Safety and Immunogenicity of novel, live-attenuated V4020 vaccine for Venezuelan Equine Encephalitis (VEE) in healthy adults

新型 V4020 减毒活疫苗针对健康成人的委内瑞拉马脑炎 (VEE) 的安全性和免疫原性

基本信息

批准号：
10581707
负责人：
Peter M. Pushko
金额：
$ 60.45万
依托单位：
MEDIGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581707
关键词：
Adjuvant Adult Adverse effects Age Years Alphavirus Animals Attenuated Attenuated Vaccines Bioterrorism CMV promoter Capsid Categories Central America Chikungunya virus Clinical Clinical Research Clinical Trials Design Collaborations Combined Vaccines Communicable Diseases Communication Complementary DNA Controlled Clinical Trials Cyclic GMP DNA DNA Sequence Rearrangement DNA Vaccines Data Development Disease Outbreaks Dose Double-Blind Method Engineering Epidemic Equilibrium Evaluation Flavivirus FluMist Gene Rearrangement Genes Genetic Genetic Transcription Genome Genotype Glycoproteins Health Personnel Human Human Resources Immune response Immunity Immunologics In Vitro Inbred BALB C Mice Individual Investigational Drugs Laboratories Lead Legal patent Length Licensing Life Macaca fascicularis Medical Medical Research Mission Modeling Morbidity - disease rate Mus Mutagenesis Mutation National Institute of Allergy and Infectious Disease Pathogenicity Persons Phase Phase I Clinical Trials Phase Ia Clinical Trial Phenotype Placebo Control Placebos Plasma Plasmids Population Preparation Process RNA RNA Viruses Randomized Regimen Research Research Institute Research Personnel Research Support Resistance Risk Safety Saliva Sampling Silent Mutation Strategic Planning Structural Genes Subunit Vaccines T cell response Technology Texas United States United States National Institutes of Health Universities Urine Vaccination Vaccine Production Vaccinee Vaccines Variant Venezuelan Equine Encephalitis Virus Venezuelan Equine Encephalomyelitis Vero Cells Virus Virus Diseases Virus Shedding Volunteer Group Western Equine Encephalitis Virus Yellow Fever attenuation biodefense bioweapon cytokine design epizootic experience first-in-human genomic RNA human pathogen human study human subject immunogenicity improved infection risk innovation insight manufacture mortality neutralizing antibody nonhuman primate novel outbreak control pathogen prevent primary endpoint rational design research clinical testing safety assessment subcutaneous technology platform vaccination protocol vaccine development vaccine safety vector vaccine volunteer

项目摘要

ABSTRACT 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 VEEV reemergence in the U.S. demand an effective vaccine to protect immunologically naïve 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 the U.S. population and at-risk personnel unprotected. Furthermore, in the absence of a vaccine, VEEV may fit the CDC definition of a BSL4 Select Agent. During previous NIH-supported research, Medigen evaluated a new platform technology for the development of vaccines against VEEV and, potentially, other viral diseases. The proposed V4020 vaccine includes attenuating rearrangement of the capsid and glycoprotein genes within the full-length genomic RNA. The attenuating rearrangement effectively prevents reversion because many independent mutations would be needed to revert to the pathogenic genotype. In addition, vaccine is made from a DNA copy of the rearranged RNA genome placed in the iDNA® infectious clone downstream from the CMV promoter. The key feature of iDNA infectious clone (and the difference from standard cDNA clone) is that live attenuated virus is launched from the plasmid, without the need for in vitro transcription. The use of genetically stable iDNA improves vaccine safety. In preliminary research, the V4020 virus containing rearranged genomic RNA and prepared from iDNA clone showed safety advantages and protection against VEEV challenges in BALB/c mice and in a cynomolgus macaque non-human primate (NHP) model. Specific Aim 1. Safety of V4020 live-attenuated VEEV vaccine in human subjects. Medigen in collaboration with U.S. Army Medical Research Institute for Infectious diseases (USAMRIID), to conduct Phase 1a, first-in- human study evaluating safety of V4020 VEEV vaccine in healthy adults. We propose a double blinded, placebo controlled, single-dose escalation study in 39 healthy adults, 18-50 years of age. Medigen will manufacture cGMP lot of V4020 vaccine and communicate with the FDA regarding clinical trial design. Groups of volunteers (13 subjects/group) will receive a single 104, 105, or 106 PFU dose of V4020 vaccine (10/group), with 3 subjects from each group randomized to receive placebo. The low dose will be administered first, and there will be at least 14 days delay before another group will start receiving the higher dose of vaccine. The study is designed to assess the safety of V4020 vaccine administered by subcutaneous (SC) administration. Specific Aim 2. Evaluate immune responses from human subjects vaccinated with V4020. In this aim, we will evaluate clinical samples (plasma, saliva, urine) to be collected during the clinical study to identify a dosing regimen that provides a multi-faceted immune response (neutralizing antibody, T-cell response, cytokines, etc). Putative early signatures will be identified that could be used to predict later immunogenicity and obtain insight into mechanisms of V4020 immunogenicity in human subjects. Our preliminary data suggest that the rational design, attenuating rearrangement, and iDNA technology can provide a safe and effective solution for V4020 VEEV vaccine by improving safety, genetic stability, and immunogenicity. Furthermore, the attenuating rearrangement can be easily adapted for the development of other vaccines including preparation of live attenuated vaccines for WEEV, EEEV, other alphaviruses, and other RNA viruses. If successful, this technology can potentially transform the field of live attenuated vaccines for many viral diseases.

