The development of a recombinant vaccine against human onchocerciasis

人盘尾丝虫病重组疫苗的研制

• 批准号: 8306946
• 负责人: Sara Lustigman
• 金额: $ 65.32万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-25 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306946
• 关键词: Address; Adjuvant; Adult; Africa; African; Aftercare; Americas; Animal Model; Antibodies; Antigen Targeting; Antigens; Apolipoproteins C; Area; B-Lymphocytes; Benchmarking; Biochemical; Blindness; Blood; Brugia malayi; Cattle; Chronic; Clinical; Clinical Trials; Cloning; Communities; Complement; Complication; Country; Data; Development; Disease; Dose; Drug Formulations; Drug resistance; Drug usage; Effector Cell; Ensure; Escherichia coli; Female; Foundations; Funding; Generations; Goals; Hand; Helminths; Homologous Gene; Hookworms; Human; Human Activities; Immune; Immune response; Immune system; Immunity; Immunization; Infection; Infection prevention; Intestinal Volvulus; Intestines; Investigational New Drug Application; Ivermectin; Jird; Laboratories; Laboratory Animal Models; Larva; Leadership; Life; Louisiana; Lymphatic; Measures; Memory; Microfilaria; Modeling; Molecular Biology; Monitor; Mus; Nematoda; New York; Ocular Onchocerciasis; Onchocerca; Onchocerca volvulus; Onchocerciasis; Parasites; Pathology; Pharmaceutical Preparations; Phase; Population; Predisposition; Probability; Procedures; Process; Proteins; Protocols documentation; Public Health; Publishing; Recombinant Vaccines; Recombinants; Reporting; Research; Resistance development; Risk; Route; Schedule; Screening procedure; Staging; System; T-Lymphocyte; Techniques; Testing; Time; Toxicology; Tropical Disease; Tropical Medicine; Universities; Vaccination; Vaccine Antigen; Vaccines; Validation; Vulnerable Populations; Washington; Work; World Health; World Health Organization; Yeasts; base; bioprocess; cytokine; design; disability; disorder control; efficacy evaluation; efficacy testing; experience; filaria; in vitro Assay; innovation; killings; manufacturing process development; mouse model; neglect; news; pre-clinical research; preclinical study; product development; programs; protective efficacy; public-private partnership; research and development; research clinical testing; research study; response; skin disorder; success; symposium; tool; transmission process; vaccine development; vaccine effectiveness; vaccine efficacy

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.

人类盘尾丝虫病是一种严重被忽视的热带疾病，由盘尾丝虫 (Ov) 和 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 凭借伊维菌素，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，在实现消除这一目标之前，必须克服巨大的技术和后勤障碍。 非洲是可以达到的。除了该地区的合规困难外，证据正在积累 盘尾丝虫对伊维菌素药物存在耐药性，伊维菌素是目前用于大规模治疗的唯一药物 对这一人群的治疗。因此，迫切需要额外的工具，包括疫苗 防治盘尾丝虫病以“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。我们预计盘尾丝虫疫苗将被指定为保护产品 生活在流行地区的易受感染和疾病（皮肤病和失明）的人群。 成虫负担的减少将减少雌性成虫产生的微丝蚴的数量 以及这些流行地区内的病理学和潜在的传播率。 重要的是，针对卵子幼虫的保护性免疫力现已在人类身上得到明确证明， 牛和小鼠，从而证明了可以针对这种情况生产疫苗的概念基础 感染。使用专为该项目设计的创新选择策略，我们现在拥有以下产品组合： 八种保护性抗原已被证明不仅可以在 Ov 小鼠模型中发挥疫苗作用，而且可以作为疫苗使用 也在其他线虫动物模型中使用该物种，例如淋巴丝虫和肠道蠕虫 特异性同源疫苗抗原。拟议的研究将扩展和完善现有的研究 这些抗原的基础。我们的方法是从已完成的抗原发现阶段继续前进 并启动所需的临床前研究和开发过程，该过程将通过强大的 筛选过程，发现了最佳的 2 种重组 Ov 疫苗抗原，具有最高的 成功诱导人类保护性免疫力的概率。已知该疫苗将针对 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： 1) 根据两个实验室的保护功效，从 8 种盘尾丝虫疫苗抗原组合中选择 4 种 动物模型； 2) 使用疫苗确定4种选定抗原的最大寄生虫杀灭潜力 优化，然后选择2种最佳的疫苗抗原/佐剂配方； 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。我们提出的策略将导致选定 Ov 疫苗的鉴定 可以进入产品开发和制造的抗原，最终目标是临床 第一代重组盘尾丝虫疫苗的开发和测试。