title: Novel chimpanzee adenovirus-vectored respiratory mucosal tuberculosis vaccine: overcoming local anti-human adenovirus immunity for potent TB protection.
abstract: Pulmonary tuberculosis (TB) remains to be a major global health problem despite many decades of parenteral use of Bacillus Calmette-Guérin (BCG) vaccine. Developing safe and effective respiratory mucosal TB vaccines represents a unique challenge. Over the past decade or so, the human serotype 5 adenovirus (AdHu5)-based TB vaccine has emerged as one of the most promising candidates based on a plethora of preclinical and early clinical studies. However, anti-AdHu5 immunity widely present in the lung of humans poses a serious gap and limitation to its real-world applications. In this study we have developed a novel chimpanzee adenovirus 68 (AdCh68)-vectored TB vaccine amenable to the respiratory route of vaccination. We have evaluated AdCh68-based TB vaccine for its safety, T-cell immunogenicity, and protective efficacy in relevant animal models of human pulmonary TB with or without parenteral BCG priming. We have also compared AdCh68-based TB vaccine with its AdHu5 counterpart in both naive animals and those with preexisting anti-AdHu5 immunity in the lung. We provide compelling evidence that AdCh68-based TB vaccine is not only safe when delivered to the respiratory tract but, importantly, is also superior to its AdHu5 counterpart in induction of T-cell responses and immune protection, and limiting lung immunopathology in the presence of preexisting anti-AdHu5 immunity in the lung. Our findings thus suggest AdCh68-based TB vaccine to be an ideal candidate for respiratory mucosal immunization, endorsing its further clinical development in humans.
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: M
authors: M
authors: Jeyanathan
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: N
authors: N
authors: Thanthrige-Don
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: S
authors: S
authors: Afkhami
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: R
authors: R
authors: Lai
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: D
authors: D
authors: Damjanovic
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: A
authors: A
authors: Zganiacz
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: X
authors: X
authors: Feng
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: X-D
authors: XD
authors: Yao
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: K L
authors: KL
authors: Rosenthal
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: M Fe
authors: MF
authors: Medina
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: J
authors: J
authors: Gauldie
authors: Department of Immunology, The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors: H C
authors: HC
authors: Ertl
authors: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine and Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors: Z
authors: Z
authors: Xing
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D002679:Pan troglodytes; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D032581:Tuberculosis Vaccines