title: Protective efficacy of a novel alpha hemolysin subunit vaccine (AT62) against Staphylococcus aureus skin and soft tissue infections.
abstract: Alpha hemolysin (Hla) is a pore-forming toxin produced by most Staphylococcus aureus isolates. Hla is reported to play a key role in the pathogenesis of staphylococcal infections, such as skin and soft tissue infection, pneumonia, and lethal peritonitis. This study makes use of a novel recombinant subunit vaccine candidate (AT62) that was rationally designed based on the Hla heptameric crystal structure. AT62 comprises a critical structural domain at the N terminus of Hla, and it has no inherent toxic properties. We evaluated the efficacy of AT62 in protection against surgical wound infection and skin and soft tissue infection. Mice were vaccinated on days 0, 14, and 28 with 20μg AT62 or bovine serum albumin (BSA) mixed with Sigma adjuvant system®. Mice immunized with AT62 produced a robust antibody response against native Hla. In the surgical wound infection model, mice immunized with AT62 and challenged with a USA300 S. aureus strain showed a significantly reduced bacterial burden in the infected tissue compared to animals given BSA. Similarly, mice passively immunized with rabbit IgG to AT62 showed reduced wound infection and tissue damage. Subcutaneous abscess formation was not prevented by immunization with AT62. However, in a skin necrosis infection model, immunization with the AT62 vaccine resulted in smaller lesions and reduced mouse weight loss compared to controls. Although AT62 immunization reduced tissue necrosis, it did not reduce the bacterial burdens in the lesions compared to controls. Our data indicate that AT62 may be a valuable component of a multivalent vaccine against S. aureus.
authors.affiliation: Integrated Biotherapeutics, Inc., Gaithersburg, MD, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Adhikari
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Thompson
authors.affiliation: Integrated Biotherapeutics, Inc., Gaithersburg, MD, USA.
authors.forename: M Javad
authors.initials: MJ
authors.lastname: Aman
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: jclee@bwh.harvard.edu.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D058491:Bacterial Load; D001427:Bacterial Toxins / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006460:Hemolysin Proteins / Q000276:immunology*; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood; D008807:Mice, Inbred BALB C; D018461:Soft Tissue Infections / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014946:Wound Infection / Q000517:prevention & control*
chemical_list: D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D007074:Immunoglobulin G; D013209:Staphylococcal Vaccines; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C021091:staphylococcal alpha-toxin
keywords: Alpha hemolysin; Mouse infection models; Skin and soft tissue infection; Staphylococcus aureus; Vaccine