title: Immune subdominant antigens as vaccine candidates against Mycobacterium tuberculosis.
abstract: Unlike most pathogens, many of the immunodominant epitopes from Mycobacterium tuberculosis are under purifying selection. This startling finding suggests that M. tuberculosis may gain an evolutionary advantage by focusing the human immune response against selected proteins. Although the implications of this to vaccine development are incompletely understood, it has been suggested that inducing strong Th1 responses against Ags that are only weakly recognized during natural infection may circumvent this evasion strategy and increase vaccine efficacy. To test the hypothesis that subdominant and/or weak M. tuberculosis Ags are viable vaccine candidates and to avoid complications because of differential immunodominance hierarchies in humans and experimental animals, we defined the immunodominance hierarchy of 84 recombinant M. tuberculosis proteins in experimentally infected mice. We then combined a subset of these dominant or subdominant Ags with a Th1 augmenting adjuvant, glucopyranosyl lipid adjuvant in stable emulsion, to assess their immunogenicity in M. tuberculosis-naive animals and protective efficacy as measured by a reduction in lung M. tuberculosis burden of infected animals after prophylactic vaccination. We observed little correlation between immunodominance during primary M. tuberculosis infection and vaccine efficacy, confirming the hypothesis that subdominant and weakly antigenic M. tuberculosis proteins are viable vaccine candidates. Finally, we developed two fusion proteins based on strongly protective subdominant fusion proteins. When paired with the glucopyranosyl lipid adjuvant in stable emulsion, these fusion proteins elicited robust Th1 responses and limited pulmonary M. tuberculosis for at least 6 wk postinfection with a single immunization. These findings expand the potential pool of M. tuberculosis proteins that can be considered as vaccine Ag candidates.
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and mark.orr@idri.org.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Ireton
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and.
authors.forename: Elyse A
authors.initials: EA
authors.lastname: Beebe
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and.
authors.forename: Po-Wei D
authors.initials: PW
authors.lastname: Huang
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Reese
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and.
authors.forename: David
authors.initials: D
authors.lastname: Argilla
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and Department of Global Health, University of Washington, Seattle, WA 98105.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98102; and Department of Global Health, University of Washington, Seattle, WA 98105.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D005260:Female; D016056:Immunodominant Epitopes / Q000276:immunology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000517:prevention & control; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016056:Immunodominant Epitopes; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines
references.citation: Nat Rev Immunol. 2012 Nov;12(11):786-98
references.pmid: 23059428
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2301-6
references.pmid: 19188599
references.citation: J Immunol. 2005 May 15;174(10):6332-9
references.pmid: 15879133
references.citation: J Immunol. 2008 Dec 1;181(11):7948-57
references.pmid: 19017986
references.citation: Trends Pharmacol Sci. 2011 Oct;32(10):601-6
references.pmid: 21803435
references.citation: BMC Immunol. 2013 Dec 07;14:53
references.pmid: 24313934
references.citation: Future Microbiol. 2011 Feb;6(2):161-77
references.pmid: 21366417
references.citation: Clin Vaccine Immunol. 2010 Oct;17(10):1539-47
references.pmid: 20719988
references.citation: Nat Genet. 2010 Jun;42(6):498-503
references.pmid: 20495566
references.citation: Mol Microbiol. 2002 Nov;46(3):623-35
references.pmid: 12410821
references.citation: Eur J Immunol. 2010 Aug;40(8):2211-20
references.pmid: 20540114
references.citation: Microbes Infect. 2005 May;7(5-6):962-7
references.pmid: 15890555
references.citation: Lancet. 2013 Mar 23;381(9871):1021-8
references.pmid: 23391465
references.citation: PLoS One. 2009 Jun 16;4(6):e5930
references.pmid: 19529771
references.citation: Sci Transl Med. 2011 Jun 22;3(88):88ra56
references.pmid: 21697532
references.citation: Annu Rev Immunol. 2009;27:393-422
references.pmid: 19302046
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6482-7
references.pmid: 23559373
references.citation: Indian J Med Res. 1980 Jul;72 Suppl:1-74
references.pmid: 7005086
references.citation: Thorax. 2013 Dec;68(12):1092-4
references.pmid: 23749816
references.citation: J Immunol. 2007 Mar 15;178(6):3721-30
references.pmid: 17339470
references.citation: J Infect Dis. 2008 Aug 15;198(4):544-52
references.pmid: 18582195
references.citation: PLoS One. 2013 May 17;8(5):e63331
references.pmid: 23691024
references.citation: J Immunol. 2003 Aug 1;171(3):1602-9
references.pmid: 12874255
references.citation: J Control Release. 2013 Nov 28;172(1):190-200
references.pmid: 23933525
references.citation: J Immunol. 2004 Jun 15;172(12):7618-28
references.pmid: 15187142
references.citation: Br Med J. 1977 Jul 30;2(6082):293-5
references.pmid: 326347
references.citation: Clin Exp Immunol. 1992 Jan;87(1):94-8
references.pmid: 1733641
references.citation: PLoS One. 2011;6(5):e19826
references.pmid: 21611197
references.citation: mBio. 2014 Jan 14;5(1):e00960-13
references.pmid: 24425732
references.citation: PLoS Pathog. 2013 Jan;9(1):e1003130
references.pmid: 23358848
references.citation: Tuberculosis (Edinb). 2014 Mar;94(2):105-10
references.pmid: 24369986
references.citation: Annu Rev Immunol. 2001;19:93-129
references.pmid: 11244032
references.citation: Health Technol Assess. 2013 Sep;17(37):1-372, v-vi
references.pmid: 24021245
references.citation: PLoS One. 2008 Aug 13;3(8):e2921
references.pmid: 18698342
references.citation: Tuberculosis (Edinb). 2012 Mar;92 Suppl 1:S6-13
references.pmid: 22441160
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1096-101
references.pmid: 24395772
references.citation: Sci Transl Med. 2010 Oct 13;2(53):53ra74
references.pmid: 20944089
references.citation: Infect Immun. 2008 Jun;76(6):2333-40
references.pmid: 18347040
references.citation: Nat Rev Immunol. 2012 Jul 13;12(8):581-91
references.pmid: 22790178
references.citation: PLoS One. 2011 Jan 26;6(1):e16333
references.pmid: 21298114
references.citation: J Infect Dis. 2014 Apr 15;209(8):1259-68
references.pmid: 24273174
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13022-7
references.pmid: 20615947
references.citation: J Immunol. 2013 Aug 15;191(4):1753-64
references.pmid: 23833235
references.citation: Eur J Immunol. 2009 Mar;39(3):723-9
references.pmid: 19224636
references.citation: Nat Med. 2011 Feb;17(2):189-94
references.pmid: 21258338
references.citation: Drugs. 2013 Jul;73(10):1015-24
references.pmid: 23794129