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.

Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations

“…Whilst it is recognised that neither IV nor IT BCG delivery strategies are appropriate for deployment in the clinical setting, recent NHP vaccine evaluation studies and early stage clinical trials have demonstrated that alternative vaccination strategies such as aerosol delivery are a practical, safe and immunogenic approach for the delivery of TB vaccines [43], [44], [57], [58], [59], [60]. The identification of IV-delivered BCG as a highly protective vaccination strategy may prove a pivotal step towards deciphering protective immunological mechanisms against M. tb infection in pre-clinical models, potentially leading to the identification of immune correlates of protection, which could be used to accelerate the vaccine development pipeline.…”

CXCR3 Signaling Is Required for Restricted Homing of Parenteral Tuberculosis Vaccine–Induced T Cells to Both the Lung Parenchyma and Airway

“…For intracellular cytokine staining cells were cultured in the presence of GolgiPlug (5 mg/ml brefeldin A; BD Pharmingen) with or without stimulation for 5-6 h with an Ag85Aspecific CD8 T cell-specific peptide (MPVGGQSSF) as previously described (11,31,32) at a concentration of 1 mg per well. In some experiments lung mononuclear cells were stimulated with crude bacillus Calmette-Guérin and M. tuberculosis culture filtrate Ags at a concentration of 1 mg per well of each stimuli (34). The cytotoxicity of CD8 T cells was evaluated by adding CD107a-FITC during the period of Ag stimulation (32).…”

New vaccines on the horizon

“…Virusni vektori mogu da se koriste za zaštitu od različitih infektivnih bolesti, npr. protiv onih koji su izazvani protozoama (malarija) (33), mikobakterijama (tuberkuloza) (34,35) ili virusima (HIV, Denga virus) (36,37). Od virusnih vektora najčešće se primenjuju adenovirusni vektori, za koje je pokazano da indukuju izuzetno snažan CD8+ T ćelijski odgovor kao i produkciju antitela (38).…”