Development of sG as a human vaccine against Nipah/Hendra

描述(申请人提供)：尼帕病毒(NIV)和亨德拉病毒(HEV)是副粘病毒科中形成亨尼帕病毒属的密切相关的人畜共患病。它们是有包膜的负义RNA病毒，会在各种动物宿主和人类中引起一种系统性和致命性疾病。在一些疫情中，死亡人数高达75%。它们被归类为生物安全级别4(BSL4)病毒，并具有几个特征，证明NIH和CDC将其列为C类生物制剂是合理的，包括通过气雾剂传播的能力。目前还没有针对新城疫或戊型肝炎的疫苗或治疗方法。孟加拉国和其他地区每年暴发的新城疫人类感染证明预防性疫苗有利于改善公共卫生，并降低其作为生物疗法的潜力。在猫、雪貂和非人灵长类动物中使用重组HEV可溶性附着蛋白G(HEV-SG)进行的免疫和攻击研究表明，HEV-SG亚单位疫苗可以完全有效地对抗HEV和新城疫。事实上，HEV-SG亚单位目前正在澳大利亚作为马匹疫苗进行评估。我们在这里的目标是生产1克HEV-SG，它将适合进行IND支持的毒理学和有效性研究，作为支持评估HEV-SG作为人类疫苗对抗新城疫和HEV的必要步骤。我们将通过以下具体目标来实现这一目标：1)优化HEV-SG免疫原/佐剂配方；2)确定HEV-SG的释放试验；3)生产1 g HEV-SG；4)进行IND支持性动物研究。到资助期结束时，我们将完成：(I)确定适合进一步临床开发的佐剂；(Ii)准备用于生产HEV-SG主细胞库的特征性研究级“预种”；(Iii)根据未来的建议，优化适合生产cGMP临床试验材料的开发规模流程；(Iv)生产至少1克开发级疫苗，以进行IND支持毒理学和有效性研究；以及(V)执行上述动物实验。随后的应用将包括1)主细胞库和2)临床批量HEV-SG疫苗的cGMP制造，用于第一阶段临床评估。

DESCRIPTION (provided by applicant): Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that form the genus Henipavirus in the family Paramyxoviridae. They are enveloped, negative-sense RNA viruses that cause a systemic and fatal disease in a variety of animal hosts and in humans. In some outbreaks, the death toll has reached as high as 75%. They are classified as biological safety level-4 (BSL4) viruses and possess several characteristics that justify their listing as Category C biothreat agents by the NIH and CDC including the ability to be transmitted via aerosol. There is currently no approved vaccine or therapeutic against either NiV or HeV. Annual outbreaks of NiV human infections in Bangladesh and other areas justify the benefit of a prophylactic vaccine for improving public health as well as reducing their potential as a biothreat. Immunization and challenge studies performed in cats, ferrets, and nonhuman primates using recombinant HeV soluble attachment protein G, HeV-sG, have demonstrated that a HeV-sG subunit vaccine can be completely effective against both HeV and NiV. In fact, HeV-sG subunit is currently being evaluated in Australia as an equine vaccine. Our objective here is to produce 1 gram of HeV-sG that will be suitable to perform IND-supportive toxicology and efficacy studies as necessary steps to support the evaluation of HeV-sG as a human vaccine against NiV and HeV. We will do so through the following specific aims: 1) Optimize HeV-sG immunogen/adjuvant formulation; 2) Identify release assays for HeV-sG; 3) Manufacture 1 g of HeV-sG; 4) Perform IND supportive animal studies. By the end of the funding period, we will have (i) identified an adjuvant suitable for further clinical development; ii) prepared a characterized research-grade "pre-seed" for use to manufacture a HeV-sG Master Cell Bank; (iii) optimized a development-scale process suitable for the manufacturing of cGMP clinical trial materials under future proposals; (iv) manufactured at least 1 g of development-grade vaccine to perform IND supportive toxicology and efficacy studies, and (v) executed said animal studies. Subsequent applications will pursue cGMP manufacture of 1) a master cell bank and 2) clinical lots of HeV-sG vaccine for Phase 1 clinical evaluation.