The development of a recombinant vaccine against human onchocerciasis

描述（由申请人提供）：人类盘尾丝虫病是由盘尾丝虫病引起的一种被严重忽视的热带疾病，是发展中国家致盲和慢性残疾的重要原因。通过大规模使用伊维菌素，盘尾丝虫病已被世卫组织确认为全球消灭的潜在候选疾病。但是，必须克服巨大的技术和后勤障碍，才能实现在非洲消灭艾滋病毒的目标。除了在该地区难以遵守规定外，正在建立证据表明盘尾丝虫对伊维菌素存在耐药性，伊维菌素是目前用于该人群大规模治疗的唯一药物。因此，迫切需要更多的工具，包括需要一种针对盘尾丝虫病的疫苗，以“补充”目前的控制措施，从而有可能消除这种人间感染。我们设想盘尾丝虫病疫苗将被列为一种产品，以保护生活在流行地区的弱势群体免受感染和疾病（皮肤病和失明）的侵害。减少成虫负担将减少成虫雌虫产生的微丝虫数量，从而降低病理性，并可能降低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、牛和小鼠中得到明确证明，从而证明了可以生产针对这种感染的疫苗的概念基础。使用为该项目设计的创新选择策略，我们现在已经掌握了8种保护性抗原的组合，这些抗原已被证明不仅在Ov -小鼠模型中起疫苗作用，而且在其他线虫动物模型中也起疫苗作用，例如使用物种特异性同源疫苗抗原的淋巴丝虫病和肠蠕虫。拟议的研究将扩大和完善这些抗原的现有研究基础。我们的方法是从完成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，通过强大的筛选过程，发现最佳的2种重组Ov疫苗抗原，这些抗原最有可能成功诱导人类产生保护性免疫。疫苗将针对易受宿主免疫攻击的Ov幼虫。这将通过三个具体目标来实现：1)根据8种盘尾丝虫疫苗抗原在两种实验动物模型中的保护效果，从8种疫苗组合中选择4种疫苗抗原；2)通过疫苗优化确定4种抗原的最大杀虫潜能，筛选出2种最佳的疫苗抗原/佐剂配方；3)建立两种最有效的疫苗抗原/佐剂配方诱导保护性免疫的机制和免疫相关性。我们提出的策略将导致选定的Ov疫苗抗原的鉴定，这些抗原可以进入产品开发和生产，最终目标是临床开发和测试第一代重组盘尾丝虫病疫苗。公共卫生相关性：盘尾丝虫病是发展中国家致盲和慢性残疾的一个重要原因，通过大规模使用伊维菌素已成为消除该疾病的目标。然而，巨大的技术和后勤障碍仍然存在，另外的消息是，经过多年的药物治疗，一些人群中出现了耐药寄生虫，这令人震惊。因此，迫切需要更多的工具来支持现有的控制措施，针对卷尾蛔虫感染幼虫的疫苗是最重要的新工具，也是控制盘尾丝虫病工作中必不可少的额外组成部分。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Human onchocerciasis caused by Onchocerca volvulus is an important cause of blindness and chronic disability in the developing world and has become a target for elimination through the mass drug administration of ivermectin. However, formidable technical and logistical obstacles remain, and the additional news that drug resistant parasites are developing in some populations after years of drug treatment is alarming. Therefore, additional tools are critically needed to support the existing control measures with a vaccine targeting the O. volvulus infective larvae being a most important new tool and essential additional component in the effort to control onchocerciasis.