The development of a recombinant vaccine against human onchocerciasis

人类盘尾丝虫病是一种严重被忽视的热带疾病，由螺旋体丝虫(Ov)和一种 这是发展中世界失明和慢性残疾的重要原因。通过大规模的药物管理 在伊维菌素的作用下，盘尾丝虫病已被世界卫生组织确认为全球消除的潜在候选者。 然而，在实现消除#年的目标之前，必须克服巨大的技术和后勤障碍。 非洲是可以实现的。除了在这一地区遵守规定的困难之外，证据正在为 钉螺存在对伊维菌素的抗药性，伊维菌素是目前用于该人群的唯一药物 对这群人的待遇。因此，迫切需要更多的工具，包括需要疫苗。 预防盘尾丝虫病，以“补充”目前的控制措施，从而有可能消除这一现象 来自人类的感染。我们设想，钉螺疫苗将被指定为一种需要保护的产品 生活在流行地区的脆弱人群免受感染和疾病(皮肤病和失明)的伤害。 成虫负担的减少将减少成年雌虫产生的微丝虫数量。 因此还有病理学和潜在的在这些流行地区的传播率。 重要的是，对卵子幼虫的保护性免疫现在已经在人类身上得到了明确的证明， 牛和老鼠，从而证明了可以生产针对这种疾病的疫苗的概念基础 感染。使用为该项目设计的创新选择策略，我们现在手中有一系列 八种保护性抗原不仅在卵子鼠模型中被证明具有疫苗功能，而且 在其他线虫动物模型中也使用该物种，如淋巴丝虫和肠道蠕虫 特定的同源疫苗抗原。拟议的研究将扩展和完善现有的研究 这些抗原的基础。我们的方法是从完成的抗原发现阶段向前迈进 并启动所需的临床前研究和开发过程，这将通过强大的 筛选过程中，发现了最好的2种重组Ov疫苗抗原，最高 成功诱导人类保护性免疫的可能性。疫苗将针对卵子幼虫，已知 容易受到宿主的免疫攻击。这将通过三个具体目标来实现：1) 根据两个实验室的保护效果，从8种钉螺疫苗抗原组合中选择4种 动物模型；2)用疫苗测定4种抗原的最大寄生虫杀伤力 优化并选择2个最佳疫苗抗原/佐剂配方；以及3)建立机制 以及与两种最有效疫苗诱导的保护性免疫相关的免疫相关性 抗原/佐剂制剂。我们建议的策略将导致鉴定选定的卵子疫苗 可以进入产品开发和制造的抗原，最终目标是临床 第一代重组钉螺疫苗的研制与检测。

Human onchocerciasis is a serious neglected tropical disease caused by Onchocerca volvulus (Ov) and an important cause of blindness and chronic disability in the developing world. Through mass drug administration of ivermectin, onchocerciasis has been recognized by the WHO as a potential candidate for global elimination. However, formidable technical and logistical obstacles must be overcome before the goal of elimination in Africa can be attained. In addition to difficulties of compliance in this region, evidence is building for the existence of Onchocerca resistance to the drug ivermectin, which is at present the only drug used for the mass treatment of this population. Therefore, additional tools are critically needed and include the need for a vaccine against onchocerciasis to "complement" the present control measures and thus potentially eliminate this infection from humans. We envision that the Onchocerca vaccine will be indicated as a product to protect vulnerable populations living in endemic areas against infection and disease (skin disease and blindness). Reduction in adult worm burden will reduce the number of microfilariae produced by the adult female worms and thus pathology and potentially also the rates of transmission within these endemic regions. Importantly, protective immunity against Ov larvae has now been definitively demonstrated in humans, cattle and mice, thereby proving the conceptual underpinnings that a vaccine can be produced against this infection. Using an innovative selection strategy designed for this project we now have in hand a portfolio of eight protective antigens that have been proven to function as vaccines not only in the Ov - mouse model but also in other nematode animal models such as lymphatic filariae and intestinal worms using the species specific homologous vaccine antigens. The proposed studies will expand and refine the existing research foundations on these antigens. Our approach is to move forward from the completed antigen discovery stage and initiate the required preclinical research and development process that will result, through a robust screening process, with the discovery of the best 2 recombinant Ov vaccine antigens with the highest probability for success at inducing protective immunity in humans. The vaccine will target the Ov larvae, known to be vulnerable to host immunological attack. This will be accomplished through three specific aims: 1) To select 4 Onchocerca vaccine antigens from the portfolio of 8 based on their protective efficacy in two laboratory animal models; 2) To determine the maximum parasite killing potential of the 4 selected antigens using vaccine optimization and then select the 2 best vaccine antigen/adjuvant formulations; and 3) To establish mechanisms and immune correlates associated with protective immunity induced by the 2 most efficacious vaccine antigen/adjuvant formulations. Our proposed strategy will result in the identification of selected Ov vaccine antigens that could be moved into product development and manufacturing with the ultimate goal of clinical development and testing of a first-generation recombinant Onchocerca vaccine.