Programming effective respiratory immunity to influenza with combination microparticle adjuvants

Abstract

Abstract T cell-mediated immunity (CMI) can provide long-lived protection following parenteral immunization, but eliciting durable and protective CMI in the mucosa remains a significant challenge. Here, using polylactic-co-glycolic acid (PLGA)-based cationic pathogen-like particles (PLPs) for delivery of TLR agonists, we have investigated novel ways of presenting vaccine components to the immune system to simulate the potent innate immune stimulating effects of pathogens. We generated micro particle sized PLPs loaded with TLR4 (glucopyranosyl lipid adjuvant, GLA) and/or TLR9 (CpG) agonists, and formulated them with and without a mucosal delivery enhancing carbomer-based nano-emulsion adjuvant (ADJ). These adjuvants delivered intranasally to mice safely elicited robust and durable influenza nucleoprotein (NP)-specific CD8+/CD4+ effector and tissue-resident memory responses in lungs and airways. PLPs delivering TLR4 versus TLR9 agonists drove phenotypically and functionally distinct populations of effector and memory T cells. Following influenza virus challenge, functional and phenotypic attributes of effector T cells unique to the individual PLP formulation were associated with disparate levels of viral control in the respiratory tract. These studies demonstrate: (1) how adjuvant formulations affect effector/memory T cell differentiation in the lungs; (2) feasibility of using PLGA-based PLPs in vaccine formulations to elicit protective T cell immunity in the respiratory tract.