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: 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
• 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

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）：人类的尾尾症是由Onchocerca volvulus（OV）引起的严重忽视的热带疾病，也是发展中国家失明和慢性残疾的重要原因。通过大规模药物给药伊维菌素，世界卫生组织已被认为是全球消除的潜在候选者。但是，必须克服强大的技术和后勤障碍，然后才能实现非洲消除目标。除了该地区的合规性困难外，有证据表明存在对药物伊维菌素的耐药性，目前这是该人群大规模治疗的唯一药物。因此，至关重要的是需要其他工具，并包括对抗尾cariasias的疫苗“补充”当前的控制措施，从而有可能消除人类的这种感染。我们设想，OnChocerca疫苗将被指定为保护居住在地方性地区的脆弱人群免受感染和疾病（皮肤病和失明）的产品。成年蠕虫负担的减轻将减少成年雌性蠕虫产生的微毛虫的数量，从而减少病理学，并有可能在这些地方性地区内传播的速度。重要的是，现在已经在人类，牛和小鼠中明确证明了对OV幼虫的保护性免疫，从而证明了概念上的基础，即可以针对这种感染产生疫苗。使用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投资组合，这些抗原不仅在OV-小鼠模型中，而且还可以用作其他线虫动物模型，例如使用特定物种的特定物种同源疫苗抗原。拟议的研究将扩大和完善这些抗原的现有研究基础。我们的方法是从完整的抗原发现阶段前进，并启动所需的临床前研究和开发过程，这将通过强大的筛选过程，发现最佳2重组OV OV疫苗抗原，并在人类诱导保护性免疫方面取得成功的最高可能性。该疫苗将针对OV幼虫，已知容易受到宿主免疫攻击的影响。这将通过三个特定的目标来完成：1）根据两个实验室动物模型中的保护效果，从8个投资组合中选择4种OnChocerca疫苗抗原； 2）使用疫苗优化确定4种选定抗原的最大寄生虫杀死潜力，然后选择2种最佳疫苗抗原/辅助配方； 3）建立机制和免疫与由2种最有效的疫苗抗原/辅助配方引起的保护性免疫相关。我们提出的策略将导致鉴定所选的OV疫苗抗原，这些抗原可以将其转移到产品开发和制造中，以实现临床开发和测试第一代重组OnChocerca疫苗的最终目标。公共卫生相关性：由OnChocerca Volvulus引起的人类尾cer虫是发展中国家失明和慢性残疾的重要原因，并已通过大规模药物管理Ivermectin的大规模药物管理成为消除的目标。但是，仍然存在强大的技术和后勤障碍，并且在药物治疗多年后，某些人群中耐药寄生虫正在发育的其他消息令人震惊。因此，迫切需要使用其他工具来支持现有的控制措施，该疫苗的疫苗针对O. volvulus感染性幼虫是最重要的新工具，并且是控制尾cer虫的努力。