LASSA FEVER BIVALENT VACCINE EFFICACY IN MARMOSETS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 黄热病（YF）和拉沙热（LF）是西非流行的两种病毒性出血热（VHF）。在VHF的病原体中，拉沙（LAS）和YF病毒影响最多的人。相当大的疾病负担和这些病毒可能被用作生物战剂的可能性，为疫苗的开发提供了强有力的理由。目前尚无LF疫苗。相比之下，自1936年以来，YF 17 D减毒活疫苗已可用于人类免疫。然而，YF 17 D疫苗的可获得性差导致了对疾病的控制不足，这代表了公共卫生政策的失败。在过去的15年里，YF重新出现在非洲和南美洲。因此，迫切需要增加YF 17 D疫苗的产量。 YF 17 D是目前世界上最有效、最安全的疫苗之一，被认为是病毒表达载体的最佳候选者之一。YF 17 D激活树突状细胞上的多种TLR，以引发混合的Th 1/Th 2细胞因子谱和抗原特异性CD 8 + T细胞。重要的是，基于YF 17 D的重组构建体引发针对克隆在YF 17 D载体中的不相关（非黄病毒）表位的强且持久的体液和细胞介导的免疫应答。我们已经使用疫苗株YF 17 D的全长感染性cDNA克隆作为载体来设计将LAS糖蛋白表达到感染细胞中的重组（非嵌合）YF 17 D/LAS-GPC疫苗。我们证明了重组YF 17 D/LAS-GPC病毒在体外和体内都具有复制能力，诱导针对两种病原体的免疫应答，并保护豚鼠免受致命性LF的侵害。 我们以前使用绒猴作为LF模型，用重组疫苗ML 29进行先进的证明研究。该候选疫苗作为有效性、广度和免疫原性的极好标准。 然而，当前CDC载体生物安全性状态（ML 29被归类为BSL-3）使ML 29疫苗的进一步开发变得复杂。YF 17 D/LAS双价重组疫苗的设计是一个非常有吸引力的替代控制重叠流行区的两种感染。 目前的项目将测试的假设，即YF 17 D/LAS重组将是高度免疫原性和诱导保护性免疫反应，在绒猴攻击与LAS病毒。我们的具体目标是：1）免疫原性;检验YF 17 D/LAS免疫接种将刺激LAS和YF特异性免疫应答的假设; 2）效力;检验YF 17 D/LAS接种将保护免受LAS攻击的假设。该项目的成功完成将产生一个有希望的LF和YF双价候选疫苗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Yellow Fever (YF) and Lassa Fever (LF) are two viral hemorrhagic fevers (VHFs) endemic for West Africa. Among causative agents of VHFs, Lassa (LAS) and YF viruses affect the largest number of people. The sizeable disease burden and the possibility that these viruses can be used as an agent of biological warfare make a strong case for vaccine development. There is no vaccine available for LF. In contrast, a live attenuated YF17D vaccine has been available for human immunization since 1936. However, poor availability of YF17D vaccine has led to inadequate control of the disease representing a failure of public health policy. In the past 15 years, YF re-emerged in Africa and in South America. Therefore, there is an urgent need to increase YF17D vaccine production. The YF17D is one of the most effective and safest vaccines in the world and is regarded as one of the best candidates for viral expression vector. YF17D activates multiple TLRs on dendritic cells to elicit a mixed Th1/Th2 cytokine profile and antigen-specific CD8+ T cells. Importantly, YF17D-based recombinant constructs elicit strong and long-lasting humoral and cell-mediated immune responses against unrelated (non-flavivirus) epitopes cloned in the YF17D vector. We have used a full-length infectious cDNA clone of the vaccine strain YF17D as a vector to design recombinant (not chimeric) YF17D/LAS-GPC vaccine expressing LAS glycoproteins into infected cells. We demonstrated that recombinant YF17D/LAS-GPC virus is replication competent in vitro and in vivo, induces immune responses against both pathogens, and protects guinea pigs against fatal LF. We previously used marmosets as a model of LF to perform advanced-proof studies with reassortant vaccine ML29. This vaccine candidate serves as an excellent standard for efficacy, breadth, and immunogenicity. However, the current CDC vector biosafety status (ML29 is classified as BSL-3) has complicated further development of the ML29 vaccine. The design of bivalent YF17D/LAS recombinant vaccine is a very attractive alternative to control both infections in overlapping endemic areas. The current project will test the hypothesis that the YF17D/LAS recombinant will be highly immunogenic and induce protective immune responses in marmosets challenged with LAS virus. Our specific aims are: 1)immunogenicity; test the hypothesis that YF17D/LAS immunization will stimulate LAS-and YF-specific immune responses; 2) efficacy; test the hypothesis that YF17D/LAS-vaccinated will be protected against LAS challenge. Successful completion of this project will result in a promising bivalent vaccine candidate for LF and YF.