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 立克西亚是一组与节肢动物相关的，有规律的细胞内革兰氏阴性bakteria，它们是紧密的 相关的屁股会导致人类威胁生命的感染 由于已塑造已成已成的已培养者，越来越构成严重威胁的公共卫生 因此，可预防的商业疫苗。 一个重要的资源，可以确保国家的疾病危险。 术语目标是开发新的TBR安全性免疫预防的方法 发表和试点研究表明，活体衰减的R. Parkeri突变体3A2授予了全部保护 反对小鼠模型中两个高度耐利性立克的致命挑战，伴随着高滴度 IgG抗体对几种致病性立克物种的反应，并显着升高1型T细胞 记忆的免疫力。 可行有效的方法来预防TBR并研究疫苗诱导的对TBR的记忆免疫。 因此，R01应用程序的目标是生成安全有效的实时疫苗 （lav）反对TBR，定义LAV对同源和异质性Rickkettsial的保护作用 菌株，并机械地确定疫苗引诱的防护疫苗保护的免疫相关性 TBR的传播。 假设具有具有高质量CD8+ T记忆细胞和立克特异性中和的LAV 抗体保护TBR自然采集的抗体作为ASAFE和有效的多价 疫苗候选人1将在遗传上优化R. Parkeri Muts，以降低毒力，增强安全性 维持免疫原性。 防止针挑战和滴答传输动物模型中的TBR。 疫苗诱导的TBR的免疫学相关。 研究，我们希望定义第一个用于TBR和Revel的多价疫苗候选者，并揭示 主机不受TBR自然传播的影响。 对人类健康的影响，因为它将提供最终开发安全的基本信息 对TBR的有效疫苗和可拖动疫苗。