Leptospirosis Vaccine Development

钩端螺旋体病疫苗开发

• 批准号: 10698579
• 负责人: Carla Devillers
• 金额: $ 30万
• 依托单位: LUNA BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698579
• 关键词: Adjuvant; Adverse effects; Affect; Animal Model; Animal Testing; Animals; Antibodies; Antibody titer measurement; Antigens; Bacterial Vaccines; Biological Assay; Biological Markers; Biological Process; Canis familiaris; Case Fatality Rates; Cessation of life; Chemicals; Cholera; Clinical; Clinical Trials; Connecticut; Country; Cytotoxin; Data; Development; Disease; Dose; Economics; Escherichia coli; Exotoxins; Fermentation; Frequencies; Genetic; Hamsters; Health; Human; Immune response; Immunity; Immunoglobulin G; In Vitro; Incidence; Inclusion Bodies; Income; Infection; International; Kidney; Knowledge; Laboratories; Lead; Legal patent; Leptospira; Leptospira interrogans; Leptospirosis; Letters; Licensure; Liver; Livestock; Measures; Mediating; Mediation; Military Personnel; Modeling; Molecular Conformation; Morbidity - disease rate; Mus; Mutate; Occupations; Organism; Outcome; Pathogenicity; Persons; Phase; Prausnitz-Kustner Test; Process; Protein Family; Proteins; Public Health; Publishing; Recombinant Proteins; Recombinants; Regimen; Regulatory Pathway; Reporting; Risk; Safety; Sanitation; Security; Severities; Small Business Technology Transfer Research; Structural Models; Technology; Testing; Time; Toxicology; Toxin; Toxoids; Typhoid Fever; Universities; Urbanization; Vaccination; Vaccine Antigen; Vaccines; Virulence; Water; Work; Zoonotic Bacterial Infection; burden of illness; climate change; clinical development; commercial application; commercialization; companion animal; cross reactivity; data modeling; disulfide bond; experimental study; extracellular; immunogenicity; low and middle-income countries; mortality; neglect; novel; novel vaccines; pilot lot production; pre-clinical; prevent; primary outcome; protective efficacy; protein purification; prototype; vaccine access; vaccine candidate; vaccine development; vaccine trial

Summary/abstract. Leptospirosis is a globally important neglected disease caused by pathogenic Leptospira. It is estimated to cause more than 1 million global cases annually with a 5-20% case-fatality rate, significant morbidity, and important public health consequences. Currently there is no safe and effective vaccine to prevent human leptospirosis. LeptoX, Inc. proposes to develop the first human leptospirosis vaccine. Pathogenic Leptospira are extracellular organisms, but mechanisms by which they exert their pathogenetic effects were unclear until our discovery of the leptospiral Virulence Modifying (VM) proteins’ cytotoxin function, followed by our demonstration of the potential for VM proteins to be the antigen components of a pan- leptospirosis vaccine. Severe human leptospirosis has almost exclusively been reported to be due to strains of L. interrogans. This proposal focuses on a L. interrogans VM protein-based leptospirosis vaccine, although cross species protection may be possible. Recently published animal model data demonstrated that as few as two recombinant VM proteins provide robust cross-serovar protection from disease/death after lethal L. interrogans challenge in mice. These data indicate strong potential for VM proteins as pan-L. interrogans protective antigens. In this Phase I, we will optimize dose, delivery and composition of recombinant E. coli- produced VM proteins in combination with human-compatible adjuvant to determine protective efficacy in the lethal hamster challenge model of leptospirosis. In Aim 1, we will produce recombinant tagless VM protein immunogens, analyze their immunogenicity and, in the standard hamster model, compare their protective efficacy to standard, commercially available bacterin vaccines; contingency experiments will also assess chemically inactivated wild type proteins and proteins purified from inclusion bodies as alternative forms of the VM protein immunogen; structural modeling suggests that VM protein disulfide bond-dependent conformation may not be critical for antigenicity. In Aim 2, we will compare wild type and genetically mutated toxoid-forms of tagless, recombinant E. coli-produced VM proteins in the lethal hamster model. Protective immune responses for both Aims will be assessed by protection from clinical disease and death and by determination of bacterial load and viability in liver and kidney at various time points. Biomarkers of protective immunity (i.e., antibody titers against the prototype vaccine antigens and cross-reactivity among serovars and between different Leptospira species’ VM proteins) will be measured; the putative antibody-mediated protective mechanism of immunity will be tested by passive transfer experiments. At the end of this Phase I project, we will have developed final pan-L. interrogans VM-protein-based vaccine prototypes for further animal testing. Following Phase I, this prototype will be tested in dog clinical trials, which will lead to a first commercial product for these companion animals. Animal vaccine development will lead towards FDA IND submission for a human leptospirosis vaccine, upon which strategic partnerships for leptospirosis vaccine development will be formed.

摘要/摘要。钩端螺旋体是一种由致病性钩端螺旋体引起的全球重要忽视疾病。 据估计，每年造成超过100万个全球案例，案件策略率为5-20％ 发病率和重要的公共卫生后果。目前没有安全有效的疫苗 预防人钩端螺旋体病。 Leptox，Inc。开发第一种人钩端螺旋体病疫苗的提案。 致病性钩端螺旋体是细胞外生物，但它们发挥致病性的机制 效果尚不清楚，直到我们发现钩端螺旋力毒力修饰（VM）蛋白的细胞毒素功能， 其次是我们证明VM蛋白是泛元素成分的潜力 钩端螺旋体病疫苗。据报道，严重的人钩端螺旋体病几乎完全是由于菌株 L. erentogans。该提案的重点是基于VM蛋白质蛋白质的钩端螺旋体病疫苗，尽管 跨物种保护是可能的。最近发布的动物模型数据表明，很少 两种重组VM蛋白可为致命Lethal L后的疾病/死亡提供强大的跨锯齿保护。 探索者在小鼠中挑战。这些数据表明VM蛋白作为PAN-L的强大潜力。讯问 保护性抗原。在这一第一阶段，我们将优化重组大肠杆菌的剂量，递送和组成 产生的VM蛋白与人类兼容的调整结合起来，以确定保护性效率 致命的仓鼠挑战钩端螺旋体病模型。在AIM 1中，我们将产生重组无标记的VM蛋白 免疫原子，分析其免疫原性，并在标准仓鼠模型中比较其受保护的 标准可获得的细菌疫苗的效率；应急实验还将评估 化学灭活的野生型蛋白质和蛋白质从包含体纯化为替代形式 VM蛋白免疫原；结构建模表明VM蛋白二硫键依赖性构象 对于抗原性可能并不重要。在AIM 2中，我们将比较野生型和遗传突变的毒素形式 致命的仓鼠模型中无标记的重组大肠杆菌产生的VM蛋白。 保护性免疫调查 因为这两个目标将通过保护临床疾病和死亡以及通过细菌的测定来评估 在不同时间点肝脏和肾脏的负载和生存能力。保护性免疫的生物标志物（即抗体 针对原型疫苗抗原和血清中的交叉反应性和不同的滴度 将测量钩端螺旋体的VM蛋白）；推定的抗体介导的保护机制 免疫力将通过被动转移实验测试。在这个阶段I项目结束时，我们将拥有 开发了最终pan-l。基于VM蛋白质的探究疫苗原型用于进一步的动物测试。下列的 第一阶段，该原型将在狗临床试验中进行测试，这将导致第一个商业产品 伴侣动物。动物疫苗的开发将导致FDA IND提交人类 钩端螺旋病疫苗，将形成钩端螺旋体病疫苗发育的战略伙伴关系。