The development of a recombinant vaccine against human onchocerciasis

人盘尾丝虫病重组疫苗的研制

基本信息

批准号：
7738645
负责人：
Sara Lustigman
金额：
$ 70.83万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
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/7738645
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

项目摘要

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由盘尾丝虫（Ov）引起的严重被忽视的热带疾病，也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，在非洲实现消灭病毒的目标之前，必须克服巨大的技术和后勤障碍。除了该地区难以遵守规定外，证据表明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该人群的唯一药物。因此，迫切需要额外的工具，包括需要一种针对盘尾丝虫病的疫苗来“补充”现有的控制措施，从而有可能消除人类的这种感染。我们设想盘尾丝虫疫苗将作为一种产品来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）。成虫负担的减少将减少雌性成虫产生的微丝蚴的数量，从而减少病理学，也可能减少这些流行地区的传播率。重要的是，针对卵细胞幼虫的保护性免疫力现已在人类、牛和小鼠身上得到明确证明，从而证明了可以生产针对这种感染的疫苗的概念基础。使用专为该项目设计的创新选择策略，我们现在拥有八种保护性抗原的组合，这些抗原已被证明不仅可以在 Ov 小鼠模型中发挥疫苗作用，而且还可以在其他线虫动物模型（如淋巴丝虫和肠道蠕虫）中发挥疫苗作用。使用物种特异性同源疫苗抗原。拟议的研究将扩展和完善这些抗原的现有研究基础。我们的方法是从已完成的抗原发现阶段开始，启动所需的临床前研究和开发过程，通过强有力的筛选过程，发现最好的 2 种重组 Ov 疫苗抗原，最有可能成功诱导人类的保护性免疫力。该疫苗将针对卵子幼虫，已知卵子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) 根据盘尾丝虫疫苗抗原在两种实验动物模型中的保护功效，从 8 种盘尾丝虫疫苗抗原组合中选择 4 种； 2) 通过疫苗优化确定4种选定抗原的最大寄生虫杀灭潜力，然后选择2种最佳疫苗抗原/佐剂配方； 3) 建立与两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制造，最终目标是第一代重组盘尾丝虫疫苗的临床开发和测试。公共卫生相关性：由盘尾丝虫引起的人类盘尾丝虫病是发展中国家失明和慢性残疾的重要原因，并已成为通过伊维菌素大规模给药消除的目标。然而，巨大的技术和后勤障碍仍然存在，而且在经过多年的药物治疗后，一些人群中出现耐药寄生虫的消息令人震惊。因此，迫切需要额外的工具来支持现有的控制措施，其中针对盘尾丝虫感染性幼虫的疫苗是控制盘尾丝虫病的最重要的新工具和重要的附加组成部分。