Vaccines for Prevention of RG3 and RG4 Emerging Tickborne Viral Deseases

用于预防 RG3 和 RG4 新出现蜱传病毒性疾病的疫苗

基本信息

批准号：
9990349
负责人：
PAULO H VERARDI
金额：
$ 52.61万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9990349
关键词：
Accounting Address Agriculture Ambylomma americanum Animal Model Antibody titer measurement Antigens Asia Asians Categories Cell Culture Techniques Centers for Disease Control and Prevention (U.S.)Connecticut Containment Crimean-Congo Hemorrhagic Fever Virus DNA DNA Viruses Development Disease Electron Microscopy Emerging Communicable Diseases Encephalitis Ensure Funding Generations Genes Geographic state Goals Gold Habitats Haemaphysalis longicornis Heartland virus Human Immune response Immunocompetent Infectious Diseases Research Interferon Receptor Investigation Knockout Mice Label Laboratories Modeling Mus National Institute of Allergy and Infectious Disease New England Omsk hemorrhagic fever virus Orthobunyavirus Play Powassan virus Prevention Public Health Quick Test for Liver Function Regimen Reporting Risk Serum Severe Fever with Thrombocytopenia Syndrome Virus Subunit Vaccines Testing Tick-Borne Diseases Tick-Borne Encephalitis Tick-Borne Encephalitis Virus Ticks Universities Vaccinated Vaccines Vaccinia virus Vector-transmitted infectious disease Viral Viral Genes Viral Hemorrhagic Fevers Viral Vector Virus Virus-like particle Western Blotting arthropod-borne base cell mediated immune response climate change design efficacy testing environmental change experimental study hemorrhagic fever virus immunogenicity mouse model neutralizing antibody poxvirus vectors prevent priority pathogen protein expression rapid technique research and development tick feeding tick transmission tick-borne tick-borne flavivirus tick-borne virus transmission process vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccinia virus vector vector-borne vector-induced

项目摘要

PROJECT SUMMARY Tickborne illnesses continue to be a significant public health concern in the US and worldwide, as environmental and climate changes have allowed the dramatic expansion of ticks, tick habitats, and their mammalian hosts. In the New England region alone, Lone Star ticks were first reported in 2017, followed by the establishment of exotic Asian longhorned ticks in 2018. A recent CDC report indicates that tickborne diseases in the US have more than doubled from 2004 to 2016, accounting for 77% of all reported vector-borne diseases. The report also indicates that the US is not fully prepared to prevent and control these threats. A number of tickborne viruses that cause encephalitis and hemorrhagic fever in humans are of particular concern in the US, such as the re-emerging Powassan virus (POWV), as well as the recently discovered Heartland virus (HRTV). Another emerging tickborne virus in Asia is severe fever with thrombocytopenia syndrome virus (SFTSV), closely related to HRTV, which is transmitted by the Asian longhorned tick that is spreading rapidly and is now present in 12 US states. A number of additional exotic tickborne viral agents are of concern to the US, including tickborne encephalitis virus (TBEV), Omsk hemorrhagic fever virus (OHFV), and Crimean-Congo hemorrhagic fever virus (CCHFV). To better prepare for these emerging threats, we assembled a team of experts in (1) vaccine development at the University of Connecticut, (2) tickborne viruses at the Connecticut Agricultural Experiment Station, and (3) animal models in maximum biocontainment at the National Emerging Infectious Diseases Laboratories and propose the development and testing of vaccines for four Risk Group 3 (RG3) and RG4 tickborne encephalitis and hemorrhagic fever viruses classified as NIAID Category A or C Priority Pathogens, and prioritized by the WHO under its most recent 2018 Blueprint list of priority diseases in need of accelerated research and development. We developed a rapid method to generate vaccinia virus (VACV) vectors that will allow us to quickly test a number of tickborne viral genes to ensure robust expression of protective antigens and secretion of virus-like particles (VLPs). This platform is based on a gold-standard viral vector (VACV) that induces high levels of humoral and cell-mediated immune responses. These VACV vectors are replication-defective when administered as a vaccine, yet easy to propagate in standard cell culture at high titers, unlike other replication-defective poxvirus vectors such as MVA. We will also generate DNA- based vaccines and purified VLPs (as a subunit vaccine), so that three different classes of vaccine candidates can be tested for immunogenicity, either alone or in prime-boost regimens. Finally, we will test the efficacy of the vaccines using tick-transmission animal models to recapitulate the enhancement of transmission and dissemination that has been documented by tick feeding.

项目概要蜱传疾病仍然是美国和全世界的一个重大公共卫生问题，环境和气候变化使得蜱虫、蜱虫栖息地及其栖息地急剧扩大哺乳动物宿主。仅在新英格兰地区，孤星蜱于 2017 年首次报道，随后 2018 年外来亚洲长角蜱的建立。CDC 最近的一份报告表明从 2004 年到 2016 年，美国蜱传疾病增加了一倍多，占全部疾病的 77% 报告了媒介传播的疾病。报告还指出，美国尚未做好充分准备来防范和应对控制这些威胁。许多蜱传病毒可引起脑炎和出血热人类在美国尤其令人担忧，例如重新出现的波瓦桑病毒（POWV）以及最近发现的心脏病毒（HRTV）。亚洲另一种新出现的蜱传病毒是严重发烧血小板减少综合征病毒 (SFTSV)，与 HRTV 密切相关，通过血小板传播亚洲长角蜱正在迅速传播，现已出现在美国 12 个州。一些额外的外来蜱传病毒引起美国关注，包括蜱传脑炎病毒（TBEV）、鄂木斯克出血热病毒（OHFV）和克里米亚-刚果出血热病毒（CCHFV）。为了更好为应对这些新出现的威胁，我们在 (1) 疫苗开发方面组建了一个专家团队康涅狄格大学，(2) 康涅狄格州农业实验站的蜱传病毒，以及 (3) 国家新发传染病实验室最大程度生物防护的动物模型并建议开发和测试四种风险组 3 (RG3) 和 RG4 蜱传疫苗脑炎和出血热病毒被列为 NIAID A 类或 C 类优先病原体，以及世界卫生组织根据其最新的 2018 年需要加速的优先疾病蓝图清单将其列为优先事项研究与开发。我们开发了一种快速方法来生成痘苗病毒 (VACV) 载体将使我们能够快速测试一些蜱传病毒基因，以确保保护性基因的稳健表达抗原和病毒样颗粒（VLP）的分泌。该平台基于黄金标准病毒载体（VACV）可诱导高水平的体液和细胞介导的免疫反应。这些 VACV 载体当作为疫苗施用时存在复制缺陷，但在标准细胞培养物中易于繁殖与其他复制缺陷型痘病毒载体（例如 MVA）不同，滴度高。我们还将生成 DNA- 基于疫苗和纯化的VLP（作为亚单位疫苗），因此三种不同类别的疫苗可以单独或在初免-加强方案中测试候选者的免疫原性。最后我们来测试一下使用蜱传播动物模型来概括疫苗的功效已记录通过蜱喂食传播和传播。