Begier Elizabeth, Seiden David Joshua, Patton Michael, Zito Edward, Severs Joseph, Cooper David, Eiden Joseph, Gruber William C, Jansen Kathrin U, Anderson Annaliesa S, Gurtman Alejandra
Pfizer Vaccine Clinical Research & Development, Pearl River, NY, USA.
Broward Research Group, Hollywood, FL 33024, USA.
Vaccine. 2017 Feb 22;35(8):1132-1139. doi: 10.1016/j.vaccine.2017.01.024. Epub 2017 Jan 28.
Staphylococcus aureus is a leading cause of healthcare-associated infections. No preventive vaccine is currently licensed. SA4Ag is an investigational 4-antigen S. aureus vaccine, composed of capsular polysaccharide conjugates of serotypes 5 and 8 (CP5 and CP8), recombinant surface protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (rMntC). This Phase 1 study aimed to confirm the safety and immunogenicity of SA4Ag produced by the final manufacturing process before efficacy study initiation in a surgical population.
Healthy adults (18-<65years) received one intramuscular SA4Ag injection. Serum functional antibodies were measured at baseline and Day 29 post-vaccination. An opsonophagocytic activity (OPA) assay measured the ability of vaccine-induced antibodies to CP5 and CP8 to kill S. aureus clinical isolates. For MntC and ClfA, antigen-specific immunogenicity was assessed via competitive Luminex® immunoassay (cLIA) and via fibrinogen-binding inhibition (FBI) assay for ClfA only. Reactogenicity and adverse event data were collected.
One hundred participants were vaccinated. SA4Ag was well tolerated, with a satisfactory safety profile. On Day 29, OPA geometric mean titers (GMTs) were 45,738 (CP5, 95% CI: 38,078-54,940) and 42,652 (CP8, 95% CI: 32,792-55,477), consistent with 69.2- and 28.9-fold rises in bacteria-killing antibodies, respectively; cLIA GMTs were 2064.4 (MntC, 95% CI: 1518.2-2807.0) and 3081.4 (ClfA, 95% CI: 2422.2-3920.0), consistent with 19.6- and 12.3-fold rises, respectively. Similar to cLIA results, ClfA FBI titers rose 11.0-fold (GMT: 672.2, 95% CI: 499.8-904.2). The vast majority of participants achieved the pre-defined biologically relevant thresholds: CP5: 100%; CP8: 97.9%, ClfA: 87.8%; and MntC 96.9%.
SA4Ag was safe, well tolerated, and rapidly induced high levels of bacteria-killing antibodies in healthy adults. A Phase 2B efficacy trial in adults (18-85years) undergoing elective spinal fusion is ongoing to assess SA4Ag's ability to prevent postoperative invasive surgical site and bloodstream infections caused by S. aureus. Clinicaltrials.gov Identifier: NCT02364596.
金黄色葡萄球菌是医疗保健相关感染的主要原因。目前尚无预防性疫苗获得许可。SA4Ag是一种研究性的4抗原金黄色葡萄球菌疫苗，由血清型5和8的荚膜多糖缀合物（CP5和CP8）、重组表面蛋白聚集因子A（rmClfA）和重组锰转运蛋白C（rMntC）组成。这项1期研究旨在在外科人群中开展疗效研究之前，确认最终生产工艺生产的SA4Ag的安全性和免疫原性。
健康成年人（18 - <65岁）接受一次SA4Ag肌肉注射。在基线和接种疫苗后第29天测量血清功能性抗体。采用吞噬细胞杀菌活性（OPA）试验来检测疫苗诱导的针对CP5和CP8的抗体杀灭金黄色葡萄球菌临床分离株的能力。对于MntC和ClfA，通过竞争性Luminex®免疫测定法（cLIA）评估抗原特异性免疫原性，对于ClfA仅通过纤维蛋白原结合抑制（FBI）试验进行评估。收集反应原性和不良事件数据。
100名参与者接种了疫苗。SA4Ag耐受性良好，安全性令人满意。在第29天，OPA几何平均滴度（GMT）分别为45,738（CP5，95%置信区间：38,078 - 54,940）和42,652（CP8，95%置信区间：32,792 - 55,477），分别相当于杀菌抗体升高69.2倍和28.9倍；cLIA GMT分别为2064.4（MntC，95%置信区间：1518.2 - 2807.0）和3081.4（ClfA，95%置信区间：2422.2 - 3920.0），分别相当于升高19.6倍和12.3倍。与cLIA结果相似，ClfA的FBI滴度升高了11.0倍（GMT：672.2，95%置信区间：499.8 - 904.2）。绝大多数参与者达到了预先定义的生物学相关阈值：CP5：100%；CP8：97.9%，ClfA：87.8%；MntC：96.9%。
SA4Ag在健康成年人中是安全的、耐受性良好的，并且能迅速诱导产生高水平的杀菌抗体。一项针对接受择期脊柱融合手术的成年人（18 - 85岁）的2B期疗效试验正在进行，以评估SA4Ag预防由金黄色葡萄球菌引起的术后侵袭性手术部位感染和血流感染的能力。Clinicaltrials.gov标识符：NCT02364596。
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