title: Prime-boost vaccination strategy with bacillus Calmette-Guérin (BCG) and liposomized alpha-crystalline protein 1 reinvigorates BCG potency.
abstract: Bacillus Calmette-Guérin (BCG) remains the only available and most widely administered vaccine against Mycobacterium tuberculosis (Mtb), yet it fails to protect vaccinated individuals either from primary infection or reactivation of latent tuberculosis (TB). Despite BCG's variable efficacy against TB, the fact remains that BCG imparts protection in children against the disease, indicating that BCG possesses a wide protective antigenic repertoire. However, its failure to impart protection in adulthood can be linked to its failure to generate long-lived memory response and elicitation of an inadequate immune response against latency-associated antigens. Therefore, to improve the protective efficacy of BCG, a novel vaccination strategy is required. Consequently, in the present study, we have exploited the vaccination potential of liposomized α-crystalline 1 (Acr1L), a latency-associated antigen to induce enduring protective immunity against Mtb in BCG-primed animals. It is noteworthy that an increase in the multi-functional [interferon (IFN)-γ(hi) /tumour necrosis factor (TNF)-α(hi) ] CD4 and CD8 T cells were observed in BCG-primed and Acr1L-boosted (BCG-Acr1L) animals, compared to BCG alone. Further, substantial expansion of both central memory (CD44(hi) /CD62L(hi) ) and effector memory (CD44(hi) /CD62L(lo) ) populations of CD4 and CD8 T cells was noted. Importantly, BCG-Acr1L exhibited significantly better protection than BCG, as evidenced by a reduction in the bacterial burden and histopathological data of the lungs. In essence, BCG-Acr1L could be a potent future vaccination strategy to reinvigorate BCG potency.
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: K F
authors.initials: KF
authors.lastname: Siddiqui
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: M
authors.initials: M
authors.lastname: Amir
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: N
authors.initials: N
authors.lastname: Khan
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: G
authors.initials: G
authors.lastname: Rama Krishna
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: J A
authors.initials: JA
authors.lastname: Sheikh
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: K
authors.initials: K
authors.lastname: Rajagopal
authors.affiliation: Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: J N
authors.initials: JN
authors.lastname: Agrewala
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D058491:Bacterial Load / Q000187:drug effects; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005260:Female; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007117:Immunization, Secondary; D007156:Immunologic Memory / Q000187:drug effects; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D055985:Latent Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D008081:Liposomes / Q000737:chemistry / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009163:Mycobacterium bovis / Q000737:chemistry / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D038201:alpha-Crystallins / Q000235:genetics / Q000276:immunology*
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D008081:Liposomes; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D038201:alpha-Crystallins; D019041:L-Selectin; D007371:Interferon-gamma
keywords: Acr1; BCG; CD4 cells; CD8 cells; prime boost; tuberculosis; vaccine
references.citation: JAMA. 1994 Mar 2;271(9):698-702
references.pmid: 8309034
references.citation: Infect Immun. 2004 Nov;72(11):6622-32
references.pmid: 15501795
references.citation: Lancet. 1995 Nov 18;346(8986):1339-45
references.pmid: 7475776
references.citation: Cytokines Mol Ther. 1996 Mar;2(1):59-65
references.pmid: 9384690
references.citation: J Bacteriol. 1998 Feb;180(4):801-8
references.pmid: 9473032
references.citation: Nature. 1988 Jul 21;334(6179):255-8
references.pmid: 2456466
references.citation: Clin Exp Immunol. 1998 Dec;114(3):392-7
references.pmid: 9844048
references.citation: Eur J Immunol. 1999 Jun;29(6):1753-61
references.pmid: 10382737
references.citation: Nat Med. 2004 Nov;10(11):1240-4
references.pmid: 15502839
references.citation: Nat Rev Immunol. 2005 Aug;5(8):661-7
references.pmid: 16056257
references.citation: J Clin Invest. 2005 Sep;115(9):2472-9
references.pmid: 16110326
references.citation: Vaccine. 2005 Dec 1;23(48-49):5655-65
references.pmid: 16157425
references.citation: Clin Vaccine Immunol. 2006 Feb;13(2):179-86
references.pmid: 16467323
references.citation: Vaccine. 2006 Jul 7;24(27-28):5559-70
references.pmid: 16730102
references.citation: Immunol Rev. 2006 Jun;211:8-22
references.pmid: 16824113
references.citation: J Immunol. 2006 Nov 1;177(9):6353-60
references.pmid: 17056566
references.citation: Infect Immun. 2007 Feb;75(2):941-9
references.pmid: 17145953
references.citation: J Biol Chem. 2007 Mar 2;282(9):6106-15
references.pmid: 17197446
references.citation: Eur J Immunol. 2007 Mar;37(3):729-37
references.pmid: 17304630
references.citation: Vaccine. 2009 Nov 16;27(49):6939-49
references.pmid: 19748578
references.citation: Clin Vaccine Immunol. 2010 Apr;17(4):618-25
references.pmid: 20107011
references.citation: J Infect Dis. 2010 Aug 15;202(3):480-9
references.pmid: 20569158
references.citation: Vaccine. 2010 Jul 19;28(32):5237-44
references.pmid: 20538090
references.citation: Tuberculosis (Edinb). 2010 Nov;90(6):346-53
references.pmid: 20933471
references.citation: PLoS One. 2011;6(1):e16097
references.pmid: 21283805
references.citation: Nat Med. 2011 Feb;17(2):189-94
references.pmid: 21258338
references.citation: PLoS One. 2011;6(8):e23360
references.pmid: 21858087
references.citation: J Infect Dis. 2011 Nov;204(9):1328-38
references.pmid: 21933875
references.citation: Bioeng Bugs. 2010 Jan-Feb;1(1):61-5
references.pmid: 21327127
references.citation: Crit Rev Microbiol. 2011 Nov;37(4):349-57
references.pmid: 21919701
references.citation: J Infect Dis. 2014 May 1;209(9):1436-45
references.pmid: 24218502
references.citation: Vaccine. 2014 Sep 22;32(42):5475-83
references.pmid: 25110295
references.citation: Curr Mol Med. 2007 May;7(3):327-37
references.pmid: 17504117
references.citation: Infect Immun. 2007 Jun;75(6):2914-21
references.pmid: 17387166
references.citation: Nat Rev Microbiol. 2007 Jul;5(7):484-7
references.pmid: 17571458
references.citation: Nat Med. 2007 Jul;13(7):843-50
references.pmid: 17558415
references.citation: Expert Rev Vaccines. 2008 Jul;7(5):635-50
references.pmid: 18564018
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10961-6
references.pmid: 18667699
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000392
references.pmid: 19381260
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12210-5
references.pmid: 11035787
references.citation: Eur J Biochem. 2000 Jul;267(13):3946-56
references.pmid: 10866793
references.citation: PLoS One. 2009;4(5):e5590
references.pmid: 19440342
references.citation: Infect Immun. 2001 Jul;69(7):4195-201
references.pmid: 11401954
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7534-9
references.pmid: 11416222
references.citation: Scand J Immunol. 2001 Jul-Aug;54(1-2):125-32
references.pmid: 11439158
references.citation: Arch Intern Med. 2003 May 12;163(9):1009-21
references.pmid: 12742798
references.citation: Nat Med. 2003 Aug;9(8):1039-46
references.pmid: 12872166
references.citation: Infect Immun. 2004 Jan;72(1):381-8
references.pmid: 14688119
references.citation: JAMA. 1994 Sep 14;272(10):766
references.pmid: 8078132