Rational development of a vaccine against tick-borne rickettsioses

摘要 立克次体是一组节肢动物相关的专性细胞内革兰氏阴性细菌， 相关但可能导致危及生命的人类感染。蜱传立克次体病（Tick-borne Rickettsioses，TBRs） 由于发病率的增加和缺乏预防措施， 市售疫苗用于预防。因此，一种安全有效的结核分枝杆菌疫苗将是 这是确保国家预防这类疾病能力的重要资源。我们长久以来- 长期目标是开发安全有效的TBRs免疫预防的新方法。我们最近 已发表和初步研究表明，减毒活R. parkeri突变体3A 2赋予完全保护 在小鼠模型中对抗两种高毒力立克次体的致死性攻击，并伴随产生高滴度 IgG抗体对几种致病性立克次体的反应和显着升高的1型T细胞 记忆免疫这些发现支持了概念验证，即减毒活疫苗候选物可用于 为预防结核分枝杆菌的发生和研究疫苗诱导的记忆免疫提供了一条可行有效的途径。 因此，该R 01申请的目的是产生安全有效的减毒活疫苗 (LAV)确定LAV对同源和异源立克次体的保护效力 菌株，并从机制上确定疫苗引起的抗蜱保护的免疫相关性 TBRs的传播。为了实现这些目标，我们提出了三个具体目标，以测试中央 假设LAV将引发高质量的CD 8 + T记忆细胞和立克次体特异性中和， 作为安全有效的多价抗体， 候选疫苗目标1将优化R。帕克氏突变体的基因，以降低毒力，提高安全性， 维持免疫原性。目的2将确定遗传优化的R.帕克氏突变体 在针击和蜱传播动物模型中保护免受结核分枝杆菌感染。目标3将确定 疫苗诱导的针对TBRs的保护的免疫学相关性。在完成拟议的 研究中，我们希望确定第一个TBR的多价候选疫苗，并揭示TBR的新元素。 负责防止结核分枝杆菌自然传播的宿主免疫力。这将产生重大积极影响。 对人类健康的影响，因为它将提供最终开发安全， 有效和易处理的抗结核分枝杆菌疫苗。

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.