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 正布尼亚病毒属是布尼亚病毒目中研究不足的属，在布尼亚病毒目中没有疫苗或疗法。 临床发展。根据NIAID最近的鉴定，该属中的原型病原体之一是Cache 谷病毒（CVV）。CVV是一种新出现的节肢动物传播的病毒，可引起自然流产， 反刍动物和人类的先天性畸形。考虑到CVV的流行及其广泛的宿主范围， 随着CVV多种感受态载体地理范围的扩大，CVV的流行潜力 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， 需要制定针对该属病毒的疫苗路线图，如果该属发生流行病， 未来随着mRNA疫苗技术在COVID-19大流行期间的迅速采用， 随着HDT Bio的自扩增mRNA疫苗平台最近获得紧急使用批准，我们建议 应用HDT的技术开发正布尼亚病毒属的原型疫苗， 疫苗在新型CVV感染和疾病小鼠模型中预防CVV感染。这个创新的，及时的， R21旨在研究这种疫苗的安全性和保护效力，并确定 疫苗接种后广泛交叉反应性免疫所需的重要抗原，通过两个特定目的： 1.评价LIONTM配方复制子的安全性、免疫原性和最佳给药方案， CVV的RNA疫苗。 2.研究LION配制的复制子-RNA疫苗的保护效力和相关性， 在鼠模型中预防CVV诱导的疾病。 考虑到一个健康的方法，并认识到人类和动物健康之间的联系， 这种疫苗可以在兽医/农业市场上产生直接影响，同时防止 经济损失、动物疾病和人类疾病的出现。如果出现流行病， 人类，这种方法可以迅速适应和扩大人体试验。