The development of a recombinant vaccine against human onchocerciasis

人类盘尾丝虫病是由盘尾丝虫引起的一种严重的热带疾病， 是发展中国家失明和慢性残疾的重要原因。通过大规模药物管理 在伊维菌素的作用下，盘尾丝虫病已被世卫组织确认为全球消除的潜在候选者。 然而，在实现消除地雷的目标之前，必须克服巨大的技术和后勤障碍。 非洲可以实现。除了在这一区域遵守方面的困难外， 盘尾丝虫对伊维菌素药物存在抗药性，伊维菌素是目前唯一用于大规模 对待这个群体。因此，迫切需要更多的工具，包括疫苗的需要 以“补充”目前的控制措施，从而有可能消除这种情况。 人类的感染。我们设想盘尾丝虫疫苗将作为一种产品， 生活在流行病地区的易受感染和疾病（皮肤病和失明）影响的弱势群体。 成虫负担的减少将减少成虫雌蠕虫产生的微丝蚴数量 以及病理学和潜在的在这些流行区域内的传播率。 重要的是，针对Ov幼虫的保护性免疫现已在人类中得到明确证明， 牛和老鼠，从而证明了可以生产疫苗的概念基础。 感染使用为这个项目设计的创新选择策略，我们现在手头有一个投资组合， 八种保护性抗原已被证明不仅在Ov小鼠模型中发挥疫苗作用， 在其它线虫动物模型如淋巴丝虫和肠道蠕虫中， 特异性同源疫苗抗原。拟议的研究将扩大和完善现有的研究 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推进 并启动所需的临床前研究和开发过程， 筛选过程中，发现了最好的2种重组Ov疫苗抗原， 成功诱导人类保护性免疫的可能性。疫苗将针对已知的Ov幼虫， 容易受到宿主免疫攻击这将通过三个具体目标来实现： 根据盘尾丝虫疫苗抗原在两个实验室中的保护效力，从8种疫苗抗原组合中选择4种 动物模型; 2）使用疫苗测定4种选择的抗原的最大杀虫潜力 优化，然后选择2种最佳疫苗抗原/佐剂配方;和3）建立机制 以及与2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。我们提出的战略将导致选定的Ov疫苗的鉴定 抗原，可以转移到产品开发和生产，最终目标是临床 开发和测试第一代重组盘尾丝虫疫苗。

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.