title: Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis.
abstract: Responsible for 9 million new cases of active disease and nearly 2 million deaths each year, tuberculosis (TB) remains a global health threat of overwhelming dimensions. Mycobacterium bovis BCG, the only licensed vaccine available, fails to confer lifelong protection and to prevent reactivation of latent infection. Although 15 new vaccine candidates are now in clinical trials, an effective vaccine against TB remains elusive, and new strategies for vaccination are vital. BCG vaccination fails to induce immunity against Mycobacterium tuberculosis latency antigens. Synthetic long peptides (SLPs) combined with adjuvants have been studied mostly for therapeutic cancer vaccines, yet not for TB, and proved to induce efficient antitumor immunity. This study investigated an SLP derived from Rv1733c, a major M. tuberculosis latency antigen which is highly expressed by "dormant" M. tuberculosis and well recognized by T cells from latently M. tuberculosis-infected individuals. In order to assess its in vivo immunogenicity and protective capacity, Rv1733c SLP in CpG was administered to HLA-DR3 transgenic mice. Immunization with Rv1733c SLP elicited gamma interferon-positive/tumor necrosis factor-positive (IFN-γ(+)/TNF(+)) and IFN-γ(+) CD4(+) T cells and Rv1733c-specific antibodies and led to a significant reduction in the bacterial load in the lungs of M. tuberculosis-challenged mice. This was observed both in a pre- and in a post-M. tuberculosis challenge setting. Moreover, Rv1733c SLP immunization significantly boosted the protective efficacy of BCG, demonstrating the potential of M. tuberculosis latency antigens to improve BCG efficacy. These data suggest a promising role for M. tuberculosis latency antigen Rv1733c-derived SLPs as a novel TB vaccine approach, both in a prophylactic and in a postinfection setting.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Coppola
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susan J F
authors.initials: SJ
authors.lastname: van den Eeden
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands ageluk@lumc.nl.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Geluk
mesh_terms: D000276:Adjuvants, Immunologic; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000276:immunology; D055985:Latent Tuberculosis / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000627:therapeutic use; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control* / Q000628:therapy; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D010446:Peptide Fragments; C000589489:Rv1733c protein, Mycobacterium tuberculosis; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma