Abstract
BackgroundAdenovirus-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.MethodsThirty-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.ResultsThe 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.ConclusionInhaled 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 registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.
Highlights
Pulmonary tuberculosis (TB) continues to be a major global health issue, accounting for 1.4 million deaths and 10 million new cases in 2019 [1]
Four participants were excluded (2 withdrew consent and 2 were withdrawn before vaccination because they were unable to comply with the study visit requirements) and 1 did not complete any follow-up visits after vaccination because of COVID restrictions
A fill volume (FV) of 0.5 mL in the nebulizer was determined to be optimal for vaccine delivery in saline
Summary
Pulmonary tuberculosis (TB) continues to be a major global health issue, accounting for 1.4 million deaths and 10 million new cases in 2019 [1]. Among the promising vaccine platforms is a recombinant replication-defective human serotype 5 adenovirus-vectored (AdHu5-vectored) TB vaccine expressing M. tuberculosis antigen 85A (AdHu5Ag85A) This vaccine has been extensively evaluated in a number of preclinical models, shown to be highly effective when administered via the respiratory tract, as opposed to its parenteral delivery [3, 4]. It is widely believed that the most effective vaccine strategy ought to induce both innate memory and adaptive memory responses [5, 7] It remains unclear whether such highly compartmentalized distribution of immunity dictated by the route of Ad-vectored immunization is true in humans. 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
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