Integrated Biotherapeutics Inc., Gaithersburg, Maryland, United States of America.
PLoS One. 2012;7(6):e38567. doi: 10.1371/journal.pone.0038567. Epub 2012 Jun 6.
Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection.
金黄色葡萄球菌（S. aureus）是一种与皮肤和软组织感染（SSTI）以及危及生命的败血症和肺炎相关的人类病原体。开发针对金黄色葡萄球菌的有效疫苗的努力在很大程度上尚未成功，部分原因是该生物体产生的多种毒力因子。金黄色葡萄球菌α-溶血素（Hla）是大多数金黄色葡萄球菌菌株表达的一种成孔毒素，据报道在 SSTI 和肺炎的发病机制中发挥关键作用。在这里，我们报告了一种基于七聚体晶体结构合理设计的金黄色葡萄球菌 Hla 新型重组亚单位疫苗候选物。该疫苗候选物称为 AT-62aa，已在使用金黄色葡萄球菌菌株 Newman 和大流行菌株 USA300（LAC）的肺炎和菌血症感染模型中进行了测试。用 AT-62aa 与目前正在临床试验中的葡聚糖脂质佐剂稳定乳液（GLA-SE）接种疫苗可显著预防致命菌血症/败血症和肺炎。针对 AT-62aa 的兔免疫球蛋白（AT62-IgG）的被动转移可保护小鼠免受 USA300 的腹腔内和鼻内攻击，并可显著减少血液、脾脏、肾脏和肺部的细菌负荷。我们基于 Hla 的疫苗是第一个被报道可减少细菌传播并在金黄色葡萄球菌感染的败血症模型中提供保护的疫苗。接种疫苗的小鼠的 AT62-IgG 和血清可有效中和毒素体外和 AT62-IgG 抑制 Hla 七聚体的形成，表明抗体介导的中和作用是主要作用机制。这种显著的功效使这种基于 Hla 的疫苗成为未来金黄色葡萄球菌多价疫苗的首选候选物。此外，鉴定 AT-62aa 内的保护性表位可能会导致金黄色葡萄球菌感染的新型免疫疗法。
