A Vaccine for Lymphatic Filariasis, LFGuard™

项目摘要 淋巴丝虫病（LF）是一种由蚊子传播、被忽视的热带疾病（NTD），影响超过1.2亿人 生活在72个国家的人。目前的LF感染控制策略依赖于每年大量药物 向“高危”人群施用丙二醛（MDA）未能中断疾病传播，部分原因是慢性 再感染目前还没有获得许可的预防性疫苗可用于LF，并且在2009年测试的那些疫苗中， 在过去的20年里已经超越了啮齿类动物测试。这部分是由于保护不力，但也由于 缺乏资源来推动这项技术，因为它确实被忽视了。 我们已经开发并建立了第一个成功的多价重组融合蛋白（Bm-HAXT）， LF的预防称为LFGuard™。该疫苗由蛋白抗原Bm-HAXT组成， 与TLR 4激动剂GLA-on-Alum进行对比当配制时，我们的疫苗是高度稳定的， 在啮齿类动物中具有免疫力（>95%），在非人灵长类动物中具有显著保护作用（70%）。到目前为止，LFGuard™已经 在不同的动物模型中进行了广泛的测试和确认其预防潜力和安全性， 作为小鼠（n=980）、蒙古沙鼠（沙鼠）（n=220）和恒河猴（n=60）。除了治疗LF外， LFGuard™在犬中作为心丝虫疫苗也显示出巨大的前景。 SBIR第2阶段的提案将使我们能够将LFGuard™推进到临床前开发阶段，包括GMP 生产、装瓶以及稳定性和功效测试。将进行一项临床研究和一项支持性毒理学研究 设计，稳定性将通过短期和长期稳定性计划进行确认。最后我们将 在执行毒理学研究之前，与FDA召开IND前会议。当这些研究 完成后，这种重要的抗原将准备进入第一个人类临床试验， 丝虫病疫苗我们建议SBIR第二阶段赠款的目标如下：（1）根据 cGMP（2）进行临床前IND使能研究。

PROJECT SUMMARY Lymphatic filariasis (LF) is a mosquito-transmitted, neglected tropical disease (NTD) affecting over 120 million people living in 72 countries. Current control strategies for LF infection which rely on annual mass drug administration (MDA) to the “at-risk” populations has failed to interrupt disease transmission partly due to chronic reinfection. There is no licensed prophylactic vaccine currently available for the LF, and of those tested over the last 2 decades have advanced beyond rodent testing. This is partly because of poor protection, but also due to lack of resources to advance the technology given its truly neglected nature. We have developed and established the first successful multivalent recombinant fusion protein (Bm-HAXT) for the prophylaxis of LF called LFGuard™. This vaccine is comprised of a protein antigen, Bm-HAXT, formulated with the TLR4 agonist GLA-on-Alum. When formulated, our vaccine is highly stable and provides nearly sterile immunity in rodents (>95%) and significant protection in non-human primates (70%). To date LFGuard™ has been extensively tested and confirmed for its prophylactic potential and safety in different animal models such as mice (n=980), Mongolian gerbils (jirds) (n=220), and rhesus macaques (n=60). In addition to treatment of LF, LFGuard™ has also shown significant promise in dogs as a vaccine for heartworms. This SBIR Phase 2 proposal will allow us to move LFGuard™ into pre-clinical development including GMP manufacture, vialing, and stability and efficacy testing. A clinical study and a supporting toxicology study will be designed, and stability will be confirmed through both short- and long-term stability programs. Finally, we will conduct a pre-IND meeting with the FDA prior to execution of the toxicology study. When these studies are complete, this important antigen will be poised to enter the first human clinical trials for the first ever lymphatic filariasis vaccine. We propose the following aims for this SBIR Phase 2 grant: (1) Manufacture of BmHAXT under cGMPs (2) Perform pre-clinical IND-enabling studies.