Devera T Scott, Lang Gillian A, Lanis Jordi M, Rampuria Pragya, Gilmore Casey L, James Judith A, Ballard Jimmy D, Lang Mark L
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Oklahoma Clinical and Translational Science Institute, Oklahoma City, Oklahoma, USA.
Infect Immun. 2015 Oct 26;84(1):194-204. doi: 10.1128/IAI.00011-15. Print 2016 Jan.
Secreted toxin B (TcdB) substantially contributes to the pathology observed during Clostridium difficile infection. To be successfully incorporated into a vaccine, TcdB-based immunogens must stimulate the production of neutralizing antibody (Ab)-encoding memory B cells (Bmem cells). Despite numerous investigations, a clear analysis of Bmem cellular responses following vaccination against TcdB is lacking. B6 mice were therefore used to test the ability of a nontoxigenic C-terminal domain (CTD) fragment of TcdB to induce Bmem cells that encode TcdB-neutralizing antibody. CTD was produced from the historical VPI 10463 strain (CTD1) and from the hypervirulent strain NAP1/BI/027 (CTD2). It was then demonstrated that CTD1 induced strong recall IgG antibody titers, and this led to the development of functional Bmem cells that could be adoptively transferred to naive recipients. Bmem cell-driven neutralizing Ab responses conferred protection against lethal challenge with TcdB1. Further experiments revealed that an experimental adjuvant (Imject) and a clinical adjuvant (Alhydrogel) were compatible with Bmem cell induction. Reactivity of human Bmem cells to CTD1 was also evident in human peripheral blood mononuclear cells (PBMCs), suggesting that CTD1 could be a good vaccine immunogen. However, CTD2 induced strong Bmem cell-driven antibody titers, and the CTD2 antibody was neutralizing in vitro, but its protection against lethal challenge with TcdB2 was limited to delaying time to death. Therefore, CTD from different C. difficile strains may be a good immunogen for stimulating B cell memory that encodes in vitro neutralizing Ab but may be limited by variable protection against intoxication in vivo.
分泌型毒素B（TcdB）在艰难梭菌感染期间观察到的病理过程中起重要作用。为了成功纳入疫苗，基于TcdB的免疫原必须刺激产生编码中和抗体（Ab）的记忆B细胞（Bmem细胞）。尽管进行了大量研究，但缺乏针对TcdB疫苗接种后Bmem细胞反应的清晰分析。因此，使用B6小鼠来测试TcdB的无毒C末端结构域（CTD）片段诱导编码TcdB中和抗体的Bmem细胞的能力。CTD由历史菌株VPI 10463（CTD1）和高毒力菌株NAP1/BI/027（CTD2）产生。然后证明CTD1诱导强烈的回忆性IgG抗体滴度，这导致了功能性Bmem细胞的产生，这些细胞可以过继转移到未免疫的受体中。Bmem细胞驱动的中和抗体反应赋予了对TcdB1致死性攻击的保护作用。进一步的实验表明，一种实验性佐剂（Imject）和一种临床佐剂（Alhydrogel）与Bmem细胞诱导兼容。人Bmem细胞对CTD1的反应性在人外周血单个核细胞（PBMC）中也很明显，这表明CTD1可能是一种良好的疫苗免疫原。然而，CTD2诱导了强烈的Bmem细胞驱动的抗体滴度，并且CTD2抗体在体外具有中和作用，但其对TcdB2致死性攻击的保护作用仅限于延迟死亡时间。因此，来自不同艰难梭菌菌株的CTD可能是刺激编码体外中和抗体的B细胞记忆的良好免疫原，但可能受到体内抗中毒可变保护的限制。
