Superior protection and distinct phenotype of pulmonary CD8+ T cells elicited by mucosal vaccination (MUC5P.863)

Abstract

Abstract CD8-positive T cells (CTLs) confer protective immunity against many infectious diseases, and thus the development of safe and efficient CTL-targeted vaccination is of high clinical significance. Although many respiratory pathogens invade the host through the lung mucosa, most licensed human vaccines elicit limited and systemic T cell responses, rather than strong local pulmonary responses. We therefore wondered whether elicitation of pulmonary CTL response with microbe-free CTL-targeted subunit vaccine might benefit the host and protect against respiratory infections. We discovered superior protection of humanized mice from lethal respiratory challenge with vaccinia virus with intranasal, but not intra-peritoneal, vaccination. Critically, this superior protection did not correlate with the magnitude of the systemic CTL response but was dependent on in situ elicitation of robust pulmonary epitope-specific CTLs, which were able to limit viral replication and prevent disease. Global transcriptome analysis revealed that pulmonary CTLs elicited by vaccination possessed distinct phenotypic and functional properties when compared to CTLs that homed to the spleen. To extend this finding, we developed an approach for eliciting protective CTL responses that utilizes nanoparticle-based mucosal delivery of epitope-targeted vaccine formulated with an optimal adjuvant.