Polymeric Pathogen-Like Particles-Based Combination Adjuvants Elicit Potent Mucosal T Cell Immunity to Influenza A Virus

• Type of Material: Article
• Authors: Brock Kingstad-Bakke, University of Wisconsin-Madison; Randall Toy, Georgia Institute of Technology; Woojong Lee, Univ Wisconsin; Pallab Pradhan, Georgia Institute of Technology; Gabriela Vogel, Georgia Institute of Technology; Chandranaik B Marinaik, University of Wisconsin-Madison; Autumn Larsen, University of Wisconsin-Madison; Daisy Gates, University of Wisconsin-Madison; Tracy Luu, University of Wisconsin-Madison; Bhawana Pandey, Georgia Institute of Technology; Yoshihoro Kawaoka, Univ Wisconsin; Krishnendu Roy, Emory University; M Suresh, University of Wisconsin-Madison
• Language: English
• Date: 2021-03-04
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Kingstad-Bakke, Toy, Lee, Pradhan, Vogel, Marinaik, Larsen, Gates, Luu, Pandey, Kawaoka, Roy and Suresh
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2020.559382
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 11
• Start Page: 559382
• End Page: 559382
• Grant/Funding Information: This study was supported by PHS grants from the National Institutes of Health (grant# U01AI124299 and R21 AI149793 ) and funds from the John E. Butler Professorship to MS. WL was supported by a pre-doctoral fellowship from the American Heart Association. KR was supported by a PHS grant from the National institutes of Health (grant #:U01AI124270).
• Keywords: Life Sciences & Biomedicine; adjuvants; tissue-resident memory; influenza A virus; CD8; vaccine; polyfunctional; FTY720; AGONISTS; CD4; Immunology; Science & Technology
• Research Categories: Engineering, Biomedical

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.