Abstract
While most pathogens infect via mucosal surfaces, most current vaccines are delivered by injection. This situation remains despite awareness of the potential benefits of mucosal delivery for inducing protection against mucosa-infecting pathogens. A major obstacle to the development of such vaccines is the paucity of safe and effective adjuvants that induce mucosal responses in non-rodents. Previously we demonstrated in sheep the potency of pulmonary-delivered influenza ISCOMATRIX™ vaccine, which induces both mucosal and systemic immunity, even with low antigen doses. In the current study, lung pre-exposure to influenza antigen alone significantly reduced the immune response to subsequent pulmonary-delivered influenza ISCOMATRIX™ vaccine. A single dose of influenza antigen, delivered to the lung without exogenous adjuvant, upregulated IL-10 expression in bronchoalveolar lavage cells and FOXP3 expression in lung tissue, suggestive of induction of a regulatory T cell (Treg) response. However, this effect was inhibited by addition of ISCOMATRIX™ adjuvant. Moreover, effective pulmonary immunization with influenza ISCOMATRIX™ vaccine was associated with a depletion of Treg markers within lung tissues. Lung exposure to influenza antigen induced a localized mucosal tolerance that reduced the efficacy of subsequent influenza ISCOMATRIX™ vaccination. An important role of ISCOMATRIX™ adjuvant in pulmonary vaccination appears to be the depletion of Treg in lung tissues. Pulmonary vaccination remains capable of inducing a strong immune response against mucosal pathogens, but likely requires an adjuvant to overcome mucosal tolerance. ISCOMATRIX™ appears to have considerable potential as a mucosal adjuvant for use in humans, a major unmet need in mucosal vaccine development.