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（由适用提供）：委内瑞拉马脑炎病毒（VEEV）是一种威胁生命的NIH/NIAID类别B人类病原体和潜在的生物恐怖主义威胁。 VEEV的爆发发生在中美洲，以前已经蔓延到美国。该病毒再次出现在美国的潜在毁灭性影响要求有效的疫苗保护人群。目前，根据IND方案使用了活衰减的TC-83疫苗，用于有风险的医务人员的疫苗。该疫苗会引起不利影响，并正在进行开发改善的VEEV疫苗的努力。但是，由于疫苗开发是一个漫长的过程，并且TC-83疫苗的供应受到限制，因此美国很快可能会出现VEEV疫苗的短缺。这可能会使美国人口和处于危险的人员不受保护。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。在第一阶段SBIR中，我们开发了一种针对VEEV以及其他病毒疾病的疫苗的新技术。拟议的IDNA疫苗技术代表了常规DNA免疫与高效率衰减疫苗的独特组合。该技术的关键特征是，活体病毒是由IDNA质粒在体内发射的，该病毒具有增强的安全性和免疫原性特征的VEEV疫苗的分子克隆。在第一阶段的SBIR研究中，我们表明，从TC-83疫苗衍生的原型IDNA的体内注射已成功发射了小鼠中的活衰减疫苗。在此II期SBIR中，我们根据TC-83克隆和IDNA免疫抑制技术的合理工程提出了IDNA VEEV疫苗的高级临床前评估。 sp。 AIM 1，我们提出（i）在体内进行IDNA疫苗的优化，包括IDNA公式以及具有和没有电穿孔的给药途径，以及（ii）剂量升级研究，以确定足以发射疫苗病毒和在BALB/C小鼠中诱导保护的IDNA量最小。 IDNA将被配制，以最大程度地减少对电穿孔和冷链的需求。总而言之，Sp。 AIM 1是开发IDNA疫苗的患者和医生友好程序。在sp。 AIM 2，与肯塔基州路易斯维尔大学（UOFL）合作，我们提出了对小鼠，兔子以及恒河猴非人类素质（NHP）的实验性VEEV IDNA疫苗的安全性，免疫原性和有效性的评估，该疫苗代表了人Veev感染的最佳模型。作为对照，将使用标准的TC-83疫苗。经过这些研究，将在SP期间选择铅VEEV IDNA疫苗作为CGMP的产生。 AIM 3。此外，我们提议与FDA进行预先会议，以寻求有关（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，理性疫苗设计和 IDNA技术可以通过提高安全性，遗传稳定性和免疫原性来为VEEV疫苗提供革命性的解决方案，并消除常规制造过程中许多昂贵的步骤。从本质上讲，活疫苗将在免疫个体内“生产”。该技术还利用了DNA疫苗（遗传均匀性和稳定性，低成本，存储和运输的低成本，没有冷链）的许多优势，更重要的是，它增强了免疫原性。作为任何重组DNA，IDNA都激活CGAS-CGAMP-sting依赖性信号传导途径，从而导致细胞环和趋化因子的强大产生，从而诱导强启动效应并刺激获得性的病毒特异性免疫复杂。最终的IDNA VEEV疫苗将代表一类新型的疫苗，结合了DNA和活疫苗的优势。 IDNA技术可以很容易地适应其他疫苗的开发，包括用于WEEV，EEEV，其他α病毒和黄病毒的活疫苗。如果成功，该技术可能会改变许多病毒疾病的活疫苗领域。