Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans
Mangalakumari Jeyanathan, … , Zhou Xing, Fiona Smaill
Mangalakumari Jeyanathan, … , Zhou Xing, Fiona Smaill
Published January 6, 2022
Citation Information: JCI Insight. 2022;7(3):e155655. https://doi.org/10.1172/jci.insight.155655.
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Clinical Medicine Infectious disease Vaccines

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans

Abstract

Background Adenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. 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 i.m. injection.Methods Thirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. 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 i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue–resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. 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.Trial registration ClinicalTrial.gov, NCT02337270.Funding The Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Authors

Mangalakumari Jeyanathan, Dominik K. Fritz, Sam Afkhami, Emilio Aguirre, Karen J. Howie, Anna Zganiacz, Anna Dvorkin-Gheva, Michael R. Thompson, Richard F. Silver, Ruth P. Cusack, Brian D. Lichty, Paul M. O’Byrne, Martin Kolb, Maria Fe C. Medina, Myrna B. Dolovich, Imran Satia, Gail M. Gauvreau, Zhou Xing, Fiona Smaill

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Figure 4

Induction of airway tissue TRM following aerosol or i.m. vaccination.

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Induction of airway tissue TRM following aerosol or i.m. vaccination. (A...
(A) Representative dot plots of airway antigen–specific CD4+ and CD8+ TRM at wk2 in LD aerosol participants. (B) Frequencies of airway antigen–specific IFN-γ+CD4+ TRM coexpressing CD69 and CD103 surface markers at various time points in LD aerosol, HD aerosol, and i.m. vaccine cohorts. (C) Frequencies of airway antigen–specific IFN-γ+CD8+ TRM coexpressing CD69 and CD103 at various time points in LD aerosol, HD aerosol, and i.m. vaccine cohorts. (D) Comparison of frequencies of airway antigen–specific CD4+ and CD8+ TRM coexpressing CD69 and CD103 at 8 weeks after LD and HD aerosol vaccination. (E) Representative dot plots of peripheral blood antigen–specific IFN-γ+CD4+ T cells expressing CD49d at wk2 from LD aerosol participants, and frequencies of circulating antigen-specific CD4+ T cells expressing CD49d at various time points in LD aerosol, HD aerosol, and i.m. vaccine cohorts. (F) Representative dot plots of airway antigen–specific IFN-γ+CD4+ T cells expressing CD49d at wk2 from LD aerosol participants, and frequencies of airway antigen–specific CD4+ T cells expressing CD49d at various time points in LD aerosol, HD aerosol, and i.m. vaccine cohorts. (G) Comparison of frequencies of airway antigen–specific IFN-γ+CD4+ T cells coexpressing CD49d at the peak time point in LD aerosol, HD aerosol, and i.m. vaccine cohorts. Data in dot plots are expressed as the mean value (horizontal line) with 95% CI. Wilcoxon matched pairs signed-rank test (B, C, E, and F) was used to compare various time points with baseline values within the same vaccination group. Mann-Whitney U test (D and G) was used when comparing between vaccination groups.