel novel vaccines pathogen plasmid DNA preclinical evaluation prototype public health relevance response vaccine candidate vaccine delivery vaccine development weapons

项目摘要

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（由申请人提供）：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，VEEV 的爆发发生在中美洲，并可能已传播到美国。该病毒在美国重新出现的破坏性影响需要有效的疫苗来保护人群。目前，根据 IND 协议，使用减毒活疫苗 TC-83 进行医疗疫苗接种。该疫苗造成不良影响，改进的 VEEV 疫苗的开发工作正在进行中，但由于疫苗开发过程漫长，而且 TC-83 疫苗的供应有限，美国可能很快就会出现短缺。 VEEV 疫苗。这可能会使美国民众和高危人员得不到保护。此外，在没有疫苗的情况下，VEEV 可能需要重新分类为 BSL4 选择剂。在 I 期 SBIR 中，我们开发了一项新技术。所提出的 iDNA 疫苗接种技术代表了传统 DNA 免疫与高效减毒活疫苗的独特结合，该技术的主要特点是在体内发射减毒活病毒。携带 VEEV 疫苗分子克隆的 iDNA 质粒具有增强的安全性和免疫原性特征。在 I 期 SBIR 研究中，我们表明源自 TC-83 疫苗的原型 iDNA 的体内注射已成功启动。在该 II 期 SBIR 中，我们提出基于 TC-83 克隆和 iDNA 免疫技术的合理工程对 iDNA VEEV 疫苗进行高级临床前评估。体内研究，包括 iDNA 配方以及使用和不使用电穿孔的给药途径，以及 (ii) 剂量递增研究，以确定足以启动疫苗病毒并在体内诱导保护的 iDNA 的最小量BALB/c 小鼠的配方将最大限度地减少电穿孔和冷链的需要。 Sp Aim 1 的目标是开发对患者和医生友好的 iDNA 疫苗接种程序。与肯塔基州路易斯维尔大学 (UofL) 合作，我们建议评估实验性 VEEV iDNA 疫苗在小鼠、兔子以及恒河非人类灵长类动物 (NHP) 中的安全性、免疫原性和功效，作为人类 VEEV 感染的最佳模型，将使用标准 TC-83 疫苗。在这些研究之后，将选择主要 VEEV iDNA 疫苗用于 Sp 目标 3 的生产。建议与 FDA 召开 IND 前会议，寻求有关 (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，并消除制造过程中的许多昂贵步骤，为 VEEV 疫苗提供革命性的解决方案。本质上，减毒活疫苗将在免疫个体体内“制造”。 iDNA具有DNA疫苗的许多优点（遗传同质性和稳定性、制造、储存和运输成本低、无冷链），更重要的是，与任何重组DNA一样，iDNA可以增强免疫原性。 cGAS-cGAMP-STING 依赖性信号通路导致细胞因子和趋化因子的大量产生，从而诱导强烈的启动效应并刺激获得性病毒特异性免疫反应。最终的 iDNA VEEV 疫苗将代表一类结合了 DNA 优点的新型疫苗。 iDNA 技术可以轻松应用于其他疫苗的开发，包括 WEEV、EEEV、其他甲病毒和黄病毒的减毒活疫苗。如果成功，该技术可能会带来变革。用于许多病毒性疾病的减毒活疫苗领域。