title: Prime-boost vaccination with rBCG/rAd35 enhances CD8⁺ cytolytic T-cell responses in lesions from Mycobacterium tuberculosis-infected primates.
abstract: To prevent the global spread of tuberculosis (TB) infection, a novel vaccine that triggers potent and long-lived immunity is urgently required. A plasmid-based vaccine has been developed to enhance activation of major histocompatibility complex (MHC) class I-restricted CD8⁺ cytolytic T cells using a recombinant Bacille Calmette-Guérin (rBCG) expressing a pore-forming toxin and the Mycobacterium tuberculosis (Mtb) antigens Ag85A, 85B and TB10.4 followed by a booster with a nonreplicating adenovirus 35 (rAd35) vaccine vector encoding the same Mtb antigens. Here, the capacity of the rBCG/rAd35 vaccine to induce protective and biologically relevant CD8⁺ T-cell responses in a nonhuman primate model of TB was investigated. After prime/boost immunizations and challenge with virulent Mtb in rhesus macaques, quantification of immune responses at the single-cell level in cryopreserved tissue specimen from infected organs was performed using in situ computerized image analysis as a technological platform. Significantly elevated levels of CD3⁺ and CD8⁺ T cells as well as cells expressing interleukin (IL)-7, perforin and granulysin were found in TB lung lesions and spleen from rBCG/rAd35-vaccinated animals compared with BCG/rAd35-vaccinated or unvaccinated animals. The local increase in CD8⁺ cytolytic T cells correlated with reduced expression of the Mtb antigen MPT64 and also with prolonged survival after the challenge. Our observations suggest that a protective immune response in rBCG/rAd35-vaccinated nonhuman primates was associated with enhanced MHC class I antigen presentation and activation of CD8⁺ effector T-cell responses at the local site of infection in Mtb-challenged animals.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Sayma
authors.initials: S
authors.lastname: Rahman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Magalhaes
authors.forename: Jubayer
authors.initials: J
authors.lastname: Rahman
authors.forename: Raija K
authors.initials: RK
authors.lastname: Ahmed
authors.forename: Donata R
authors.initials: DR
authors.lastname: Sizemore
authors.forename: Charles A
authors.initials: CA
authors.lastname: Scanga
authors.forename: Frank
authors.initials: F
authors.lastname: Weichold
authors.forename: Frank
authors.initials: F
authors.lastname: Verreck
authors.forename: Ivanela
authors.initials: I
authors.lastname: Kondova
authors.forename: Jerry
authors.initials: J
authors.lastname: Sadoff
authors.forename: Rigmor
authors.initials: R
authors.lastname: Thorstensson
authors.forename: Mats
authors.initials: M
authors.lastname: Spångberg
authors.forename: Mattias
authors.initials: M
authors.lastname: Svensson
authors.forename: Jan
authors.initials: J
authors.lastname: Andersson
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.forename: Susanna
authors.initials: S
authors.lastname: Brighenti
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D001500:BCG Vaccine / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D007117:Immunization, Secondary; D015851:Interleukin-7 / Q000378:metabolism; D008253:Macaca mulatta; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000517:prevention & control*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000378:metabolism; D014400:Tuberculosis, Splenic / Q000276:immunology / Q000378:metabolism; D014611:Vaccination
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D024042:Collagen Type I; D015851:Interleukin-7; C080865:MPB64 protein, Mycobacterium