title: Demonstration of the preclinical correlate of protection for Staphylococcus aureus clumping factor A in a murine model of infection.
abstract: 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.
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Ingrid L
authors: IL
authors: Scully
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Yekaterina
authors: Y
authors: Timofeyeva
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: David
authors: D
authors: Keeney
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Yury V
authors: YV
authors: Matsuka
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Elena
authors: E
authors: Severina
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Lisa K
authors: LK
authors: McNeil
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Jasdeep
authors: J
authors: Nanra
authors: Pfizer Drug Safety Research & Development, Pearl River, NY 10965, USA.
authors: George
authors: G
authors: Hu
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Paul A
authors: PA
authors: Liberator
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA.
authors: Kathrin U
authors: KU
authors: Jansen
authors: Pfizer Vaccine Research and Development, Pearl River, NY 10965, USA. Electronic address: Annaliesa.anderson@pfizer.com.
authors: Annaliesa S
authors: AS
authors: Anderson
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D003030:Coagulase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007114:Immunization; D013294:Lactococcus lactis / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics
chemical_list: D000907:Antibodies, Bacterial; C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D011994:Recombinant Proteins; D005340:Fibrinogen
keywords: Clumping factor A; Correlate of protection; Fibrinogen binding; Staphylococcus aureus; Virulence factor