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: 7919994
• 负责人: Sara Lustigman
• 金额: $ 71.43万
• 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/7919994
• 关键词: Address; Adjuvant; Adult; Africa; African; Aftercare; Americas; Animal Model; Antibodies; Antigen Targeting; Antigens; 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 health relevance; 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

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.

描述（由申请人提供）：人类盘尾丝虫病是一种严重的被忽视的热带疾病，由盘尾丝虫（Ov）引起，是发展中国家失明和慢性残疾的重要原因。通过伊维菌素的大规模药物管理，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，在实现在非洲消除地雷的目标之前，必须克服巨大的技术和后勤障碍。除了该区域遵守规定方面的困难外，越来越多的证据表明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治疗盘尾丝虫的药物。因此，迫切需要更多的工具，包括需要一种盘尾丝虫病疫苗，以“补充”目前的控制措施，从而有可能从人类中消除这种感染。我们设想盘尾丝虫疫苗将作为一种产品，用于保护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）。成虫负担的减少将减少雌蠕虫产生的微丝蚴数量，从而减少病理学，并可能降低这些流行地区的传播率。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，从而证明了可以针对这种感染生产疫苗的概念基础。使用为该项目设计的创新选择策略，我们现在手头上有八种保护性抗原的组合，这些抗原已被证明不仅在Ov -小鼠模型中而且在其他线虫动物模型如淋巴丝虫和肠道蠕虫中使用物种特异性同源疫苗抗原作为疫苗起作用。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，通过强大的筛选过程，发现最好的2种重组Ov疫苗抗原，其成功诱导人类保护性免疫的可能性最高。该疫苗将针对已知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）基于盘尾丝虫疫苗抗原在两种实验室动物模型中的保护效力，从8种盘尾丝虫疫苗抗原组合中选择4种盘尾丝虫疫苗抗原; 2）使用疫苗优化来确定所选择的4种抗原的最大寄生虫杀灭潜力，然后选择2种最佳疫苗抗原/佐剂制剂;和3）建立与由2种最有效的疫苗抗原/佐剂制剂诱导的保护性免疫相关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，最终目标是第一代重组盘尾丝虫疫苗的临床开发和测试。公共卫生关系：由盘尾丝虫引起的人类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，已成为通过大规模施用伊维菌素消除的目标。然而，巨大的技术和后勤障碍仍然存在，而且经过多年的药物治疗后，一些人群中的抗药性寄生虫正在发展的额外消息令人震惊。因此，迫切需要额外的工具来支持现有的控制措施，并针对O。扭转感染性幼虫是一种最重要的新工具，也是控制盘尾丝虫病的必要补充成分。