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.

抽象的 矫形病毒是在没有疫苗或疗法的Bunyvirales中的一种理解的属 临床发展。该属内的原型病原体之一，如NIAID最近确定的是缓存 山谷病毒（CVV）。 CVV是一种新兴的节肢动物传播病毒，可引起自发流产和 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，耦合 随着其潜水员竞争载体的潜水员阵列的扩大，CVV的流行潜力 继续增加，让人联想到以前观察到的基孔肯尼亚和寨卡病毒。迄今为止， 该病毒尚无报道的疫苗开发活动，原型方法急切地是 需要在该属内开发针对病毒的疫苗的道路图。 未来。随着持续的共同19日大流行期间mRNA疫苗技术的迅速采用，耦合 随着HDT Bio自我扩增mRNA疫苗平台的最近紧急使用批准，我们建议 应用HDT的技术开发原型疫苗，用于概念证明 在新型的CVV感染和疾病模型中预防CVV感染的疫苗。这种创新的，及时的 至关重要的R21旨在研究该疫苗的安全性和保护效率，并确定 疫苗接种后广泛的交叉反应免疫所需的重要抗原，通过两个具体目的： 1。评估liontm形成的，复制品的安全性，免疫原性和最佳剂量方案 CVV的RNA疫苗。 2。研究狮子形成的，复制品RNA疫苗的保护效率和相关性 在鼠模型中预防CVV诱导的疾病。 考虑一种健康方法，并认识到人类和动物的健康之间的联系， 这样的疫苗可能会直接对兽医/农业市场产生影响，只是阻止 人类的经济损害，动物疾病和疾病紧急情况。如果发生流行紧急情况 人类，这种方法可以迅速适应并缩放为人类试验。