Integrated Biotherapeutics, Inc., Rockville, MD, USA.
Daiichi Sankyo, Tokyo, Japan.
Sci Rep. 2019 Mar 1;9(1):3279. doi: 10.1038/s41598-019-39890-z.
Superantigens (SAgs) play a major role in the pathogenesis of Staphylococcus aureus and are associated with several diseases, including food poisoning, bacterial arthritis, and toxic shock syndrome. Monoclonal antibodies to these SAgs, primarily TSST-1, SEB and SEA have been shown to provide protection in animal studies and to reduce clinical severity in bacteremic patients. Here we quantify the pre-existing antibodies against SAgs in many human plasma and IVIG samples and demonstrate that in a major portion of the population these antibody titers are suboptimal and IVIG therapy only incrementally elevates the anti-SAg titers. Our in vitro neutralization studies show that a combination of antibodies against SEA, SEB,and TSST-1 can provide broad neutralization of staphylococcal SAgs. We report a single fusion protein (TBA) consisting of the toxoid versions of TSST-1, SEB and SEA and demonstrate its immunogenicity and protective efficacy in a mouse model of toxic shock. Antibodies raised against this fusion vaccine provide broad neutralization of purified SAgs and culture supernatants of multiple clinically relevant S. aureus strains. Our data strongly supports the use of this fusion protein as a component of an anti-virulence based multivalent toxoid vaccine against S. aureus disease.
超抗原 (SAgs) 在金黄色葡萄球菌的发病机制中起主要作用，并与多种疾病相关，包括食物中毒、细菌性关节炎和中毒性休克综合征。针对这些 SAg 的单克隆抗体，主要是 TSST-1、SEB 和 SEA，已被证明在动物研究中提供保护，并降低菌血症患者的临床严重程度。在这里，我们定量检测了许多人血浆和 IVIG 样本中的抗 SAg 抗体，并证明在人群的很大一部分中，这些抗体滴度不理想，IVIG 治疗仅略微提高抗 SAg 滴度。我们的体外中和研究表明，针对 SEA、SEB 和 TSST-1 的抗体组合可以提供对葡萄球菌 SAg 的广泛中和。我们报告了一种由 TSST-1、SEB 和 SEA 的类毒素版本组成的单一融合蛋白 (TBA)，并在毒性休克的小鼠模型中证明了其免疫原性和保护效力。针对这种融合疫苗产生的抗体提供了对纯化 SAg 和多种临床相关金黄色葡萄球菌菌株的培养上清液的广泛中和。我们的数据强烈支持将这种融合蛋白用作针对金黄色葡萄球菌疾病的基于抗病毒的多价类毒素疫苗的组成部分。
