title: Role of antibodies in protection elicited by active vaccination with genetically inactivated alpha hemolysin in a mouse model of staphylococcus aureus skin and soft tissue infections.
abstract: Due to the emergence of highly virulent community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, S. aureus has become a major threat to public health. A majority of CA-MRSA skin and soft tissue infections in the United States are caused by S. aureus USA300 strains that are known to produce high levels of alpha hemolysin (Hla). Therefore, vaccines that contain inactivated forms of this toxin are currently being developed. In this study, we sought to determine the immune mechanisms of protection for this antigen using a vaccine composed of a genetically inactivated form of Hla (HlaH35L). Using a murine model of skin and soft tissue infections (SSTI), we found that BALB/c mice were protected by vaccination with HlaH35L; however, Jh mice, which are deficient in mature B lymphocytes and lack IgM and IgG in their serum, were not protected. Passive immunization with anti-HlaH35L antibodies conferred protection against bacterial colonization. Moreover, we found a positive correlation between the total antibody concentration induced by active vaccination and reduced bacterial levels. Animals that developed detectable neutralizing antibody titers after active vaccination were significantly protected from infection. These data demonstrate that antibodies to Hla represent the major mechanism of protection afforded by active vaccination with inactivated Hla in this murine model of SSTI, and in this disease model, antibody levels correlate with protection. These results provide important information for the future development and evaluation of S. aureus vaccines.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mocca
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Brady
authors.forename: Drusilla L
authors.initials: DL
authors.lastname: Burns
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D057134:Antibodies, Neutralizing / Q000097:blood; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006460:Hemolysin Proteins / Q000235:genetics / Q000276:immunology*; D008297:Male; D008807:Mice, Inbred BALB C; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D018461:Soft Tissue Infections / Q000276:immunology / Q000517:prevention & control*; D013207:Staphylococcal Skin Infections / Q000276:immunology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D050505:Mutant Proteins; D013209:Staphylococcal Vaccines; D014614:Vaccines, Synthetic; C021091:staphylococcal alpha-toxin