The in vivo expressed Mycobacterium tuberculosis (IVE-TB) antigen Rv2034 induces CD4⁺ T-cells that protect against pulmonary infection in HLA-DR transgenic mice and guinea pigs.
Tuberculosis (TB) remains a life-threatening infectious disease of global proportions with serious negative health and economic consequences. The lack of sufficient protection induced by Mycobacterium bovis BCG, the current vaccine for TB, as well as the impact of HIV co-infection and the emergence of drug resistant Mycobacterium tuberculosis (Mtb) strains all urge for improved vaccines against TB. A minimal requirement for Mtb vaccine antigens is their in vivo expression during Mtb infection and ability to trigger significant immune responses. Recently we identified a new class of Mtb antigens, designated IVE-TB (in vivo expressed) antigens. These included Rv2034, a protein that was expressed during pulmonary infection and strongly recognized by human T-cells. Here, the in vivo immunogenicity and protective efficacy of Rv2034 was further analyzed using HLA-DR transgenic mice that lack endogenous murine MHC class II molecules. The Rv2034 protein indeed was highly immunogenic in HLA-DR3 transgenic mice and induced HLA-DR3 restricted IFN-γ(+)/TNF(+) and IFN-γ(+) CD4(+) T-cells, specific for an epitope encoded in peptide 31-50. CD4(+) T-cell responses were optimally induced when using TLR9- and TLR3-ligand-adjuvants or CAF09. Rv2034-specific antibodies were observed following immunization with either TLR2-, TLR3-, TLR4-, TLR5-, TLR7- or TLR9-ligands or CAF09. Importantly, immunization with Rv2034 or the hybrid-protein Ag85B-ESAT6-Rv2034 adjuvanted with CpG or CAF09, induced over one log reduction, relative to unvaccinated controls, in the number of bacilli in the lungs of Mtb challenged HLA-DR3 transgenic mice and guinea pigs. These data demonstrate the potential of Rv2034 as a novel, IVE-TB antigen for future TB vaccination.
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Susanna
S
Commandeur
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Susan J F
SJ
van den Eeden
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Karin
K
Dijkman
Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
Simon O
SO
Clark
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Krista E
KE
van Meijgaarden
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Louis
L
Wilson
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Kees L M C
KL
Franken
Public Health England, Microbiology Services, Porton Down, Salisbury, Wiltshire, United Kingdom.
Ann
A
Williams
Statens Serum Institut, Copenhagen, Denmark.
Dennis
D
Christensen
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands.
Tom H M
TH
Ottenhoff
Department of Infectious Diseases, Leiden University Medical Centre, The Netherlands. Electronic address: a.geluk@lumc.nl.
Annemieke
A
Geluk
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D015803:HLA-DR3 Antigen / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology; D008024:Ligands; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D012097:Repressor Proteins / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018984:Epitopes, T-Lymphocyte; D015803:HLA-DR3 Antigen; D008024:Ligands; D011994:Recombinant Proteins; D012097:Repressor Proteins; C000593589:Rv2034 protein, Mycobacterium tuberculosis; D051193:Toll-Like Receptors; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; D007371:Interferon-gamma
HLA-DR3; IVE-TB antigen; Infection-specific; Mtb; Rv2034; TB vaccine