Scully Ingrid L, Timofeyeva Yekaterina, Keeney David, Matsuka Yury V, Severina Elena, McNeil Lisa K, Nanra Jasdeep, Hu George, Liberator Paul A, Jansen Kathrin U, Anderson Annaliesa S
Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
Pfizer Drug Safety Research & Development, Pearl River, NY 10965, USA.
Vaccine. 2015 Oct 5;33(41):5452-5457. doi: 10.1016/j.vaccine.2015.08.029. Epub 2015 Aug 28.
The Staphylococcus aureus virulence factor clumping factor A (ClfA) is a component of an investigational S. aureus prophylactic vaccine. ClfA enables S. aureus to bind to fibrinogen and platelets during the initial stages of invasive disease. Here we demonstrate that ectopic expression of ClfA is sufficient to render nonpathogenic Lactococcus lactis lethal in a murine model of systemic infection. In contrast, L. lactis expressing ClfAY338A, which cannot bind fibrinogen, did not cause death in the mice. Pathogenicity was also prevented by immunization with ClfA. This model was then used to define a preclinical correlate of protection by measuring functional antibody in a S. aureus fibrinogen binding inhibition assay (FBI) and correlating that titer with protective outcomes. Although many humans have pre-existing antibodies that bind to ClfA, only sera with a threshold functional titer in the FBI were protective in this preclinical model. This confirms that fibrinogen binding is critical for ClfA-mediated pathogenesis and demonstrates that functional antibodies against ClfA are sufficient to protect against ClfA-mediated pathogenesis in vivo, enabling the definition of a preclinical correlate of protection for ClfA-containing vaccines based on FBI titer.
金黄色葡萄球菌毒力因子凝聚因子A（ClfA）是一种正在研究的金黄色葡萄球菌预防性疫苗的成分。在侵袭性疾病的初始阶段，ClfA使金黄色葡萄球菌能够与纤维蛋白原和血小板结合。在此，我们证明，在系统性感染的小鼠模型中，ClfA的异位表达足以使非致病性乳酸乳球菌具有致死性。相比之下，表达不能结合纤维蛋白原的ClfAY338A的乳酸乳球菌不会导致小鼠死亡。用ClfA免疫也可预防致病性。然后，通过在金黄色葡萄球菌纤维蛋白原结合抑制试验（FBI）中测量功能性抗体，并将该滴度与保护结果相关联，使用该模型来定义保护的临床前相关指标。尽管许多人预先存在与ClfA结合的抗体，但在该临床前模型中，只有在FBI中具有阈值功能性滴度的血清才具有保护作用。这证实了纤维蛋白原结合对于ClfA介导的发病机制至关重要，并表明针对ClfA的功能性抗体足以在体内预防ClfA介导的发病机制，从而能够基于FBI滴度定义含ClfA疫苗保护的临床前相关指标。
