School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, 2006 NSW, Australia; Tuberculosis Research Program, Centenary Institute, The University of Sydney, 2006 NSW, Australia.
Department of Endocrinology, Flinders University, Adelaide, Australia; Vaxine Pty Ltd, Adelaide 5042, Australia.
Vaccine. 2021 Apr 1;39(14):1990-1996. doi: 10.1016/j.vaccine.2021.02.041. Epub 2021 Mar 11.
The development of safe and effective adjuvants is a critical goal of vaccine development programs. In this report, we defined the immunostimulatory profile and protective effect against aerosol Mycobacterium tuberculosis infection of vaccine formulations incorporating the semi-crystalline adjuvant δ-inulin (Advax). Advax formulated with CpG oligonucleotide and the QS-21 saponin (Advax) was the most effective combination, demonstrated by the capacity of CysVac2/Advax to significantly reduce the bacterial burden in the lungs of M. tuberculosis-infected mice. CysVac2/Advax protection was associated with rapid influx of neutrophils, macrophages and monocytes to the site of vaccination and the induction of antigen-specific IFN-γ/IL-2/TNF polyfunctional CD4 T cells in the lung. When compared to the highly potent adjuvant combination of monophosphoryl lipid A and dimethyldioctadecylammonium bromide (MPL/DDA), Advax imparted a similar level of protective efficacy yet without the profound stimulation of inflammatory cytokines and vaccination site ulceration observed with MPL/DDA. Addition of DDA to CysVac2/Advax further improved the protective effect of the vaccine, which correlated with increased polyfunctional CD4 T cells in the lung but with no increase in vaccine reactogenicity. The data demonstrate that Advax formulations can decouple protective tuberculosis immunity from reactogenicity, making them ideal candidates for human application.
开发安全有效的佐剂是疫苗开发计划的一个关键目标。在本报告中，我们定义了免疫刺激特征和对包含半结晶佐剂 δ-菊糖（Advax）的疫苗制剂针对气溶胶分枝杆菌结核感染的保护作用。与 CpG 寡核苷酸和 QS-21 皂苷（Advax）联合使用的 Advax 是最有效的组合，这表现在 CysVac2/Advax 能够显著降低感染结核分枝杆菌的小鼠肺部的细菌负荷。CysVac2/Advax 的保护作用与中性粒细胞、巨噬细胞和单核细胞迅速涌入疫苗接种部位以及在肺部诱导抗原特异性 IFN-γ/IL-2/TNF 多功能 CD4 T 细胞有关。与单磷酰脂质 A 和二甲基双十八烷基溴化铵（MPL/DDA）这一强效佐剂组合相比，Advax 赋予了类似水平的保护效力，但没有 MPL/DDA 观察到的促炎细胞因子的强烈刺激和疫苗接种部位溃疡。在 CysVac2/Advax 中添加 DDA 进一步提高了疫苗的保护作用，这与肺部多功能 CD4 T 细胞的增加有关，但疫苗反应原性没有增加。这些数据表明，Advax 制剂可以将保护性结核病免疫与反应原性分离，使其成为人类应用的理想候选物。
