Chakraborty Subhra, Randall Arlo, Vickers Tim J, Molina Doug, Harro Clayton D, DeNearing Barbara, Brubaker Jessica, Sack David A, Bourgeois A Louis, Felgner Philip L, Liang Xiaowu, Mani Sachin, Wenzel Heather, Townsend R Reid, Gilmore Petra E, Darsley Michael J, Rasko David A, Fleckenstein James M
1Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
2Antigen Discovery, Inc. (ADI), Irvine, CA USA.
NPJ Vaccines. 2019 Aug 28;4:37. doi: 10.1038/s41541-019-0131-7. eCollection 2019.
Enterotoxigenic (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance.
产肠毒素大肠杆菌（ETEC）感染是低收入和中等收入国家严重腹泻病的常见病因。减毒活疫苗ACE527（佐剂为双突变不耐热毒素（dmLT））在人类志愿者中对ETEC攻击提供了明确但部分的保护。相比之下，最初的野生型ETEC攻击能完全保护机体免受同源再次攻击时的严重腹泻。为了研究保护的决定因素，将疫苗抗原含量与野生型ETEC进行比较，并使用蛋白质组微阵列评估疫苗接种和ETEC攻击后的免疫反应。尽管对疫苗的分子分析证实了靶向经典抗原的表达，但相对于野生型ETEC，疫苗株在鞭毛抗原产生方面存在缺陷，无运动能力，且缺乏EtpA黏附素的产生。同样，接种疫苗±dmLT引发了对靶向经典抗原的反应，但相对于野生型攻击，疫苗对一些潜在保护性非经典抗原（包括EtpA和YghJ金属蛋白酶）的反应减弱或缺失。这些研究突出了疫苗和野生型ETEC抗原含量的重要差异，并提醒人们注意不同的免疫特征，这些特征可为保护相关性的研究提供信息，并指导针对这些具有全球重要性的病原体的疫苗抗原选择。
