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/抽象。钩端螺旋体病是由致病性钩端螺旋体引起的一种全球重要的被忽视疾病。