title: Evaluation of the sublingual route for administration of influenza H5N1 virosomes in combination with the bacterial second messenger c-di-GMP.
abstract: Avian influenza A H5N1 is a virus with pandemic potential. Mucosal vaccines are attractive as they have the potential to block viruses at the site of entry, thereby preventing both disease and further transmission. The intranasal route is safe for the administration of seasonal live-attenuated influenza vaccines, but may be less suitable for administration of pandemic vaccines. Research into novel mucosal routes is therefore needed. In this study, a murine model was used to compare sublingual administration with intranasal and intramuscular administration of influenza H5N1 virosomes (2 µg haemagglutinin; HA) in combination with the mucosal adjuvant (3',5')-cyclic dimeric guanylic acid (c-di-GMP). We found that sublingual immunisation effectively induced local and systemic H5N1-specific humoral and cellular immune responses but that the magnitude of response was lower than after intranasal administration. However, both the mucosal routes were superior to intramuscular immunisation for induction of local humoral and systemic cellular immune responses including high frequencies of splenic H5N1-specific multifunctional (IL-2+TNF-α+) CD4+ T cells. The c-di-GMP adjuvanted vaccine elicited systemic haemagglutination inhibition (HI) antibody responses (geometric mean titres ≥ 40) both when administered sublingually, intranasally and inramuscularly. In addition, salivary HI antibodies were elicited by mucosal, but not intramuscular vaccination. We conclude that the sublingual route is an attractive alternative for administration of pandemic influenza vaccines.
authors: The Gade Institute, University of Bergen, Norway. gabriel.pedersen@gades.uib.no
authors: Gabriel Kristian
authors: GK
authors: Pedersen
authors: Thomas
authors: T
authors: Ebensen
authors: Ingrid Hjetland
authors: IH
authors: Gjeraker
authors: Signe
authors: S
authors: Svindland
authors: Geir
authors: G
authors: Bredholt
authors: Carlos Alberto
authors: CA
authors: Guzmán
authors: Rebecca Jane
authors: RJ
authors: Cox
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D058956:Administration, Mucosal; D000286:Administration, Sublingual; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D049109:Cell Proliferation; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D006385:Hemagglutination Inhibition Tests; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D012463:Saliva / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015290:Second Messenger Systems / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014611:Vaccination; D022701:Virosomes
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007252:Influenza Vaccines; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D022701:Virosomes; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP