title: TLR7 and 9 agonists are highly effective mucosal adjuvants for norovirus virus-like particle vaccines.
abstract: Virus-like particles (VLPs) are an active area of vaccine research, development and commercialization. Mucosal administration of VLPs provides an attractive avenue for delivery of vaccines with the potential to produce robust immune responses. Nasal and oral delivery routes are particularly intriguing due to differential activation of mucosa-associated lymphoid tissues. We compared both intranasal and oral administration of VLPs with a panel of toll-like receptor (TLR) agonists (TLR3, 5, 7, 7/8, and 9) to determine the mucosal adjuvant activity of these immunomodulators. We selected Norwalk virus (NV) VLPs because it is an effective model antigen and an active area of research and commercialization. To prioritize these adjuvants, VLP-specific antibody production in serum (IgG, IgG1, IgG2a), vaginal lavages (IgG, IgA), and fecal pellets (IgA) were measured across a longitudinal timeseries in vaccinated mice. Additional distal mucosal sites (nasal, brochoalveolar, salivary, and gastrointestinal) were evaluated for VLP-specific responses (IgA). Intranasal co-delivery of VLPs with TLR7 or TLR9 agonists produced the most robust and broad-spectrum immune responses, systemically and at distal mucosal sites inducing VLP-specific antibodies at all sites evaluated. In addition, these VLP-specific antibodies blocked binding of NV VLPs to histo-blood group antigen (H type 1), supporting their functionality. Oral administration and/or other TLR agonists tested in the panel did not consistently enhance VLP-specific immune responses. This study demonstrates that intranasal co-delivery of VLPs with TLR7 or TLR9 agonists provides dose-sparing advantages for induction of specific and functional antibody responses against VLPs (i.e., non-replicating antigens) in the respiratory, gastrointestinal, and reproductive tract.
authors.affiliation: Center for Infectious Diseases and Vaccinology; The Biodesign Institute; Arizona State University; Tempe, AZ USA; Neurogenomics Division; The Translational Genomics Research Institute (TGen); Phoenix, AZ USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Hjelm
authors.affiliation: Center for Infectious Diseases and Vaccinology; The Biodesign Institute; Arizona State University; Tempe, AZ USA.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Kilbourne
authors.affiliation: Department of Basic Medical Sciences; University of Arizona College of Medicine-Phoenix; Phoenix, AZ USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Herbst-Kralovetz
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D058956:Administration, Mucosal; D000284:Administration, Oral; D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis / Q000097:blood; D017250:Caliciviridae Infections / Q000276:immunology / Q000517:prevention & control*; D005243:Feces / Q000737:chemistry; D005260:Female; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000097:blood; D008562:Membrane Glycoproteins / Q000819:agonists*; D008807:Mice, Inbred BALB C; D009663:Norwalk virus / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*; D014621:Vagina / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D058425:Vaccines, Virus-Like Particle
keywords: TLR agonists; antibody production; mucosal adjuvants; mucosal immunology; nasal vaccination; norovirus; oral vaccination; virus-like particles