Development of vaccines targeting a tick-borne phlebovirus

针对蜱传白斑病毒的疫苗的开发

• 批准号: 10214470
• 负责人: Paul Bates
• 金额: $ 54.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10214470
• 关键词: Affinity; Andes Virus; Animal Model; Animals; Antibodies; Antibody Response; Antibody-mediated protection; Antigen-Presenting Cells; Antigens; Antiviral Agents; 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 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 trial; vector; vector tick; vector vaccine

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.

发热伴血小板减少综合征病毒（SFTSV）是一种病原性蜱传病毒