Development of vaccines targeting a tick-borne phlebovirus

针对蜱传白斑病毒的疫苗的开发

基本信息

批准号：
10673225
负责人：
Paul Bates
金额：
$ 21.58万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673225
关键词：
Affinity Andes Virus Animal Model Animals Antibodies Antibody Response Antibody-mediated protection Antigen-Presenting Cells Antigens Asia B-Cell Activation Case Fatality Rates China Clinical Data Development Disease Disease Outbreaks Distant Domestic Animals Dose Ebola Vaccines Ebola virus Emerging Technologies Epidemic Fever Formulation Foundations Future Genes Genus Phlebovirus Geographic Distribution Glycoproteins Goals Hemorrhage Human IFNAR1 gene Immune response Immunity Immunize Immunocompetent Infection Infection prevention Influenza Innate Immune Response Interferons Intervention Japan Knock-out Knockout Mice Knowledge Korea Leukopenia Membrane Glycoproteins Messenger RNA Modeling Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease Natural Immunity Nucleosides Orthobunyavirus Pathogenicity Pathology Powassan virus RNA RNA vaccination RNA vaccine Recombinants Recommendation Regimen Reporting Research Respiratory syncytial virus Russia Severe Fever with Thrombocytopenia Syndrome Virus Structure of germinal center of lymph node Surface Symptoms Syndrome T cell response Technology Therapeutic Thrombocytopenia Translations Vaccinated Vaccination Vaccines Vesicular stomatitis Indiana virus Vietnam Viral Viral Vaccines Viral Vector Viremia Virus Virus Diseases Wild Animals ZIKA base gastrointestinal symptom human pathogen immunogenicity lipid nanoparticle mRNA Stability mortality mouse model neutralizing antibody pathogen pathogenic virus prevent programs prophylactic protective efficacy recombinant viral vector recombinant virus vaccine research and development response therapeutically effective tick transmission tick-borne vaccine development vaccine platform vaccine strategy vaccine trial vector vector tick vector vaccine

项目摘要

Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) is a pathogenic, tick-transmitted bunyavirus that can cause a severe febrile hemorrhagic-like disease with case fatality rates of up to 30%. Discovered during a 2009 outbreak of febrile illness in China, the geographic distribution of SFTSV extends into Korea and Japan with recent reports of infection in Vietnam and Russia. The tick vector for SFTSV is widespread throughout Asia. Numerous domestic and wild animals are naturally infected by SFTSV suggesting a large reservoir with potential spillover to humans. There are currently no vaccines or therapeutics for SFTSV. Because of its epidemic threat the WHO included SFTSV in its 2017 recommendation “A research and development Blueprint for action to prevent epidemics” and identified SFTSV as one of 11 pathogens most likely to cause severe outbreaks in the near future and proposed development of vaccines. Here we will explore two complementary and potentially synergistic strategies for an SFTSV vaccine: a recombinant viral vector and nucleoside-modified mRNA encoding the SFTSV viral glycoproteins. Vesicular stomatitis virus (VSV) is a cytopathic virus that has been developed as a vaccine vector due to its ability to rapidly induce strong, protective antibody and T cell responses to encoded foreign antigens after a single dose. Using a VSV vector expressing the SFTSV viral glycoproteins (similar to the currently employed VSV-Ebola vaccine), we demonstrate single dose induction of a neutralizing antibody response and protection from SFTSV challenge in an IFNAR1 knockout mouse model. Separately, we show that vaccination of wt mice with a single dose of nucleoside-modified mRNA lipid nanoparticles (mRNA-LNP) encoding the SFTSV glycoproteins elicits high levels of SFTSV neutralizing antibodies that are capable of conferring partial SFTSV protection when transferred into the IFNAR1 KO model. Based upon these strong preliminary findings we propose to characterize antibody and T-cell responses in rVSV and mRNA vaccinated mice when these vaccines are used alone or in a prime-boost regimen. These studies are significant as there is limited knowledge regarding vaccines for this highly pathogenic virus (a single report) and use of rVSV and mRNA in a prime-boost vaccination has not been reported. Finally, current small animal models of SFTSV infection are limited to animals with type I IFN responses knocked out. Because these animals lack an important innate immune response mechanism that supports amplification of cellular and humoral immune responses, we will develop an immune competent mouse vaccination model using transient monoclonal antibody blockade of IFNAR1 during SFTSV challenge.

血小板减少综合征病毒（SFTSV）严重发烧是一种致病性，tick虫传播 BUNYAVIRUS可能会引起严重的高温出血样疾病，病例死亡率为最多30％。地理 SFTSV的分布扩展到韩国和日本，最近有关于越南感染的报道和俄罗斯。 SFTSV的tick矢量在整个亚洲都广泛。许多家庭和野生动物自然受到SFTSV的感染，表明具有潜在Spilover的大型水库给人类。目前没有SFTSV的疫苗或治疗。由于其流行病威胁WHO在其2017年建议中包括SFTSV的“研究与开发” 采取行动以防止发作的蓝图”并确定SFTSV是11个病原体之一在不久的将来可能会引起严重爆发，并提议开发疫苗。这里我们将探索SFTSV疫苗的两种完整且潜在的协同策略：重组病毒载体和编码SFTSV病毒的核苷修饰的mRNA 糖蛋白。囊泡气孔病毒（VSV）是一种细胞病毒，已发育为疫苗载体由于能够快速诱导强，保护性抗体和T细胞的能力单剂量后对编码的外抗原的反应。使用表达的VSV向量 SFTSV病毒糖蛋白（类似于当前使用的VSV-EBOLA疫苗），我们证明中和抗体反应的单剂量诱导和保护 IFNAR1敲除鼠标模型中的SFTSV挑战。另外，我们表明疫苗接种具有单剂量的核修饰mRNA脂质纳米颗粒（mRNA-LNP）的WT小鼠的编码SFTSV糖蛋白会引起高水平的SFTSV中和抗体当转移到IFNAR1 KO模型中时，能够会议部分SFTSV保护。根据这些强大的初步发现，我们建议表征抗体和T细胞当这些疫苗单独或在A中使用这些疫苗时，RVSV和mRNA接种小鼠的反应 Prime-Boost方案。这些研究很重要，因为关于这种高度致病性病毒（单一报告）的疫苗以及在A中使用RVSV和mRNA 尚未报道促进疫苗。最后，SFTSV的当前小动物模型感染仅限于具有I型IFN反应的动物。因为这些动物缺乏支持细胞扩增的重要先天免疫反应机制和体液免疫调子，我们将开发一种免疫功能的小鼠疫苗接种在SFTSV挑战期间，使用IFNAR1的瞬态单克隆抗体阻断的模型。