Pre-clinical evaluation of alpha-Cache; a novel RNA vaccine for an emerging orthobunyavirus

alpha-Cache的临床前评估；

基本信息

批准号：
10727390
负责人：
Albert J. Auguste
金额：
$ 26.23万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-13 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727390
关键词：
Adoption Advisory Committees Agriculture Animal Diseases Animals Antibodies Antigens Arboviruses Brazil Bunyavirales COVID-19 pandemic Cache Valley virus Case Study Categories Cessation of life Characteristics Chikungunya virus Chronic Clinical Clinical Trials Collaborations Congenital Abnormality Coupled Coupling Culicidae Disease Dose Economic Burden Economics Emergency Situation Encephalitis Epidemic Event Fatigue Fever Food Future Genus Phlebovirus Geographic Distribution Geography Goals Headache Health Health protection High Prevalence Human Immune response Immunity Immunization Immunocompetent Immunologist In Vitro Incidence India Induced Abortion Infant Infection Licensing Lipids Livestock Longevity Macrocephaly Maps Marketing Medical Meningitis Morbidity - disease rate Musculoskeletal System National Institute of Allergy and Infectious Disease Nausea Neurologic North America Orthobunyavirus Pathogenesis Phenotype Positioning Attribute Prevalence Prevention RNA RNA Viruses RNA vaccine Recording of previous events Regimen Replicon Reporting Resources Rift Valley fever virus Risk Role Ruminants Safety Seroprevalences South Korea Spontaneous abortion Study models System T cell response Technology Teratogens Testing United States National Institutes of Health Vaccination Vaccines Venezuelan Equine Encephalitis Virus Viral Viral Antigens Viral Pathogenesis Virus Virus Diseases Virus Replication Zika Virus Zoonoses burden of illness clinical development combat cross reactivity dosage enzootic epidemic potential epizootic future epidemic human pathogen immunogenic immunogenicity in vivo innovation member mortality mouse model nanoparticle novel pathogen preclinical development preclinical evaluation prevent protective efficacy prototype response safety study transmission process vaccine candidate vaccine development vaccine efficacy vaccine platform vaccine trial vaccinology vector

项目摘要

Abstract Orthobunyaviruses are an understudied genus in the order Bunyavirales that has no vaccines or therapies in clinical development. One of the prototype pathogens within this genus, as recently identified by NIAID, is Cache Valley virus (CVV). CVV is an emerging arthropod-borne virus that induces spontaneous abortions and congenital malformations in ruminants and humans. Given CVV’s prevalence and its broad host range, coupled with the expanding geographical range of its diverse array of competent vectors, the epidemic potential of CVV continues to increase, reminiscent of what was previously observed for Chikungunya and Zika viruses. To date, there have been no reported vaccine development activities for this virus, and prototype approaches are urgently needed to develop road maps for vaccines against viruses within this genus should an epidemic occur in the future. With the rapid adoption of mRNA vaccine technology during the ongoing COVID-19 pandemic, coupled with the recent emergency use approval of HDT Bio’s self-amplifying mRNA vaccine platform, we propose to apply HDT’s technology to develop prototype vaccines for the orthobunyavirus genus with a proof-of-concept vaccine to prevent CVV infection in a novel murine model of CVV infection and disease. This innovative, timely, and critically important R21 aims to study the safety profile and protective efficacy of this vaccine, and identify the important antigens required for broad cross-reactive immunity post-vaccination, via two specific aims: 1. Evaluate the safety, immunogenicity, and optimal dosage regimen for a LIONTM-formulated, replicon- RNA vaccine for CVV. 2. Investigate the efficacy and correlates of protection of a LION-formulated, replicon-RNA vaccine for preventing CVV-induced disease in murine models. Considering a One Health approach, and recognizing the connection between the health of humans and animals, such a vaccine could have an immediate impact in the veterinary/agricultural market, simultaneously preventing economic damage, animal disease, and disease emergence in humans. In the event of epidemic emergence in humans, this approach could be rapidly adapted and scaled for human trials.

抽象的正布尼亚病毒是布尼亚病毒目中一个尚未被研究的属，目前尚无疫苗或疗法。 NIAID 最近发现，该属的原型病原体之一是 Cache。 Valley 病毒 (CVV) 是一种新兴的节肢动物传播病毒，可引起自然流产和鉴于 CVV 的流行及其广泛的宿主范围，再加上反刍动物和人类的先天性畸形。随着其多种有效载体的地理范围不断扩大，CVV 的流行潜力继续增加，让人想起迄今为止对基孔肯雅病毒和寨卡病毒的观察结果，目前还没有针对该病毒的疫苗开发活动的报道，原型方法亟待开发如果该属内发生流行病，则需要制定针对该属病毒的疫苗路线图随着 mRNA 疫苗技术在持续的 COVID-19 大流行期间的迅速采用，再加上未来的发展。随着 HDT Bio 的自放大 mRNA 疫苗平台最近获得紧急使用批准，我们建议应用 HDT 的技术开发正布尼亚病毒属原型疫苗并进行概念验证这种疫苗可在新型 CVV 感染和疾病小鼠模型中预防 CVV 感染。而至关重要的 R21 旨在研究该疫苗的安全性和保护功效，并确定通过两个具体目标，获得疫苗接种后广泛交叉反应免疫所需的重要抗原： 1. 评估 LIONTM 配制的复制子的安全性、免疫原性和最佳剂量方案 CVV RNA 疫苗。 2. 研究 LION 配制的复制子 RNA 疫苗的功效和保护相关性在小鼠模型中预防 CVV 诱发的疾病。考虑“同一个健康”方法，并认识到人类和动物健康之间的联系，这种疫苗可能会对兽医/农业市场产生直接影响，同时预防经济损失、动物疾病和人类疾病的出现。对于人类来说，这种方法可以快速适应并扩展到人体试验。