Human neutralizing monoclonal antibodies for Rift Valley fever virus

描述(申请人提供)：裂谷热(RVF)是一种病毒性人畜共患病，最常见的是引起动物疾病，但也可以导致严重的人类疾病。该病毒是布尼亚病毒科白眉病毒属的成员，已被指定为A类病原体。该病毒最常见的是东非的裂谷地区，特别是肯尼亚、索马里和坦桑尼亚，但现在也已从非洲大陆蔓延到沙特阿拉伯和也门。专家们担心，这种感染有可能进一步在地理上传播。对人类对裂谷热的免疫力了解甚少。候选疫苗正在接受测试。一种是主要由美国军队开发的灭活疫苗。陆军已经开发和测试了一种改进的RVF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)的高危工作人员接受了疫苗接种。第二项涉及肌肉注射减毒、诱变RVF第12代突变(MP-12)疫苗，该疫苗已进入第二阶段试验，美国国际开发署也在进行研究。这项研究的中心假设是，裂谷热(RVF)病毒感染的幸存者可能拥有循环中的B细胞，编码自然产生的人类抗体(Abs)，这种抗体可以中和病毒并预防疾病。用单抗成功治疗裂谷热感染的关键要求可能包括(A)使用高亲和力的单抗，以及(B)注射与不同病毒表位结合的单抗的鸡尾酒，而不是单个单抗。这种可能性将通过产生用于研究人抗体识别RVF的综合试剂来测试，该试剂将用于确定RVF的中和决定因素。这项建议吸收了分子免疫学、裂谷热病毒学和病毒发病机制方面的专家，可以使用CDC/USDA批准的BSL-3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，我们还可以获取以前接种过灭活疫苗或MP-12疫苗的研究对象的血液。这项拟议的研究具有重要意义，因为它将产生大量的人类单抗，这些单抗可以中和RVF，并可用作治疗性单抗，以及由幸存者或疫苗接种者产生的中和单抗的分子、遗传和结构基础。了解RVF的分子识别原理将对合理设计治疗性抗体以及开发和测试针对RVF和其他新出现的生物治疗病毒的疫苗具有广泛的影响。

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.