Development of recombinant VSV vaccines for emerging bunyaviruses

针对新兴布尼亚病毒的重组 VSV 疫苗的开发

• 批准号: 10603853
• 负责人: Paul Bates
• 金额: $ 25.55万
• 依托单位: ADVAC THERAPEUTIC, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-13 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603853
• 关键词: Andes Virus; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Biological Assay; Blood; Case Fatality Rates; Cell membrane; Cell surface; Cells; China; Development; Disease; Disease Outbreaks; Distant; Domestic Animals; Dose; Ebola; Ebola virus; Engineering; Far East; Fc Receptor; Fever; Foundations; Future; Gene Order; Generations; Genes; Genome; Genomic Segment; Geography; Glycoproteins; Golgi Apparatus; Hantavirus; Health; Heartland virus; Hemorrhage; Human; Immune; Immune response; Immunity; Immunization; Immunocompromised Host; In Vitro; Infection; Influenza; Injections; Interferon Receptor; Japan; Kinetics; Korea; Learning; Leukopenia; Licensing; Modification; Molecular; Mucous Membrane; Mus; Mutate; Mutation; Orthobunyavirus; Pathogenicity; Phase; Positioning Attribute; Production; Proteins; RNA; RNA Viruses; Readiness; Recombinants; Respiratory syncytial virus; Reverse engineering; Rift Valley Fever; Risk; Severe Fever with Thrombocytopenia Syndrome Virus; Site; Surface; T cell response; T-Lymphocyte; Therapeutic; Vaccinated; Vaccination; Vaccine Production; Vaccines; Vesicular stomatitis Indiana virus; Vietnam; Viral; Viral Genome; Viral Hemorrhagic Fevers; Viral Vaccines; Viral reservoir; Virion; Virus; Virus Diseases; Virus Replication; Wild Animals; Work; Zoonoses; clinically relevant; cross immunity; design; experience; global health; human pathogen; immunogenic; immunogenicity; improved; in vivo; manufacture; mortality; mouse model; neutralizing antibody; novel; outbreak concern; pandemic preparedness; particle; pathogen; pathogenic virus; pre-clinical; prophylactic; protective efficacy; protein expression; research and development; response; reverse genetics; tick-borne; transmission process; vector; vector tick; vector vaccine; vector-borne; zoonotic spillover

PROJECT SUMMARY/ABSTRACT Emerging viral infections remain a global threat to human health. Bunyaviruses are the largest order of RNA viruses that includes many clinically relevant human pathogens such as Lassa, Rift Valley Fever and various hantaviruses which cause viral hemorrhagic fever (VHF). SFTSV, or Severe fever with thrombocytopenia syndrome virus, is an emerging tick-borne bunyavirus that has caused outbreaks in Eastern Asia (China, Japan, Korea, Vietnam) with up to a 30% case fatality rate. The host tick vector has now been discovered over a large geographical setting and SFTSV has been found in numerous wild and domestic animal species highlighting a risk for zoonotic spillover into humans. Though humans are usually dead-end hosts, human to human transmission has been documented through blood and mucosal secretions. Furthermore, SFTSV has a segmented genome which increases ability to reassort genes and mutate. Due to these features, in its 2017 “Research and Development Blueprint” the WHO identified SFTSV as one of 11 pathogens likely to cause a sever outbreak in the future. As we have learned, from experience with recent zoonotic outbreaks, preparedness is of the utmost importance. We are proposing to continue development of a recombinant vesicular stomatitis virus (rVSV)-based vaccine for SFTSV. rVSV is an approved vaccination platform that is immunogenically potent and proven tolerable. Preliminary work from our group has demonstrated that rVSV-SFTSV can elicit protection in mice, is tolerable in immunocompromised animals and upon CNS injection, and can generate cross protecting responses to a related bunyavirus. Furthermore, we observe elevated SFTSV-specific T cell and antibody responses against both SFTSV spike proteins, Gn and Gc. In this Phase I, we propose to improve the design of our vector which will increase viral titers to facilitate vaccine manufacturing and increase immunogenicity in animals. In aim 1, we will focus on reverse engineering mutations into rVSV that will improve SFTSV Gn/Gc incorporation into particles thereby improving virus replication and yield in vitro. We will characterize these 2nd generation (Gen2) vaccines using molecular and cell-based assays scoring for viral replication, GnGc expression in infected cells and incorporation of GnGc in VSV virions. In aim 2, we will assess the ability of our Gen2 vaccine to protect animals in lethal SFTSV challenge studies. We hypothesize that increased GnGc expression and replication of the Gen2 vectors will lead to improved immune responses in vaccinated animals compared to the Gen1 vector. We will assess immune correlates of protection such enhanced neutralizing and cross protective antibodies as well as robust T cell responses compared to Gen1 rVSV-SFTSV vaccinated animals. If successful, our Phase I would set the foundation for a Phase II to advance manufacturing and stringently study protective capacity of our vaccine in more advanced animal models.

