Human neutralizing monoclonal antibodies for Rift Valley fever virus

描述（由申请人提供）：裂谷热（RVF）是一种病毒性人畜共患病，最常引起动物疾病，但也可引起严重的人类疾病。该病毒是布尼亚病毒科白蛉病毒属的一个成员，已被指定为a类媒介。该病毒在东非大裂谷最常见，特别是肯尼亚、索马里和坦桑尼亚，但现在也已蔓延到非洲大陆以外的沙特阿拉伯和也门。专家们担心，这种感染可能会在地理上进一步传播。人类对裂谷热的免疫力了解甚少。候选疫苗正在测试中。一种是主要由美国陆军研制的灭活疫苗。陆军已经开发并测试了一种改进型的裂谷热灭活疫苗，命名为TSI-GSD-200。作为职业安全和健康计划的一部分，美国陆军传染病医学研究所（USAMRIID）的高危工人接种了疫苗。第二种方法是肌内注射减毒、诱变的裂谷热第12突变通道（MP-12）疫苗，该疫苗已进入II期试验，也正在由USAMRIID进行研究。本研究的中心假设是，裂谷热（RVF）病毒感染的幸存者可能拥有循环B细胞，编码自然产生的人类抗体（Abs），这些抗体可以中和病毒并预防疾病。单克隆抗体（mAb）成功治疗裂谷热感染的关键要求可能包括：(A)使用高亲和力的mAb，以及(B)使用与不同病毒表位结合的mAb鸡尾酒，而不是单个mAb。这种可能性将通过研制用于研究裂谷热被人类抗体识别的综合试剂来检验，这些试剂将用于确定裂谷热中和的决定因素。该建议包括分子免疫学、裂谷热病毒学和病毒发病机制方面的专家，并可使用CDC/USDA批准的BSL3增强型（BSL3+）设施。我们可以获得东非裂谷热幸存者的血液。此外，我们还可以获得以前接种过灭活疫苗或MP-12疫苗的研究对象的血液。拟议的研究具有重要意义，因为它将导致产生大量可中和裂谷热的人单克隆抗体，并可用作治疗性单克隆抗体，并为幸存者或疫苗接种者制造的中和性单克隆抗体的开发提供分子、遗传和结构基础。了解裂谷热分子识别的基本原理将对合理设计治疗性抗体以及开发和测试针对裂谷热和其他新出现病毒和生物威胁病毒的疫苗产生广泛影响。

DESCRIPTION (provided by applicant): Rift Valley fever (RVF) is a viral zoonosis that most commonly causes disease in animals, but also can cause severe human disease. The virus is a member of the family Bunyaviridae, genus Phlebovirus and has been designated a Category A agent. The virus is most common in the Rift Valley of East Africa, especially Kenya, Somalia and Tanzania, but also has now spread outside the African continent to Saudi Arabia and Yemen. Experts have raised concerns that this infection threatens to spread further geographically. Very little is understood about human immunity to RVF. Vaccine candidates are being tested. One is an inactivated vaccine principally developed by the U.S. Army. The Army has developed and tested an improved version of inactivated RVF vaccine, designated TSI-GSD-200. At-risk workers at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) were vaccinated as part of an occupational safety and health program. The second involves intramuscular (IM) injection of live-attenuated, mutagenized RVF 12th mutagenesis passage (MP-12) vaccine, which has progressed to Phase II trials, also being studied by USAMRIID. The central hypothesis of this study is that survivors of Rift Valley fever (RVF) virus infections likely possess circulating B cells encoding naturally-occurring human antibodies (Abs) that neutralize virus and protect against disease. The key requirements for successful treatment of RVF infections with monoclonal antibodies (mAbs) may include (A) use of high-affinity mAbs, and (B) administration of a cocktail of mAbs binding to the diverse viral epitopes, rather than an individual mAb. This possibility will be tested by generation of comprehensive reagents for study of RVF recognition by human Abs that will be used to define the determinants of neutralization of RVF. This proposal incorporates experts in molecular immunology and RVF virology and viral pathogenesis with access to CDC/USDA approved BSL-3 enhanced (BSL3+) facilities. We have access to blood of survivors of RVF from East Africa. In addition, we have access to blood from research subjects who were previously inoculated with inactivated or MP-12 vaccine. The proposed research is significant because it will result in generation of large panels of human mAbs that neutralize RVF, and can be used as therapeutic Abs, and the molecular, genetic, and structural basis for development of neutralizing mAbs made by survivors or vaccinees. Understanding the principles underlying molecular recognition of RVF will have a broad impact on the rational design of therapeutic Abs and development and testing of vaccines against RVF and other emerging and biothreat viruses.