抽象的委内瑞拉马脑炎病毒 (VEEV) 是一种危及生命的 NIH/NIAID B 类人类病原体以及潜在的生物恐怖主义威胁 VEEV 在中美洲爆发，并且之前已经蔓延。 VEEV 在美国重新出现的潜在破坏性影响需要采取措施。保护未曾免疫人群的有效疫苗目前，使用减毒活疫苗 TC-83。根据 IND 协议，对处于危险中的医务人员进行疫苗接种，该疫苗会造成不良影响，并且 VEEV 正在努力开发改进的 VEEV 疫苗，但是，因为疫苗开发是一个过程。 TC-83疫苗流程漫长且供应有限，美国可能很快就会出现短缺此外，VEEV 疫苗可能会使美国民众和高危人员得不到保护。如果没有疫苗，VEEV 可能符合 CDC 对 BSL4 选择剂的定义。在之前 NIH 支持的研究中，Medigen 评估了一种新的平台技术开发针对 VEEV 和其他潜在病毒性疾病的疫苗拟议的 V4020 疫苗。包括减弱全长基因组 RNA 内衣壳和糖蛋白基因的重排。减毒重排有效地防止了回复，因为许多独立的突变将被此外，疫苗是由重排的 DNA 副本制成的。 RNA 基因组位于 CMV 启动子下游的 iDNA® 感染性克隆中。 iDNA感染性克隆（与标准cDNA克隆的区别）是发射减毒活病毒来自质粒，无需体外转录使用遗传稳定的 iDNA 可以改善。在初步研究中，V4020病毒含有重新排列的基因组RNA并制备而成。 iDNA 克隆在 BALB/c 小鼠和食蟹猴非人灵长类动物 (NHP) 模型。具体目标 1. 与 Medigen 合作开发 V4020 VEEV 减毒活疫苗在人类受试者中的安全性。与美国陆军传染病医学研究所 (USAMRIID) 合作，进行 1a 阶段，首创我们提出了一项双盲、评估 V4020 VEEV 疫苗在健康成人中安全性的人体研究。 Medigen 将在 39 名 18-50 岁健康成年人中进行安慰剂对照、单剂量递增研究。生产 V4020 疫苗的 cGMP 批次并与 FDA 就临床试验设计进行沟通。的志愿者（13 名受试者/组）将接受单剂 104、105 或 106 PFU 剂量的 V4020 疫苗（10 名/组），每组 3 名受试者随机接受安慰剂，并且首先给予低剂量。在另一组开始接受更高剂量的疫苗之前，至少会延迟 14 天。研究旨在评估皮下 (SC) 注射 V4020 疫苗的安全性。具体目标 2. 评估人类受试者对 V4020 的免疫反应在此目标中，我们。将评估临床研究期间收集的临床样本（血浆、唾液、尿液）以确定剂量提供多方面免疫反应（中和抗体、T 细胞反应、细胞因子、等）将被识别，可用于预测以后的免疫原性并获得。深入了解 V4020 在人类受试者中的免疫原性机制。我们的初步数据表明，合理的设计、减毒重排和 iDNA 技术可以通过提高安全性、遗传稳定性和稳定性，为 V4020 VEEV 疫苗提供安全有效的解决方案此外，减毒重排可以很容易地适应免疫原性的发展。其他疫苗，包括制备 WEEV、EEEV、其他甲病毒疫苗，以及如果成功，这项技术可能会改变减毒活疫苗领域。对于许多病毒性疾病。