Background

Adenovirus-vectored (Ad-vectored) vaccines are typically administered via im injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or im injection.

Methods

Thirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by im injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and im groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.

Results

The nebulized aerosol droplets were< 5.39 μm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and im injection were safe and well tolerated. Both aerosol doses, particularly LD, but not im, vaccination markedly induced airway tissue–resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, im vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.

Conclusion

Inhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.