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

• 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
• 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

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.

摘要 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暴发发生在中美洲，以前曾蔓延 进入美国。VEEV在美国重新出现的潜在破坏性影响和需求 有效的疫苗，以保护免疫幼稚的人群。目前，使用的是TC-83减毒活疫苗 根据IND协议，为处于危险中的医务人员接种疫苗。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，因为疫苗的开发是一种 漫长的过程和TC-83疫苗的供应有限，美国可能很快就会经历疫苗短缺 Veev疫苗。这可能会使美国人口和高危人员得不到保护。此外，在 在缺乏疫苗的情况下，VEEV可能符合疾控中心对BSL4选择剂的定义。 在之前由NIH支持的研究中，梅迪根评估了一种新的平台技术 开发针对VEEV和潜在的其他病毒性疾病的疫苗。拟议的V4020疫苗 包括减弱全长基因组RNA中衣壳和糖蛋白基因的重排。 衰减的重排有效地防止了逆转，因为许多独立的突变将是 需要恢复到致病基因。此外，疫苗是由重新排列的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。的主要功能 IDNA感染性克隆(与标准cdna克隆不同)是启动了活的减毒病毒 不需要体外转录。基因稳定的IDNA的使用改善了 疫苗的安全性。在初步研究中，含有重排基因组RNA的V4020病毒 来自IDNA的克隆在BALB/c小鼠和在BALB/c小鼠和 食蟹猴非人灵长类(NHP)模型。 具体目的1.V4020 VEEV减毒活疫苗对人体的安全性协作中的Medigen 与美国陆军传染病医学研究所(USAMRIID)合作，进行1a期，第一 人体研究评估V4020 VEEV疫苗在健康成年人中的安全性。我们提出了一种双盲， 在39名18-50岁的健康成年人中进行的安慰剂对照、单次剂量递增研究。梅迪根会 生产V4020疫苗的cGMP批次，并就临床试验设计与FDA沟通。群组 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/组)， 每组随机抽取3名受试者接受安慰剂治疗。低剂量将首先注射，然后 在另一组人开始接种更高剂量的疫苗之前，将至少推迟14天。这个 本研究旨在评估皮下注射V4020疫苗的安全性。 特定目的2.评估接种V4020疫苗的受试者的免疫应答。为了实现这一目标，我们 将评估在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)。将确定可能的早期签名，这些签名可用于预测以后的免疫原性并获得 探讨V4020在人体内的免疫原性机制。 我们的初步数据表明，合理的设计、衰减重排和IDNA技术可以 通过提高安全性、遗传稳定性和安全性为V4020 VEEV疫苗提供安全有效的解决方案 免疫原性。此外，衰减性重排很容易适应于发展 其他疫苗，包括制备WeeV、EEEV、其他甲型病毒的减毒活疫苗，以及 其他RNA病毒。如果成功，这项技术可能会改变减毒活疫苗领域。 治疗许多病毒性疾病。