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.

摘要 人类盘尾丝虫病(ONCHO)是传染性失明、皮肤病和慢性残疾的主要原因， 感染全球数百万99%在撒哈拉以南非洲并导致广泛的视力障碍 和失明。由丝虫线虫引起的，试图消除这一被忽视的 通过年度大规模药物管理(Mda)和捐赠的伊维菌素(Ivm)治疗热带疾病已被证明在很大程度上。 无效，在过去20年中，其发病率仅下降了31%。乐观主义者呼吁再增加11.5亿 到2045年实现消除的治疗方法。数学模型和专家意见更悲观， 这表明非洲的ONCHO不能仅通过使用IVM的丙二醛来消除。支持他们的观点 IVM在中部非洲不能安全使用，因为那里的疾病与Loa Loa共同流行 感染，早期证据表明可能出现IVM耐药性。需要新的工具， 例如，一种预防性疫苗，以加速消除ONCHO。我们的目标是开发一种安全有效的 预防接种疫苗保护疫区儿童弱势人群的研究 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虫病。 和病理学。疫苗还有助于降低传播率，并保护当地 可能已经实现了消除，从而降低了IVM的年度丙二醛数量，预防了药物 阻力，并确保现有的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)，具有已证实的生产途径，并在2个小动物模型中有效； 它们作为单价疫苗具有保护性，当两种单价疫苗 在不同地点共同接种疫苗(即ONCHO疫苗)。我们现在寻求利用这些 通过在开发卵子疫苗的关键道路上进入下一阶段而取得的成就。我们的假设是 通过进一步使用之前的小鼠模型，可以确定最佳的ONCHO疫苗配方 在幼稚的小牛身上进行测试，以对抗自然感染oochengi，这是一种与 已知的在免疫学上模仿生活在卵子流行区的人类状态的寄生虫。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最小 自然暴露于ONCHO；两者都不会引起显著的功能性IgE反应。我们有两个具体的目标 达到我们的目标：(1)在野外条件下对幼犊进行两种ONCHO疫苗的效力测试 防治华支睾吸虫感染的制剂。(2)建立小鼠免疫相关因素及相关机制 具有由两种ONCHO疫苗配方诱导的保护性免疫。确定这两种佐剂中的哪一种 ONCHO疫苗(用明矾或用Advax-2配制，加或不加明胶)对儿童更有效 在牛和小鼠模型中对其免疫相关性的平行阐明将 让我们将最优的ONCHO疫苗配方转移到第一次人体试验中。