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

alpha-Cache的临床前评估；

• 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
• 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

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.

摘要 原布尼亚病毒是布尼亚病毒目中一个未被充分研究的属，目前还没有疫苗或疗法 临床发展。NIAID最近发现的该属中的一个原型病原体是缓存 谷状病毒(CVV)。CVV是一种新出现的节肢动物传播病毒，可导致自然流产和 反刍动物和人类的先天畸形。鉴于CVV的流行及其广泛的宿主范围， 随着其不同的合格媒介的地理范围的扩大，CVV的流行潜力 继续增加，这让人想起以前在基孔肯雅和寨卡病毒中观察到的情况。到目前为止， 目前还没有针对这种病毒的疫苗开发活动的报道，原型方法迫在眉睫。 需要开发针对该属病毒的疫苗路线图，以防在中国发生疫情 未来。随着在正在进行的新冠肺炎大流行期间迅速采用信使核糖核酸疫苗技术，加上 随着HDT Bio的自我扩增mRNA疫苗平台最近获得紧急使用批准，我们建议 应用HDT的技术开发具有概念验证的正野病毒属原型疫苗 在CVV感染和疾病的新小鼠模型中预防CVV感染的疫苗。这个创新的、及时的、 至关重要的是，R21旨在研究这种疫苗的安全性和保护效力，并确定 疫苗接种后的广泛交叉反应免疫所需的重要抗原，通过两个具体目标： 1.评价LIONTM配方复制子的安全性、免疫原性和最佳剂量方案- 针对CVV的RNA疫苗。 2.调查狮子配方复制子-RNA疫苗的有效性和保护作用的相关性 预防柯萨奇病毒引起的小鼠疾病。 考虑一个健康的方法，并认识到人和动物的健康之间的联系， 这种疫苗可能会对兽医/农业市场产生立竿见影的影响，同时预防 经济损失、动物疾病和人类疾病的出现。在发生疫情时， 对于人类来说，这种方法可以迅速适应并扩大到人体试验。