Recombinant Yellow Fever 17D-Lassa Vaccine

描述(申请人提供)：黄热病(YF)和拉沙热(LF)是西非和中非流行的两种病毒性出血热(VHFs)。在VHFs的病原体中，Lassa(LAS)和YF病毒影响非洲人数最多的人。在流行地区，“危险”LAS病毒血清阴性人口可能高达5900万，年发病率为300万，死亡人数高达6.7万，再感染人数高达300万。巨大的疾病负担和LAS病毒可能被用作生物战的媒介，为疫苗的开发提供了强有力的理由。目前还没有针对LF的疫苗。相比之下，YF17D减毒疫苗是迄今为止开发出的最成功的疫苗，被广泛用于控制YF。然而，生态和社会变化、公共卫生政策无效和疫苗覆盖率不足导致YF在过去15年中死灰复燃。最近，YF17D疫苗已被成功地用作抗黄病毒活疫苗的载体和作为黄病毒无关的B和T细胞表位的疫苗载体。我们使用YF17D的全长感染性克隆作为LAS病毒基因GPC和NP的载体，分别编码主要抗原、糖蛋白和核蛋白。我们将验证YF17D/LAS重组体将有效表达LAS病毒主要抗原并在实验动物中诱导保护性免疫应答的假设。品系13的豚鼠和恒河猴是LF最好的实验模型，符合FDA的两个动物规则，用于开发生物防御疫苗。我们的目标是在非人类灵长类动物进行临床前试验之前，评估YF17D/LAS重组体在啮齿动物模型中的免疫原性和有效性。我们的具体目标是：1.重组YF17D/LAS病毒的制备和验证；验证YF/LAS重组体具有复制能力并表达LAS糖蛋白和NP蛋白的假设。2.验证疫苗将诱导针对主要LAS病毒蛋白的抗原特异性反应的假设。3.有效性，确定YF17D/LAS重组体是否能有效保护13株豚鼠免受LAS病毒攻击。我们的长期目标是开发一种YF17D/LAS双价活疫苗，以控制非洲的YF和LF。

DESCRIPTION (provided by applicant): Yellow Fever (YF) and Lassa Fever (LF) are two viral hemorrhagic fevers (VHFs) endemic for West and Central Africa. Among causative agents of VHFs, Lassa (LAS) and YF viruses affect the largest number of people in Africa. In endemic areas the "at risk" LAS virus seronegative population may be as high as 59 million, with an annual incidence of illness of 3 million, fatalities up to 67 thousand, and up to 3 million re- infections. The sizeable disease burden and the possibility that LAS virus can be used as an agent of biological warfare make a strong case for vaccine development. There is no vaccine for LF. In contrast, attenuated YF17D, the most successful vaccine developed to date, is widely used to control YF. However, ecological and social changes, ineffective public health policy and insufficient vaccine coverage resulted in a resurgence of YF during last 15 years. Recently the YF17D vaccine has been successfully used as a vector for live vaccines against flaviviruses and as a vaccine vector for flavivirus-unrelated B and T cell epitopes. We use a full-length infectious cDNA clone of the YF17D as a vector of LAS virus genes, GPC and NP, encoding major antigens, glycoproteins and nucleoprotein, respectively. We will test the hypothesis that YF17D/LAS recombinants will effectively express LAS virus major antigens and induce protective immune responses in experimental animals. Strain 13 guinea pigs and rhesus macaques are the best experimental models for LF to comply with the FDA "Two Animal Rule" for development of biodefense vaccines. Our goal is to assess the immunogenicity and efficacy of YF17D/LAS recombinants in a rodent model before pre-clinical trials in non-human primates. Our specific aims are: 1. Generation and validation of recombinant YF17D/LAS viruses; test the hypothesis that the YF/LAS recombinants will be replication-competent and express LAS GP and NP proteins. 2. Test the hypothesis that the vaccine will induce antigen-specific responses against major LAS virus proteins. 3. Efficacy, determine whether YF17D/LAS recombinants will effectively protect strain 13 guinea pigs against LAS virus challenge. Our long-term goal is to develop a live YF17D/LAS bivalent vaccine to control YF and LF in Africa.