Abstract：
Mucosal vaccines have the potential to elicit protective immune responses at the point of entry of respiratory pathogens, thus preventing even the initial seed infection. Unlike licensed injectable vaccines, mucosal vaccines comprising protein subunits are only in development. One of the primary challenges associated with mucosal vaccines has been identifying and characterizing safe yet effective mucosal adjuvants that can effectively prime multi-factorial mucosal immunity. In this study, we tested NanoSTING, a liposomal formulation of the endogenous activator of the stimulator of interferon genes (STING) pathway, cyclic guanosine adenosine monophosphate (cGAMP), as a mucosal adjuvant. We formulated a vaccine based on the H1 antigen (fusion protein of Ag85b and ESAT-6) adjuvanted with NanoSTING. Intranasal immunization of NanoSTING-H1 elicited a strong T-cell response in the lung of vaccinated animals characterized by (a) CXCR3+ KLRG1- lung resident T cells that are known to be essential for controlling bacterial infection, (b) IFNγ-secreting CD4+ T cells which is necessary for intracellular bactericidal activity, and (c) IL17-secreting CD4+ T cells that can confer protective immunity against multiple clinically relevant strains of Mtb. Upon challenge with aerosolized Mycobacterium tuberculosis Erdman strain, intranasal NanoSTING-H1 provides protection comparable to subcutaneous administration of the live attenuated Mycobacterium bovis vaccine strain Bacille-Calmette-Guérin (BCG). Our results indicate that NanoSTING adjuvanted protein vaccines can elicit a multi-factorial immune response that protects from infection by M. tuberculosis.
摘要：
粘膜疫苗有可能在呼吸道病原体进入点引发保护性免疫反应，从而防止甚至最初的种子感染。与许可的注射疫苗不同，包含蛋白质亚基的粘膜疫苗仅在开发中。与粘膜疫苗相关的主要挑战之一是鉴定和表征可以有效引发多因素粘膜免疫的安全而有效的粘膜佐剂。在这项研究中,我们测试了NanoSTING,干扰素基因刺激因子（STING）途径的内源性激活剂的脂质体制剂，环鸟苷一磷酸腺苷（cGAMP），作为粘膜佐剂。我们基于用NanoSTING佐剂化的H1抗原(Ag85b和ESAT-6的融合蛋白)配制疫苗。NanoSTING-H1的鼻内免疫在接种疫苗的动物的肺中引起强烈的T细胞应答,其特征在于(a)已知对于控制细菌感染是必需的CXCR3+KLRG1-肺驻留T细胞,(b)分泌IFNγ的CD4+T细胞，这是细胞内杀菌活性所必需的，和(c)分泌IL17的CD4+T细胞,其可以赋予针对多种临床相关的Mtb菌株的保护性免疫。在用雾化结核分枝杆菌Erdman菌株攻击后，鼻内NanoSTING-H1提供与皮下施用活的减毒牛分枝杆菌疫苗菌株Bacille-Calmette-Guérin（BCG）相当的保护。我们的结果表明，NanoSTING佐剂化的蛋白质疫苗可以引发多因素免疫反应，保护免受结核分枝杆菌感染。
