Department of Microbial Pathogenesis, University of Maryland-Baltimore, Baltimore, MD 21201, USA.
Infect Immun. 2011 Apr;79(4):1797-803. doi: 10.1128/IAI.00451-10. Epub 2011 Jan 10.
Staphylococcus aureus infections, particularly those from methicillin-resistant strains (i.e., MRSA), are reaching epidemic proportions, with no effective vaccine available. The vast number and transient expression of virulence factors in the infectious course of this pathogen have made the discovery of protective antigens particularly difficult. In addition, the divergent planktonic and biofilm modes of growth with their accompanying proteomic changes also demonstrate significant hindrances to vaccine development. In this study, a multicomponent vaccine was evaluated for its ability to clear a staphylococcal biofilm infection. Antigens (glucosaminidase, an ABC transporter lipoprotein, a conserved hypothetical protein, and a conserved lipoprotein) were chosen since they were found in previous studies to have upregulated and sustained expression in a biofilm, both in vitro and in vivo. Antibodies against these antigens were first used in microscopy studies to localize their expression in in vitro biofilms. Each of the four antigens showed heterogeneous production in various locations within the complex biofilm community in the biofilm. Based upon these studies, the four antigens were delivered simultaneously as a quadrivalent vaccine in order to compensate for this varied production. In addition, antibiotic treatment was also administered to clear the remaining nonattached planktonic cells since the vaccine antigens may have been biofilm specific. The results demonstrated that when vaccination was coupled with vancomycin treatment in a biofilm model of chronic osteomyelitis in rabbits, clinical and radiographic signs of infection significantly reduced by 67 and 82%, respectively, compared to infected animals that were either treated with vancomycin or left untreated. In contrast, vaccination alone resulted in a modest, and nonsignificant, decrease in clinical (34% reduction) and radiographic signs (9% reduction) of infection, compared to nonvaccinated animal groups untreated or treated with vancomycin. Lastly, MRSA biofilm infections were significantly cleared in 87.5% of vaccinated and antibiotic-treated animals, while antibiotics or vaccine alone could not significantly clear infection compared to controls (55.6, 22.2, and 33.3% clearance rates, respectively). This approach to vaccine development may lead to the generation of vaccines against other pathogenic biofilm bacteria.
金黄色葡萄球菌感染，特别是耐甲氧西林金黄色葡萄球菌（MRSA）感染，正呈流行趋势，但目前尚无有效的疫苗。在这种病原体的感染过程中，其大量且短暂表达的毒力因子使得保护性抗原的发现变得特别困难。此外，浮游和生物膜两种生长模式及其伴随的蛋白质组变化也极大地阻碍了疫苗的开发。在这项研究中，评估了一种多组分疫苗清除葡萄球菌生物膜感染的能力。选择这些抗原（葡糖胺酶、ABC 转运体脂蛋白、保守假定蛋白和保守脂蛋白）是因为之前的研究表明，它们在体外和体内的生物膜中都有上调和持续表达。针对这些抗原的抗体首先用于显微镜研究，以确定其在体外生物膜中的表达位置。在生物膜复杂群落的不同位置，四种抗原的产生均存在异质性。基于这些研究，将这四种抗原同时作为四价疫苗进行递送，以弥补这种差异表达。此外，由于疫苗抗原可能具有生物膜特异性，还给予抗生素治疗以清除残留的非附着浮游细胞。结果表明，在兔慢性骨髓炎生物膜模型中，将疫苗接种与万古霉素治疗相结合，与仅用万古霉素治疗或未治疗的感染动物相比，临床和放射学感染迹象分别显著降低了 67%和 82%。相比之下，与未接种疫苗的动物相比，单独接种疫苗仅使感染的临床（减少 34%）和放射学（减少 9%）迹象略有降低，但无统计学意义。最后，87.5%经疫苗接种和抗生素治疗的动物的耐甲氧西林金黄色葡萄球菌生物膜感染得到显著清除，而单独使用抗生素或疫苗与对照组相比，无法显著清除感染（清除率分别为 55.6%、22.2%和 33.3%）。这种疫苗开发方法可能会导致针对其他致病性生物膜细菌的疫苗的产生。
