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: 9444432
• 负责人: Sara Lustigman
• 金额: $ 69.48万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444432
• 关键词: 5 year old; Achievement; Adjuvant; Adult; Africa; Africa South of the Sahara; African; Amino Acid Sequence; Animal Model; Antibodies; Area; Blindness; Cattle; Cells; Central Africa; Child; Chronic; Clinic; Clinical Trials; Companions; Complement; Complex; Consensus; Country; Critical Pathways; Data; Development; Disease; Drug resistance; Effectiveness; Embryonic Development; Ensure; Expert Opinion; Exposure to; Fertility; Formulation; Funding; Genetic; Goals; Hand; Human; IgE; Immune; Immune response; Immunity; Immunize; Inbreeding; Incidence; Infection; Infection prevention; Ivermectin; Link; Loa loa; Location; Methods; Modeling; Mouse Strains; Mus; National Institute of Allergy and Infectious Disease; Nematoda; Ocular Onchocerciasis; Onchocerca volvulus; Onchocerciasis; Parasite resistance; Parasites; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Population; Positioning Attribute; Preventive vaccine; Production; Proteins; Proteomics; Protocols documentation; Published Comment; Recombinant Vaccines; Research Personnel; Skin; Source; System; Technology; Testing; Uncertainty; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Research; Vaccines; Visual impairment; Vulnerable Populations; Work; aluminum sulfate; blind; chemokine; chemotherapy; cytokine; design; disability; experience; experimental study; fighting; first-in-human; human disease; immunological status; innovation; lead candidate; mathematical model; meetings; minimal risk; mouse model; neglected tropical diseases; news; programs; response; scale up; skin disorder; success; tool; trait; transmission process; vaccine candidate; vaccine development; vaccine-induced immunity

ABSTRACT Human onchocerciasis (ONCHO) is a major cause of infectious blindness, skin disease, and chronic disability, infecting many millions worldwide99% in Sub-Saharan Africaand resulting in widespread vision impairment and blindness. Caused by the filarial nematode Onchocerca volvulus (Ov), attempts to eliminate this neglected tropical disease via annual mass drug administration (MDA) with donated ivermectin (IVM) have proved largely ineffective, decreasing its incidence only 31% in the last 20 years. Optimists call for an additional 1.15 billion treatments to achieve elimination by 2045. Mathematical modelling and expert opinions are more pessimistic, indicating that ONCHO in Africa cannot be eliminated solely through MDA with IVM. Supporting their viewpoint is that IVM cannot be administered safely in Central Africa where the disease is co-endemic with Loa loa infections, and early evidence points to the possible emergence of IVM drug resistance. New tools are needed, such as a preventive vaccine to accelerate ONCHO elimination. Our goal is to develop a safe and effective prophylactic vaccine to protect vulnerable populations of children <5 living in endemic areas against Ov infections. Reducing the adult worm burden and possibly also fecundity will inexorably reduce microfilaridermia and pathology. The vaccine could also contribute to lower transmission rates and protect areas where local elimination may have been achieved, thus lowering the number of annual MDA with IVM, forestalling drug resistance, and ensuring the success of the existing MDA. We have already identified 2 Ov protective vaccine antigens (Ov-103 and Ov-RAL-2) with a proven production pathway and with efficacy in 2 small-animal models; they were protective as monovalent vaccines, and their efficacy was enhanced when the two monovalent vaccines were co-administered in separate locations (i.e. ONCHO vaccine). We seek now to leverage these achievements by advancing to the next stage on the critical path to Ov vaccine development. Our hypothesis is that an optimal ONCHO vaccine formulation can be identified by further employing the mouse model before testing it in naïve calves against a natural infection with O. ochengi, an infection system with a closely related parasite known to mimic immunologically the status of humans living in regions endemic for Ov. Notably, both vaccine antigens pose minimal risk of generating atopic responses in children <5 years of age who are naturally exposed to ONCHO; neither elicits significant functional IgE responses. We have 2 specific aims for meeting our goal: (1) Test in naïve calves under field conditions the efficacy of two ONCHO vaccine formulations against O. ochengi infection. (2) Establish immune correlates and mechanisms associated in mice with protective immunity induced by two ONCHO vaccine formulations. Ascertaining which of the 2 adjuvanted ONCHO vaccines (formulated with alum or with Advax-2 with or without alum) is more efficacious in the vaccinated calves, and the parallel elucidation of their immune correlates in the bovine and mouse models will position us to move the optimal ONCHO vaccine formulation to first-in-human trials.

抽象的 人类盘尾丝虫病 (ONCHO) 是导致传染性失明、皮肤病和慢性残疾的主要原因， 全球数百万人感染（撒哈拉以南非洲地区 99%），并导致广泛的视力障碍 和失明。由丝虫线虫盘尾丝虫 (Ov) 引起，试图消除这种被忽视的现象 通过年度大规模药物管理（MDA）和捐赠的伊维菌素（IVM）来控制热带疾病已在很大程度上得到证明 效果不佳，过去 20 年来其发病率仅降低了 31%。乐观者呼吁追加11.5亿美元 到2045年实现消除的治疗方法。数学模型和专家意见更加悲观， 表明仅通过 MDA 和 IVM 无法消除非洲的 ONCHO。支持他们的观点 是 IVM 无法在中非安全实施，因为该病与 Loa Loa 共同流行 感染，早期证据表明可能出现 IVM 耐药性。需要新工具， 例如加速消除 ONCHO 的预防性疫苗。我们的目标是开发一种安全有效的 预防性疫苗，保护生活在 Ov 流行地区的 5 岁以下儿童的弱势群体 感染。减少成虫负担以及可能的繁殖力将不可避免地减少微丝蚴病 和病理学。该疫苗还可能有助于降低传播率并保护当地有感染的地区 可能已经实现消除，从而降低 IVM 的年度 MDA 数量，预防药物 阻力，并确保现有 MDA 的成功。我们已经确定了2个Ov保护性疫苗 抗原（Ov-103 和 Ov-RAL-2）具有经过验证的生产途径，并且在 2 个小动物模型中有效； 它们作为单价疫苗具有保护性，并且当两种单价疫苗同时使用时，其功效会增强 疫苗在不同地点共同接种（即 ONCHO 疫苗）。我们现在寻求利用这些 在 Ov 疫苗开发的关键道路上推进到下一阶段，取得了重大成就。我们的假设是 可以通过进一步使用小鼠模型来确定最佳的 ONCHO 疫苗配方 在幼牛身上进行测试，以抵抗 O. o Chengi 的自然感染，这是一种与一种密切相关的感染系统 已知在免疫学上模仿生活在 Ov 流行地区的人类状况的寄生虫。值得注意的是，两者 疫苗抗原对 5 岁以下儿童产生特应性反应的风险极小。 自然暴露于ONCHO；两者均不会引起显着的功能性 IgE 反应。我们有 2 个具体目标 实现我们的目标：(1) 在野外条件下对幼牛犊测试两种 ONCHO 疫苗的功效 抗 O. ochei 感染的制剂。 (2) 建立小鼠免疫相关性和相关机制 具有由两种 ONCHO 疫苗制剂诱导的保护性免疫。确定 2 者中哪一个起辅助作用 ONCHO 疫苗（用明矾配制或与含有或不含明矾的 Advax-2 配制）在以下方面更有效： 接种疫苗的小牛，以及在牛和小鼠模型中平行阐明其免疫相关性将 使我们能够将最佳的 ONCHO 疫苗配方推向首次人体试验。