Enhancing efficacy of pertussis vaccines

明矾是用于细菌病原体（包括博德特氏菌）的无细胞疫苗中使用最广泛的佐剂 百日咳，百日咳或百日咳的病原体。然而，这可能不是最有效的 当机制涉及 Th1 型免疫反应时，佐剂可引起长期保护，因为它 使抗体和 T 细胞反应偏向 Th2。由于明矾能激活强烈的抗原特异性反应 通过利用这些特性与塑造免疫的佐剂，在短期内提供保护 针对 Th1/Th17 型反应的全部功能可能会引发更具保护性的反应，从而赋予终生 免疫力。 尽管疫苗覆盖率很高，但美国、欧洲和其他国家的百日咳发病率仍在增加 国家。与全细胞百日咳疫苗相比，目前的无细胞百日咳疫苗（aPV）仅部分有效 疫苗（wPV）。然而，wPV 的反应原性限制了其使用。我们鉴定出一种外膜蛋白， 博德特氏菌定植因子 A (BcfA)，并显示其具有佐剂活性并增强抗体 对蛋白质抗原的反应。在百日咳博德特氏菌感染的鼻内鼠模型中，我们发现添加 BcfA 与 aPV 结合可诱导 Th1 偏向抗体反应，并提供更好的感染保护。我们 假设明矾和 BcfA 的组合活性将导致保护性的协同增强 小鼠针对百日咳博德特氏菌的免疫反应。 在具体目标 1 中，我们将单独测试 BcfA 以及与明矾一起激活的信号通路。 我们假设这些佐剂的联合治疗将重塑活化细胞因子的分布 由炎症细胞产生。在具体目标 2 中，我们将确定如何与 BcfA 联合免疫 明矾改变抗体表型和 T 细胞对百日咳博德特氏菌抗原的反应。在具体目标 3 中，我们 假设明矾和 BcfA 组合诱导的 Th1/Th17 免疫反应会发生偏差 导致更好地清除百日咳博德特氏菌攻击和长期免疫记忆。这个假设将 通过确定明矾/BcfA联合免疫对百日咳博德特氏菌从百日咳博德特氏菌清除的影响来进行测试 鼠呼吸道。 影响：我们已经确定了一种新型佐剂 BcfA，并假设由 明矾将通过 BcfA 形成 Th1 型反应，从而提供更好的针对百日咳博德特氏菌的保护 感染。这种佐剂组合可能适用于 Th1 型免疫很重要的其他疾病 为了保护。

Alum is the most widely used adjuvant in acellular vaccines for bacterial pathogens including Bordetella pertussis, the causative agent of pertussis or whooping cough. However, it may not be the most effective adjuvant to elicit long-term protection when the mechanism involves Th1-type immune responses, since it skews antibody and T cell responses towards Th2. Since alum activates strong antigen-specific responses and provides protection in the short term, leveraging these properties with an adjuvant that shapes the immune repertoire towards a Th1/Th17-type response may elicit a more protective response that confers life-long immunity. Despite high vaccine coverage, the incidence of pertussis is increasing in the USA, Europe and other countries. The current acellular pertussis vaccines (aPV) are only partly effective, compared with whole cell vaccines (wPV). However, the reactogenicity of wPV limits its use. We identified an outer membrane protein, Bordetella Colonization Factor A (BcfA), and show that it has adjuvant activity and enhances antibody responses to protein antigens. In an intranasal murine model of B. pertussis infection, we show that addition of BcfA to the aPV induces Th1-skewed antibody responses and provides better protection against infection. We hypothesize that the combined activity of alum and BcfA will result in synergistic enhancement of protective immune responses in mice against B. pertussis. In Specific Aim 1, we will test the signaling pathways activated by BcfA, alone and together with alum. We hypothesize that combination treatment with these adjuvants will reshape the profile of activated cytokines produced by inflammatory cells. In Specific Aim 2, we will determine how combined immunization with BcfA and alum alters the phenotype of antibody and T cell responses to B. pertussis antigens. In Specific Aim 3, we hypothesize that the Th1/Th17 skewed immune responses induced by the combination of alum and BcfA will result in better clearance of a B. pertussis challenge, and long-lived immunologic memory. This hypothesis will be tested by determining the effect of combined alum/BcfA immunization on B. pertussis clearance from the murine respiratory tract. IMPACT: We have identified a novel adjuvant, BcfA, and hypothesize that the potent responses induced by alum will be shaped to a Th1 type response by BcfA thereby providing better protection against B. pertussis infection. This adjuvant combination may be applicable to other diseases where Th1 type immunity is important for protection.