Misiak Alicja, Leuzzi Rosanna, Allen Aideen C, Galletti Bruno, Baudner Barbara C, D'Oro Ugo, O'Hagan Derek T, Pizza Mariagrazia, Seubert Anja, Mills Kingston H G
Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
GSK Vaccines, Via Fiorentina 1, Siena 53100, Italy.
Vaccine. 2017 Sep 18;35(39):5256-5263. doi: 10.1016/j.vaccine.2017.08.009. Epub 2017 Aug 18.
A resurgence of whooping cough (pertussis) has been observed in recent years in a number of developed countries, despite widespread vaccine coverage. Although the exact reasons of the recurrence of pertussis are not clear, there are a number of potential causes, like antigenic variation in the circulating strains of Bordetella pertussis, changes in surveillance and diagnostic tools, and potential differences in protection afforded by current acellular pertussis (aP) vaccines compared to more reactogenic whole cell (wP) vaccines, which they replaced. Studies in animal models have shown that induction of cellular as well as humoral immune responses are key to conferring effective and long lasting protection against B. pertussis. wP vaccines induce robust Th1/Th17 responses, which are associated with good protection against lung infection. In contrast, aP vaccines induce mixed Th2/Th17 responses. One research option is to modify current aP vaccines with the intention of inducing protective T cell responses, without compromising on their low reactogenicity profile. Here we found that formulation of an aP vaccine with a novel adjuvant based on a Toll-like receptor 7 agonist (TLR7a) adsorbed to aluminum hydroxide (alum) enhanced B. pertussis-specific Th1 and Th17 responses and serum IgG2a/b antibodies, which had greater functional capacity than those induced by aP formulated with alum alone. Furthermore, addition of a TLR7a enhanced the protective efficacy of the aP vaccine against B. pertussis aerosol challenge; protection was comparable to that of a wP vaccine. These findings suggest that alum-TLR7a is a promising adjuvant for clinical development of next generation pertussis vaccines.
尽管疫苗接种覆盖率很高，但近年来在一些发达国家仍观察到百日咳（pertussis）疫情有所反弹。虽然百日咳复发的确切原因尚不清楚，但有多种潜在因素，如百日咳博德特氏菌（Bordetella pertussis）流行菌株的抗原变异、监测和诊断工具的变化，以及目前的无细胞百日咳（aP）疫苗与被其取代的反应原性更强的全细胞（wP）疫苗相比，在提供保护方面可能存在差异。动物模型研究表明，诱导细胞免疫和体液免疫反应是获得针对百日咳博德特氏菌有效且持久保护的关键。wP疫苗可诱导强烈的Th1/Th17反应，这与对肺部感染的良好保护相关。相比之下，aP疫苗诱导的是混合Th2/Th17反应。一种研究选择是对现有的aP疫苗进行改造，目的是诱导产生保护性T细胞反应，同时不影响其低反应原性特征。在此，我们发现，基于吸附于氢氧化铝（明矾）的Toll样受体7激动剂（TLR7a）构建的新型佐剂配制aP疫苗，可增强百日咳博德特氏菌特异性Th1和Th17反应以及血清IgG2a/b抗体，这些抗体的功能能力比仅用明矾配制的aP疫苗诱导产生的抗体更强。此外，添加TLR7a可增强aP疫苗对百日咳博德特氏菌气溶胶攻击的保护效力；其保护效果与wP疫苗相当。这些发现表明，明矾-TLR7a是下一代百日咳疫苗临床开发中一种很有前景的佐剂。
