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：
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
项目类别：
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

项目摘要

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.

抽象的人类的尾c（Oncho）是感染性失明，皮肤病和慢性残疾的主要原因，在撒哈拉以南非洲地区感染了全球数百万的99％，并导致视力障碍。和失明。由丝状线虫OnChocerca Volvulus（OV）引起的，试图消除这种被忽视的通过捐赠的IVRMECTIN（IVM）通过年度大众药物管理（MDA）的热带疾病已证明很大程度上被证明是无效，在过去20年中，其发病率仅降低31％。乐观主义者要求另外11.5亿在2045年之前实现消除的治疗方法。数学建模和专家意见更为悲观，表明不能仅通过IVM通过MDA消除非洲的Oncho。支持他们的观点是否不能在疾病与LOA LOA共同流行的中非安全地管理IVM 感染和早期证据表明IVM耐药性可能出现。需要新工具，例如预防性疫苗加速消除。我们的目标是发展安全有效预防性疫苗保护居住在地方性地区<5的弱势儿童遭受侵害的人群免受OV 感染。减少成年蠕虫燃烧，并可能繁殖力避免降低微椰胶菌和病理。疫苗还可能有助于降低传输速率，并保护本地的区域可以实现消除，从而减少IVM的年度MDA数量，阻止药物抵抗，并确保现有MDA的成功。我们已经鉴定出2 OV受保护的疫苗抗原（OV-103和OV-ral-2）具有良好的生产途径，并且在2个小动物模型中具有效率；它们被保护为单价疫苗，并在两个单价时提高了效率疫苗在单独的位置（即Oncho疫苗）共同采用。我们现在寻求利用这些通过前进到下一阶段的成就，进入了OV疫苗开发的关键途径。我们的假设是可以通过在用幼稚的犊牛对其进行测试，以与O. o. o. o. o. o. o. o. o. o. o. o. o. o. o. o. o. o. o. o. o. 寄生虫在模仿免疫学上已知的人类居住在OV内部人体中的人类状态。值得注意的是疫苗抗原在<5岁的儿童中产生特应反应的风险很小自然暴露于Oncho；两者都没有引起重大的功能IgE响应。我们有2个具体目标实现我们的目标：（1）在野外条件下在幼稚犊牛中进行测试。两种Oncho疫苗的效率针对O. ochengi感染的公式。（2）建立小鼠相关的免疫相关性和机制由两种Oncho疫苗公式引起的保护性免疫。确定2个调整后的哪个 Oncho疫苗（用明矾或有或没有明矾的Advax-2配制）在疫苗接种的犊牛以及在牛和小鼠模型中的免疫成分平行阐明将将我们定位为将最佳的Oncho疫苗配方转移到首次人类试验中。