Key Points Novel TLR triagonist platforms have adjuvant activity in vivo. The TLR triagonist adjuvants tune immune responses to subunit vaccination. Visual Abstract Coxiella burnetii is an obligate intracellular bacterium and the causative agent of Q fever. C. burnetii is considered a potential bioterrorism agent because of its low infectious dose; resistance to heat, drying, and common disinfectants; and lack of prophylactic therapies. Q-Vax, a formalin-inactivated whole-bacteria vaccine, is currently the only prophylactic measure that is protective against C. burnetii infections but is not U.S. Food and Drug Administration approved. To overcome the safety concerns associated with the whole-bacteria vaccine, we sought to generate and evaluate recombinant protein subunit vaccines against C. burnetii. To accomplish this, we formulated C. burnetii Ags with a novel TLR triagonist adjuvant platform, which used combinatorial chemistry to link three different TLR agonists together to form one adjuvanting complex. We evaluated the immunomodulatory activity of a panel of TLR triagonist adjuvants and found that they elicited unique Ag-specific immune responses both in vitro and in vivo. We evaluated our top candidates in a live C. burnetii aerosol challenge model in C56BL/6 mice and found that several of our novel vaccine formulations conferred varying levels of protection to the challenged animals compared with sham immunized mice, although none of our candidates were as protective as the commercial vaccine across all protection criteria that were analyzed. Our findings characterize a novel adjuvant platform and offer an alternative approach to generating protective and effective vaccines against C. burnetii.

中文翻译：

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用新型 TLR Triagonist 佐剂调整亚单位疫苗以产生针对伯内氏 Coxiellaburnetii 的保护性免疫反应

要点 新型 TLR 三角素平台在体内具有佐剂活性。TLR triagonist 佐剂调节对亚单位疫苗接种的免疫反应。视觉摘要 Coxiella burnetii 是一种专性细胞内细菌，也是 Q 热的病原体。由于感染剂量低，C.burnetii 被认为是一种潜在的生物恐怖剂；耐热、干燥和常用消毒剂；并且缺乏预防性治疗。Q-Vax 是一种福尔马林灭活的全细菌疫苗，是目前唯一可以预防伯内氏念珠菌感染的预防措施，但未获得美国食品和药物管理局的批准。为了克服与全细菌疫苗相关的安全问题，我们试图生成和评估针对 C.burnetii 的重组蛋白亚单位疫苗。为了实现这一点，我们制定了 C。burnetii Ags 具有一种新型 TLR 三角素佐剂平台，该平台使用组合化学将三种不同的 TLR 激动剂连接在一起形成一个佐剂复合物。我们评估了一组 TLR Triagonist 佐剂的免疫调节活性，发现它们在体外和体内都引发了独特的 Ag 特异性免疫反应。我们在 C56BL/6 小鼠的活 C.burnetii 气溶胶攻击模型中评估了我们的主要候选者，发现与假免疫小鼠相比，我们的几种新型疫苗制剂对受攻击的动物提供了不同程度的保护，尽管我们的候选者都没有在分析的所有保护标准中，作为商业疫苗的保护性。