Enhancing efficacy of pertussis vaccines

明矾是用于包括波氏杆菌在内的细菌病原体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，它可能不是最有效的 当该机制涉及Th1型免疫反应时，佐剂可产生长期保护，因为它 歪曲抗体和T细胞对Th2的反应。由于明矾能激活强烈的抗原特异性反应， 在短期内提供保护，利用这些特性和一种塑造免疫的佐剂 Th1/Th17型反应的全套反应可能会引发更具保护性的反应，从而实现终生 豁免权。 尽管疫苗覆盖率很高，但百日咳在美国、欧洲和其他地区的发病率正在上升。 国家。与全细胞百日咳疫苗相比，目前的无细胞百日咳疫苗只有部分有效。 疫苗(WPV)。然而，WPV的反应性限制了它的使用。我们鉴定出一种外膜蛋白， 波氏定植因子A(BCFA)，并证明其具有佐剂活性和增强抗体。 对蛋白质抗原的反应。在百日咳杆菌鼻内感染小鼠模型中，我们证明了添加 针对APV的BCFA可诱导Th1偏斜的抗体应答，并提供更好的抗感染保护。我们 假设明矾和BCFA的联合活性将导致保护作用的协同增强 小鼠对百日咳杆菌的免疫应答。 在特定的目标1中，我们将测试BCFA单独和与明矾一起激活的信号通路。 我们假设，与这些佐剂的联合治疗将重塑激活的细胞因子的图谱。 由炎性细胞产生。在具体目标2中，我们将确定与BCFA联合免疫如何 明矾可改变百日咳杆菌抗原的抗体表型和T细胞反应。在具体目标3中，我们 假设明矾和BCFA联合诱导的Th1/Th17偏斜免疫反应将 结果更好地清除了百日咳杆菌的挑战，并保持了长久的免疫记忆。这一假说将 通过确定明矾/BCFA联合免疫对百日咳杆菌从 小鼠呼吸道。 影响：我们已经确定了一种新的佐剂，BCFA，并假设由 明矾将被BCFA塑造成Th1型反应，从而对百日咳杆菌提供更好的保护 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。 以求保护。

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.