title: Natural killer T cell and TLR9 agonists as mucosal adjuvants for sublingual vaccination with clade C HIV-1 envelope protein.
abstract: The vast majority of HIV-1 infections occur at mucosa during sexual contact. It may therefore be advantageous to provide mucosal barrier protection against this entry by mucosal vaccination. While a number of mucosal routes of vaccination are possible, many like enteric oral vaccines or intranasal vaccines have significant impediments that limit vaccine efficacy or pose safety risks. In contrast, immunogens applied to the sublingual region of the mouth could provide a simple route for mucosal vaccination. While sublingual immunization is appealing, this site does not always drive strong immune responses, particularly when using protein antigens. To address this issue, we have tested the ability of two mucosal adjuvants: alpha-galactosylceramide (αGalCer) that is a potent stimulator of natural killer T cells and CpG-oligodeoxynucleotide (CpG-ODN) a TLR9 agonist for their ability to amplify immune responses against clade C gp140 HIV-1 envelope protein antigen. Immunization with envelope protein alone resulted in a weak T cell and antibody responses. In contrast, CD4(+) and CD8(+) T cells responses in systemic and mucosal tissues were significantly higher in mice immunized with gp140 in the presence of either αGalCer or CpG-ODN and these responses were further augmented when the two adjuvants were used together. While both the adjuvants effectively increased gp140-specific serum IgG and vaginal IgA antibody levels, combining both significantly improved these responses. Memory T cell responses 60 days after immunization revealed αGalCer to be more potent than CpG-ODN and the combination of the αGalCer and CpG-ODN adjuvants was more effective than either alone. Serum and vaginal washes collected 60 days after immunization with gp140 with both αGalCer and CpG-ODN adjuvants had significant neutralization activity against Tier 1 and Tier 2 SHIVs. These data support the utility of the sublingual route for mucosal vaccination particularly in combination with αGalCer and CpG-ODN adjuvants.
authors.affiliation: Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Shailbala
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Guojun
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory University, Atlanta, GA, United States.
authors.forename: Siddappa N
authors.initials: SN
authors.lastname: Byrareddy
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Translational Immunovirology Program, Department of Immunology, Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
authors.affiliation: Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States; Department of Veterinary Sciences, The University of Texas M.D. Anderson Cancer Center, Bastrop, TX, United States. Electronic address: jsastry@mdanderson.org.
authors.forename: K Jagannadha
authors.initials: KJ
authors.lastname: Sastry
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000286:Administration, Sublingual; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage; D015483:HIV Antibodies / Q000032:analysis / Q000097:blood; D015497:HIV-1 / Q000276:immunology*; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000097:blood; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D014611:Vaccination / Q000379:methods*; D014621:Vagina / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D005699:Galactosylceramides; D015483:HIV Antibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C493154:alpha-galactosylceramide; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1
keywords: Clade C HIV-1; Mucosal adjuvants; Mucosal vaccine; NKT cell agonist; Sublingual; TLR9 agonist; Vaccine