Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot.
Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot.
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DOI：
10.3389/fcimb.2022.876898
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发表时间：
2022
影响因子：
5.7
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中科院分区：
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金黄色葡萄球菌骨髓炎仍然是一种非常具有挑战性的疾病；最近的临床研究表明，手术/抗生素后的感染控制率约为60%。此外，先前生产有效的金黄色葡萄球菌疫苗的努力失败了，部分原因是缺乏保护性免疫知识。先前，我们证明了抗氨基葡萄糖酶（Gmd）抗体在动物模型中具有保护作用，但在AO临床优先计划（AO- cpp）登记处发现，只有6.7%的培养证实的金黄色葡萄球菌骨髓炎患者在手术时（基线）具有基础血清抗Gmd水平（bbb10 ng/ml）。我们确定了一小部分患者具有高水平的抗gmd抗体和手术后的不良后果，这不能用Ig类转换为非功能同型来解释。在这里，我们的目的是验证手术后临床治愈与血清中抗gmd中和抗体相关的假设。因此，我们首先优化了一种体外定量测定重组Gmd裂解黄斑部细胞壁的方法，并利用它证明了人源抗Gmd单抗（TPH-101）的50%中和浓度（NC50）为~15.6 μg/ml。我们还证明，人血清中缺乏抗Gmd抗体可以用TPH-101补充，以达到与纯化的TPH-101相同的剂量依赖性Gmd中和活性。最后，我们评估了AO-CPP登记处11名患者血清中的抗gmd物理滴度和中和活性，这些患者事后被分为四组。组1患者（n=3）在基线时具有较高的抗gmd物理和中和滴度，随着时间的推移随着感染的临床治愈而降低。2组患者（n=3）在整个研究过程中均未检测到抗gmd抗体和不良结局。第3组（n=3）在基线时具有高滴度+/−中和性抗gmd，并伴有不良结局。第4组（n=2）在基线时具有低滴度的非中和性抗gmd，延迟出现高滴度和不良结局。总的来说，这些发现表明，在金黄色葡萄球菌骨髓炎患者中存在中和性和非中和性抗gmd抗体，对这些抗体的筛查对于在手术前确定需要被动免疫的患者具有价值。未来有必要进行前瞻性研究，以测试抗gmd抗体的预后价值，以评估被动免疫TPH-101的潜力。
Staphylococcus aureus osteomyelitis remains a very challenging condition; recent clinical studies have shown infection control rates following surgery/antibiotics to be ~60%. Additionally, prior efforts to produce an effective S. aureus vaccine have failed, in part due to lack of knowledge of protective immunity. Previously, we demonstrated that anti-glucosaminidase (Gmd) antibodies are protective in animal models but found that only 6.7% of culture-confirmed S. aureus osteomyelitis patients in the AO Clinical Priority Program (AO-CPP) Registry had basal serum levels (>10 ng/ml) of anti-Gmd at the time of surgery (baseline). We identified a small subset of patients with high levels of anti-Gmd antibodies and adverse outcomes following surgery, not explained by Ig class switching to non-functional isotypes. Here, we aimed to test the hypothesis that clinical cure following surgery is associated with anti-Gmd neutralizing antibodies in serum. Therefore, we first optimized an in vitro assay that quantifies recombinant Gmd lysis of the M. luteus cell wall and used it to demonstrate the 50% neutralizing concentration (NC50) of a humanized anti-Gmd mAb (TPH-101) to be ~15.6 μg/ml. We also demonstrated that human serum deficient in anti-Gmd antibodies can be complemented by TPH-101 to achieve the same dose-dependent Gmd neutralizing activity as purified TPH-101. Finally, we assessed the anti-Gmd physical titer and neutralizing activity in sera from 11 patients in the AO-CPP Registry, who were characterized into four groups post-hoc. Group 1 patients (n=3) had high anti-Gmd physical and neutralizing titers at baseline that decreased with clinical cure of the infection over time. Group 2 patients (n=3) had undetectable anti-Gmd antibodies throughout the study and adverse outcomes. Group 3 (n=3) had high titers +/− neutralizing anti-Gmd at baseline with adverse outcomes. Group 4 (n=2) had low titers of non-neutralizing anti-Gmd at baseline with delayed high titers and adverse outcomes. Collectively, these findings demonstrate that both neutralizing and non-neutralizing anti-Gmd antibodies exist in S. aureus osteomyelitis patients and that screening for these antibodies could have a value for identifying patients in need of passive immunization prior to surgery. Future prospective studies to test the prognostic value of anti-Gmd antibodies to assess the potential of passive immunization with TPH-101 are warranted.