Abstract
Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette-Guérin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB. The introduction of novel boost vaccines such as the human Adenovirus 5-vectored AdHu5Ag85A could improve and prolong the protective immunity of BCG immunization. Age at which BCG immunization is implemented varies greatly worldwide, and research is ongoing to discover the optimal stage during childhood to administer the vaccine, as well as when to boost the immune response with potential novel vaccines. Using a murine model of subcutaneous BCG immunization followed by intranasal AdHu5Ag85A boosting, we investigated the impact of age at BCG immunization on protective efficacy of BCG prime and AdHu5Ag85A boost immunization-mediated protection. Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection. However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization. Our findings hold implications for the design of new TB immunization protocols for humans.
Highlights
The unrelenting nature of the global tuberculosis (TB) epidemic is partly due to the inefficacy of Bacillus Calmette-Guérin (BCG), the only licensed vaccine against TB, as it fails to effectively control adult pulmonary TB in endemic countries [1, 2]
At specified time points post-immunization Ag-specific IFN-γ+CD4+ T cell responses were enumerated by flow cytometry after in vitro stimulation of lung and spleen mononuclear cells with crude mycobacterial antigens (CF+crude BCG (cBCG))
BCG immunization in infant and adult mice led to a comparable magnitude of Ag-specific responses at 8 and 16 weeks post-immunization, a significantly increased number of IFN-γ+CD4+ cells was found in the lung at 4 weeks in mice BCG immunized as infants compared to mice immunized as adults (Fig 1A)
Summary
The unrelenting nature of the global tuberculosis (TB) epidemic is partly due to the inefficacy of BCG, the only licensed vaccine against TB, as it fails to effectively control adult pulmonary TB in endemic countries [1, 2]. Impact of Age at BCG Priming on Mucosal AdHu5Ag85A Immunization [3,4,5] In this regard the human Adenovirus 5-vectored TB vaccine (AdHu5Ag85A) developed in our laboratory has been shown to effectively boost BCG in a variety of animal models when administered via the respiratory mucosal route [6,7,8,9,10]. It is among the major candidate vaccines currently considered to be introduced into the human immunization program for respiratory mucosal boost immunization in BCG vaccinees [7,8,9,10,11]. An advanced candidate TB vaccine, modified vaccinia virus Ankara (MVA) expressing Ag85A has already been evaluated in healthy humans for aerosol vaccination and found to be immunogenic and safe [12]
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