Abstract
Eliciting durable and protective T cell-mediated immunity in the respiratory mucosa remains a significant challenge. Polylactic-co-glycolic acid (PLGA)-based cationic pathogen-like particles (PLPs) loaded with TLR agonists mimic biophysical properties of microbes and hence, simulate pathogen-pattern recognition receptor interactions to safely and effectively stimulate innate immune responses. We generated micro particle PLPs loaded with TLR4 (glucopyranosyl lipid adjuvant, GLA) or TLR9 (CpG) agonists, and formulated them with and without a mucosal delivery enhancing carbomer-based nanoemulsion adjuvant (ADJ). These adjuvants delivered intranasally to mice elicited high numbers of influenza nucleoprotein (NP)-specific CD8+ and CD4+ effector and tissue-resident memory T cells (TRMs) in lungs and airways. PLPs delivering TLR4 versus TLR9 agonists drove phenotypically and functionally distinct populations of effector and memory T cells. While PLPs loaded with CpG or GLA provided immunity, combining the adjuvanticity of PLP-GLA and ADJ markedly enhanced the development of airway and lung TRMs and CD4 and CD8 T cell-dependent immunity to influenza virus. Further, balanced CD8 (Tc1/Tc17) and CD4 (Th1/Th17) recall responses were linked to effective influenza virus control. These studies provide mechanistic insights into vaccine-induced pulmonary T cell immunity and pave the way for the development of a universal influenza and SARS-CoV-2 vaccines.
Highlights
Respiratory infections in adults and children have been among the top three leading causes of death and disability in the world for decades [1, 2]
To circumvent this problem and mimic the biophysical attributes of pathogens and their interactions with pattern recognition receptors, we engineered biodegradable Polylactic-co-glycolic acid (PLGA) microparticles (i.e. pathogen-like particles (PLPs)) that were loaded with optimized densities of TLR agonists CpG and Glucopyranosyl Lipid Adjuvant (GLA) [19]
We document that mucosal delivery of CpG- or GLA-loaded PLPs elicit unexpectedly potent mucosally imprinted antigen-specific CD4 and CD8 T cell responses in the respiratory tract
Summary
Respiratory infections in adults and children have been among the top three leading causes of death and disability in the world for decades [1, 2]. We have tested a novel adjuvant, Adjuplex (ADJ, a nano emulsion of carbomer and soy lethicin [15]), that when combined with subunit or IIV proteins potently induced CD8+ lung TRM cell responses after mucosal administration, and conferred substantial protection to influenza virus challenge [16, 17] These studies highlight the importance for identification of novel adjuvants that can elicit mucosal CMI to non-replicating antigens, so we can dissect and study the individual effects these adjuvants have on the magnitude and nature of the resultant mucosal CMI responses. We observed that PLP-based adjuvants afforded strong and durable protection from influenza challenge that was closely associated with distinct functional recall profiles of CD4 and CD8 T cells unique to the PLP vaccine formulation These results highlight that PLP-loaded adjuvants can distinctly program effective CMI and can be leveraged to study immunity and develop vaccines to respiratory pathogens such as influenza virus and SARS-CoV-2
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