Rational development of a vaccine against tick-borne rickettsioses

蜱传立克次体病疫苗的合理研制

• 批准号: 10673846
• 负责人: Rong Megan Fang
• 金额: $ 78.34万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673846
• 关键词: Animal Model; Animals; Antibodies; Arthropods; Attenuated; Attenuated Vaccines; Bacteria; Bacteriophages; Brazil; Bypass; CD8-Positive T-Lymphocytes; CD8B1 gene; Case Fatality Rates; Cells; Cellular Immunity; Development; Diagnostic Procedure; Disease; Dose; Elements; Ensure; Evaluation; Experimental Models; Genes; Genetic Engineering; Goals; Gram-Negative Bacteria; Hand; Health; Human; Humoral Immunities; Immune; Immune signaling; Immunity; Immunization; Immunize; Immunoglobulin G; Immunologics; In Vitro; Incidence; Infection; Integrase; Interferon Type II; Interferons; Intravenous; Left; Lesion; Licensing; Life; Memory; Modeling; Mus; Mutagens; Needles; Pathogenicity; Pathologic; Phenotype; Pilot Projects; Polyvalent Vaccine; Prevention; Proteins; Public Health; Publishing; Reporting; Research; Resources; Rickettsia; Rickettsia Infections; Rickettsia parkeri; Rifampicin resistance; Rocky Mountain Spotted Fever; Role; Safety; Signal Transduction; T memory cell; TLR4 gene; Testing; Ticks; United States; Vaccination; Vaccine Design; Vaccines; Virulence; Virulent; anti-tick vaccine; cross immunity; disease transmission; efficacy evaluation; immunogenicity; immunoprophylaxis; innovation; insight; mouse model; mutant; neutralizing antibody; novel; novel strategies; novel vaccines; pathogen; prevent; protective efficacy; rational design; spotted fever; tick bite; tick transmission; tick-borne; transmission process; vaccine access; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial; vaccine-induced immunity; virulence gene

Abstract Rickettsiae are a group of arthropod-associated, obligately intracellular Gram-negative bacteria that are closely related but potentially cause life-threatening infection in humans. Tick-borne rickettsioses (TBRs) are increasingly posing serious threat to the public health in the US due to increased incidence and lack of commercially available vaccine for prevention. Therefore, a safe and effective vaccine against TBRs will be an important resource that will ensure the Nation’s capability to prevent this group of diseases. Our long- term goal is to develop novel approaches for safe and effective immunoprophylaxis of TBRs. Our recently published and pilot studies demonstrated that live-attenuated R. parkeri mutant 3A2 conferred full protection against lethal challenge of two highly virulent rickettsiae in mouse models, accompanied by generating high titers of IgG antibodies reactive against several pathogenic rickettsial species and significantly elevated type 1 T cell memory immunity. These findings support the proof-of-concept that live-attenuated vaccine candidate serves a feasible and effective approach to prevent TBRs and study vaccine-induced memory immunity against TBRs. Thus, the objectives of this R01 application are to generate a safe and efficacious live-attenuated vaccine (LAV) against TBRs, define the protective efficacy of LAV against homologous and heterologous rickettsial strains, and mechanistically determine the immune correlates of vaccine-elicited protection against tick transmission of TBRs. To achieve these objectives, we propose three specific aims to test the central hypothesis that the LAV will elicit high quality CD8+ T memory cells and rickettsiae-specific neutralizing antibodies to confer complete protection against natural acquisition of TBRs as a safe and efficacious polyvalent vaccine candidate. Aim 1 will optimize R. parkeri mutants genetically to reduce virulence, enhance safety while maintaining immunogenicity. Aim 2 will define the efficacy of genetically optimized R. parkeri mutants in protecting against TBRs in both needle-challenge and tick transmission animal models. Aim 3 will identify the immunological correlates of vaccine-induced protection against TBRs. Upon the completion of the proposed research, we expect to define the first multivalent vaccine candidate for TBR and reveal the novel elements of host immunity responsible for prevention from natural transmission of TBRs. This will have significant positive effects on human health because it will provide the basic information required to ultimately develop a safe, effective, and tractable vaccine against TBRs.

抽象的 立克次体是一组与节肢动物相关的、专性细胞内的革兰氏阴性细菌，它们与节肢动物密切相关。 相关但可能导致人类感染蜱传立克次体病（TBR）。 由于发病率增加和缺乏预防措施，该病对美国的公共卫生构成日益严重的威胁 因此，针对 TBR 的安全有效的疫苗将是可用于预防的。 将确保国家有能力预防此类疾病的重要资源。 我们最近的目标是开发安全有效的 TBR 免疫预防新方法。 已发表的初步研究表明，帕克里氏菌减毒活突变体 3A2 可提供全面保护 在小鼠模型中对抗两种高毒力立克次体的致命挑战，同时产生高滴度 IgG 抗体对多种致病性立克次体有反应，并且 1 型 T 细胞显着升高 这些发现支持了减毒活疫苗候选物可发挥作用的概念验证。 预防 TBR 的可行且有效的方法并研究疫苗诱导的针对 TBR 的记忆免疫。 因此，R01应用的目标是产生一种安全有效的减毒活疫苗 (LAV) 针对 TBR，定义 LAV 对同源和异源立克次体的保护功效 菌株，并从机制上确定疫苗引起的蜱虫保护的免疫相关性 为了实现这些目标，我们提出了三个具体目标来测试中央。 假设 LAV 将引发高质量的 CD8+ T 记忆细胞和立克次体特异性中和 抗体作为安全有效的多价抗体，可提供全面的保护，防止 TBR 的自然获得 目标 1 将从基因角度优化 R. parkeri 突变体，以降低毒力、增强安全性。 目标 2 将定义遗传优化的 R. parkeri 突变体在免疫原性方面的功效。 在针刺攻击和蜱传播动物模型中预防 TBR 的目标 3 将确定 TBR。 完成所提议的疫苗诱导的 TBR 保护的免疫学相关性。 研究中，我们期望定义第一个 TBR 多价候选疫苗，并揭示其新元素 宿主免疫负责预防 TBR 的自然传播，这将具有显着的积极作用。 对人类健康的影响，因为它将提供最终开发安全、 针对 TBR 的有效且易于处理的疫苗。