title: Evaluation of genetically inactivated alpha toxin for protection in multiple mouse models of Staphylococcus aureus infection.
abstract: Staphylococcus aureus is a major human pathogen and a leading cause of nosocomial and community-acquired infections. Development of a vaccine against this pathogen is an important goal. While S. aureus protective antigens have been identified in the literature, the majority have only been tested in a single animal model of disease. We wished to evaluate the ability of one S. aureus vaccine antigen to protect in multiple mouse models, thus assessing whether protection in one model translates to protection in other models encompassing the full breadth of infections the pathogen can cause. We chose to focus on genetically inactivated alpha toxin mutant HlaH35L. We evaluated the protection afforded by this antigen in three models of infection using the same vaccine dose, regimen, route of immunization, adjuvant, and challenge strain. When mice were immunized with HlaH35L and challenged via a skin and soft tissue infection model, HlaH35L immunization led to a less severe infection and decreased S. aureus levels at the challenge site when compared to controls. Challenge of HlaH35L-immunized mice using a systemic infection model resulted in a limited, but statistically significant decrease in bacterial colonization as compared to that observed with control mice. In contrast, in a prosthetic implant model of chronic biofilm infection, there was no significant difference in bacterial levels when compared to controls. These results demonstrate that vaccines may confer protection against one form of S. aureus disease without conferring protection against other disease presentations and thus underscore a significant challenge in S. aureus vaccine development.
authors: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
authors: Rebecca A
authors: RA
authors: Brady
authors: Christopher P
authors: CP
authors: Mocca
authors: Ranjani
authors: R
authors: Prabhakara
authors: Roger D
authors: RD
authors: Plaut
authors: Mark E
authors: ME
authors: Shirtliff
authors: Tod J
authors: TJ
authors: Merkel
authors: Drusilla L
authors: DL
authors: Burns
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D005260:Female; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D018461:Soft Tissue Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013207:Staphylococcal Skin Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D014613:Vaccines, Attenuated
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D007074:Immunoglobulin G; D013209:Staphylococcal Vaccines; D014613:Vaccines, Attenuated
references: J Infect Dis. 2012 Jun;205(11):1688-96
references: 22474033
references: Trends Microbiol. 2001 Dec;9(12):605-10
references: 11728874
references: Clin Vaccine Immunol. 2010 Nov;17(11):1746-52
references: 20826613
references: Infect Immun. 2012 Oct;80(10):3721-32
references: 22802349
references: Infect Immun. 2009 Jul;77(7):2719-29
references: 19364833
references: J Infect Dis. 2010 Oct 1;202(7):1050-8
references: 20726702
references: Infect Immun. 2013 Apr;81(4):1306-15
references: 23381997
references: PLoS One. 2008 May 21;3(5):e2206
references: 18493318
references: Infect Immun. 2010 Feb;78(2):764-72
references: 19948836
references: Vaccine. 2009 Jul 30;27(35):4867-73
references: 19406185
references: PLoS Pathog. 2010 Aug 05;6(8):e1001036
references: 20700445
references: J Clin Invest. 2004 Dec;114(12):1693-6
references: 15599392
references: Biotechniques. 1992 Aug;13(2):214-20
references: 1327007
references: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16942-7
references: 17075065
references: J Bacteriol. 2004 Jul;186(14):4665-84
references: 15231800
references: Am J Otolaryngol. 2012 Sep-Oct;33(5):572-5
references: 22503099
references: Proteomics. 2006 Mar;6(6):1867-77
references: 16470655
references: Vaccine. 2006 May 29;24(22):4830-7
references: 16616974
references: Infect Immun. 2011 Apr;79(4):1797-803
references: 21220484
references: Infect Immun. 2006 Jun;74(6):3415-26
references: 16714572
references: Infect Immun. 2000 Oct;68(10):6052-5
references: 10992521
references: Hum Vaccin. 2009 Apr;5(4):254-63
references: 18787395
references: J Infect Dis. 2001 Dec 15;184(12):1572-80
references: 11740733
references: Infect Immun. 1994 May;62(5):1843-7
references: 8168947
references: Hum Vaccin. 2006 May-Jun;2(3):89-98
references: 17012902
references: Vet Immunol Immunopathol. 2010 Aug 15;136(3-4):311-8
references: 20416953
references: J Orthop Res. 2008 Jan;26(1):96-105
references: 17676625
references: Appl Environ Microbiol. 2005 May;71(5):2663-76
references: 15870358
references: J Exp Med. 2008 Feb 18;205(2):287-94
references: 18268041
references: J Mol Biol. 1970 Oct 14;53(1):159-62
references: 4922220
references: J Infect Dis. 2008 May 1;197(9):1226-34
references: 18422434
references: FEMS Immunol Med Microbiol. 2008 Apr;52(3):389-96
references: 18312579
references: JAMA. 2007 Oct 17;298(15):1763-71
references: 17940231
references: J Exp Med. 2010 Aug 30;207(9):1863-70
references: 20713595
references: PLoS One. 2012;7(6):e38567
references: 22701668
references: J Infect Dis. 2008 Aug 15;198(4):571-5
references: 18613794
references: J Infect Dis. 2006 Apr 15;193(8):1098-108
references: 16544250
references: FEMS Immunol Med Microbiol. 1994 Nov;10(1):47-53
references: 7874078
references: Infect Immun. 2006 Apr;74(4):2145-53
references: 16552044
references: Vaccine. 2004 Nov 15;23(1):114-26
references: 15519714
references: N Engl J Med. 2001 Jan 4;344(1):11-6
references: 11136954
references: Infect Immun. 2011 Apr;79(4):1789-96
references: 21282411
references: Int J Med Microbiol. 2010 Aug;300(6):402-10
references: 20547101
references: Vaccine. 2002 May 22;20(17-18):2348-57
references: 12009291
references: Hum Vaccin Immunother. 2012 Mar;8(3):336-46
references: 22327491
references: Scand J Immunol. 2006 Mar;63(3):184-90
references: 16499571