title: Immunogenicity and protective efficacy of novel Mycobacterium tuberculosis antigens.
abstract: With tuberculosis continuing to be a major cause of global morbidity and mortality, a new vaccine is urgently needed. Tuberculosis subunit vaccines have been shown to induce robust immune responses in humans and are a potentially safer alternative to BCG for use in HIV-endemic areas. In this study, we investigated the protective efficacy of 16 different novel Mycobacterium tuberculosis antigens using an aerogenic mouse model of pulmonary tuberculosis. These antigens were tested as subunit vaccines formulated in dimethyl dioctadecyl ammonium bromide (DDA) - D(+) with trehalose 6,6 dibenenate (TDB) (DDA/TDB) adjuvant administered alone as monovalent vaccines or in combination. Six of these antigens (Rv1626, Rv1735, Rv1789, Rv2032, Rv2220, and Rv3478) were shown to consistently and significantly reduce bacterial burdens in the lungs of mice relative to nonvaccinated controls. Three of these six (Rv1789, Rv2220, and Rv3478) induced levels of protective immunity that were essentially equivalent to protection induced by the highly immunogenic antigen 85B (>0.5 log₁₀CFU reduction in the lungs relative to naïve mice). Importantly, when these three antigens were combined, protection essentially equivalent to that mediated by BCG was observed. When either Rv1626 or Rv2032 were combined with the highly protective E6-85 fusion protein (antigen 85B fused to ESAT-6), the protection observed was equivalent to BCG-induced protection at one and three months post-aerosol infection and was significantly greater than the protection observed when E6-85 was administered alone at 3 months post-infection. Using multiparameter flow cytometry, monofunctional IFNγ CD4T cells and different multifunctional CD4T cell subsets capable of secreting multiple cytokines (IFNγ, TNFα and/or IL-2) were shown to be induced by the three most protective antigens with splenocyte CD4T cell frequencies significantly greater than observed in naïve controls. The identification of these highly immunogenic TB antigens and antigen combinations should allow for improved immunization strategies against tuberculosis.
authors.affiliation: Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892, United States. Electronic address: steven.derrick@fda.hhs.gov.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Derrick
authors.forename: Idalia M
authors.initials: IM
authors.lastname: Yabe
authors.forename: Amy
authors.initials: A
authors.lastname: Yang
authors.forename: Kristopher
authors.initials: K
authors.lastname: Kolibab
authors.forename: Brynn
authors.initials: B
authors.lastname: Hollingsworth
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Kurtz
authors.forename: Sheldon
authors.initials: S
authors.lastname: Morris
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D058491:Bacterial Load; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D016207:Cytokines; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; C072681:Mycobacterium tuberculosis antigens
keywords: BCG; Tuberculosis