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

Susanna Commandeur, Susan J.F. van den Eeden, Karin Dijkman, Simon Clark, Krista E. van Meijgaarden, Louis Wilson, Kees L.M.C. Franken, Ann Williams, Dennis Christensen, Tom H.M. Ottenhoff, Annemieke Geluk*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3580-3588
Number of pages9
JournalVaccine
Volume32
Issue number29
DOIs
Publication statusPublished - 17 Jun 2014

Bibliographical note

Funding Information:
Funding : This study was supported by the European Commission [FP7 NEWTBVAC project contract no. LSHP-CT-2003-503367; FP7 VACTRAIN; FP7 IDEA; FP7 ADITEC], the Bill and Melinda Gates Foundation Grand Challenges in Global Health (GC6#74), Top Institute Pharma (project D-101-1), ISA Pharmaceuticals , EDCTP through a project entitled AE-TBC under Grant Agreement N° IP_09_32040 and the Biological Investigations Group at PHE, Porton Down, UK. The views expressed in this publication are those of the author(s) and not necessarily those of the European Commission, NHS, the National Institute for Health Research, or the Department of Health.

Keywords

  • HLA-DR3
  • IVE-TB antigen
  • Infection-specific
  • Mtb
  • Rv2034
  • TB vaccine

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