项目概要/摘要 新出现的病毒感染仍然对人类健康构成全球威胁。布尼亚病毒是 RNA 中最大的目 病毒，包括许多临床相关的人类病原体，例如拉沙热、裂谷热和各种 引起病毒性出血热（VHF）的汉坦病毒。 SFTSV，或严重发烧伴血小板减少症 综合征病毒，是一种新出现的蜱传布尼亚病毒，已在东亚（中国、日本、 韩国、越南）病死率高达30%。现在已经在大范围内发现了宿主蜱虫载体 地理环境和 SFTSV 已在许多野生和家养动物物种中发现，这突出表明 人畜共患病蔓延至人类的风险。尽管人类通常是死亡宿主，但人与人之间 已记录通过血液和粘膜分泌物传播。此外，SFTSV 还拥有 分段的基因组增加了基因重配和突变的能力。由于这些特点，在 2017 年 世界卫生组织《研发蓝图》将SFTSV确定为可能导致新冠肺炎的11种病原体之一 未来疫情严重。正如我们所知，根据最近人畜共患病疫情的经验，做好准备 是至关重要的。我们建议继续开发重组水泡性口炎 基于病毒 (rVSV) 的 SFTSV 疫苗。 rVSV 是一种经过批准的疫苗接种平台，具有强大的免疫原性 并被证明是可以忍受的。我们小组的初步工作表明 rVSV-SFTSV 可以引起保护 在小鼠中，在免疫功能低下的动物和中枢神经系统注射后是可耐受的，并且可以产生交叉保护 对相关布尼亚病毒的反应。此外，我们观察到 SFTSV 特异性 T 细胞和抗体升高 针对 SFTSV 刺突蛋白 Gn 和 Gc 的反应。在第一阶段，我们建议改进设计 我们的载体将增加病毒滴度，以促进疫苗生产并增加免疫原性 动物。在目标 1 中，我们将重点关注 rVSV 的逆向工程突变，以改善 SFTSV Gn/Gc 掺入颗粒中，从而改善病毒的体外复制和产量。我们将描述这第二个 使用分子和细胞分析对病毒复制、GnGc 表达进行评分的第二代 (Gen2) 疫苗 感染细胞中的 GnGc 并入 VSV 病毒粒子中。在目标 2 中，我们将评估第二代疫苗的能力 在致命的 SFTSV 挑战研究中保护动物。我们假设 GnGc 表达增加 与普通动物相比，Gen2 载体的复制将改善接种疫苗的动物的免疫反应 第一代向量。我们将评估保护的免疫相关性，例如增强的中和和交叉保护 与第一代 rVSV-SFTSV 疫苗接种动物相比，抗体和 T 细胞反应更强。如果成功的话， 我们的第一阶段将为第二阶段奠定基础，以推进制造并严格研究保护性 我们的疫苗在更先进的动物模型中的能力。