title: Aerosol vaccination with AERAS-402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high-dose Mycobacterium tuberculosis challenge.
abstract: Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag-specific CD4 and CD8 T cells in the lung. The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans. In this study, we used an aerosol vaccination strategy to administer AERAS-402, a replication-defective recombinant adenovirus (rAd) type 35 expressing Mycobacterium tuberculosis Ags Ag85A, Ag85B, and TB10.4, in bacillus Calmette-Guérin (BCG)-primed or unprimed rhesus macaques. Immunization with BCG generated low purified protein derivative-specific CD4 T cell responses in blood and bronchoalveolar lavage. In contrast, aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific CD4 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-γ, as well as TNF and IL-2. Such responses induced by BCG, AERAS-402, or both failed to confer overall protection following challenge with 275 CFUs M. tuberculosis Erdman, although vaccine-induced responses associated with reduced pathology were observed in some animals. Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge. Overall, our data suggest that a high M. tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model. However, the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens, alternative rAd serotypes with enhanced immunogenicity, and a physiological challenge dose may achieve protection against M. tuberculosis.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Diane L
authors.initials: DL
authors.lastname: Bolton
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lackner
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: Pyone Pyone
authors.initials: PP
authors.lastname: Aye
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: James L
authors.initials: JL
authors.lastname: Blanchard
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Didier
authors.affiliation: Tulane National Primate Research Center, Covington, LA 70433; and.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
authors.affiliation: Aeras, Rockville, MD 20850.
authors.forename: David A
authors.initials: DA
authors.lastname: Hokey
authors.affiliation: Aeras, Rockville, MD 20850.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Scanga
authors.affiliation: Aeras, Rockville, MD 20850.
authors.forename: Donata R
authors.initials: DR
authors.lastname: Sizemore
authors.affiliation: Aeras, Rockville, MD 20850.
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Sadoff
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; rseder@mail.nih.gov.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000217:Acyltransferases / Q000276:immunology; D000280:Administration, Inhalation; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008253:Macaca mulatta; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000821:virology; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology*
chemical_list: C000592463:AERAS-402; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D007376:Interleukin-2; C501710:TB10.4 antigen, Mycobacterium tuberculosis; D032581:Tuberculosis Vaccines; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; C121433:antigen 85B, Mycobacterium tuberculosis