title: Liposomal immunostimulatory DNA sequence (ISS-ODN): an efficient parenteral and mucosal adjuvant for influenza and hepatitis B vaccines.
abstract: Synthetic oligodeoxynucleotides (ODNs) containing immunostimulatory sequences (ISS-ODN, also known as CpG-ODNs) have been shown to display in experimental models potent Th1-biassed immunoadjuvant activity upon parenteral or mucosal co-administration with a variety of antigens. In an attempt to potentiate adjuvant activity, and to reduce dose and number of administrations, ISS-ODN was entrapped (up to 90% efficiency) in large (1.5 microm) multilamellar liposomes using a simple and fast (5 min) procedure. Mice were vaccinated once or twice intramuscularly (i.m.) or intranasally (i.n.) with subunit influenza vaccines (consisting of the viral hemagglutinin and neuraminidase, HN) or with hepatitis B surface antigen particles (HBsAg), either non-encapsulated or liposome-encapsulated, together with free or liposomal ISS-ODN (5-25 microg per dose). At 3-12 weeks post-vaccination, the humoral (systemic, mucosal) and cellular responses and protective immunity were assessed. Vaccine formulations containing liposomal ISS-ODN co-administered with either soluble antigen or liposomal antigen (in the same vesicles or in separate vesicles) were up to 30 times more effective than formulations containing un-encapsulated ISS-ODN in inducing: (a) antigen-specific serum and mucosal IgG2a and IgA antibodies; (b) splenocyte proliferative response, cytotoxic activity and IFNgamma production; (c) a DTH response; and (d) protection against virus challenge. The response was Th1-dominant in the influenza model and a mixed Th1+Th2 response in the hepatitis B model. No adverse reactions were noted. Thus, liposomal encapsulation of ISS-ODN further enhances its inherent adjuvant activity.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Joseph
authors.forename: Igal
authors.initials: I
authors.lastname: Louria-Hayon
authors.forename: Alla
authors.initials: A
authors.lastname: Plis-Finarov
authors.forename: Evelyne
authors.initials: E
authors.lastname: Zeira
authors.forename: Zichria
authors.initials: Z
authors.lastname: Zakay-Rones
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Takabayashi
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
authors.forename: Eli
authors.initials: E
authors.lastname: Kedar
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001483:Base Sequence; D004355:Drug Stability; D005260:Female; D006510:Hepatitis B Antibodies / Q000096:biosynthesis; D017325:Hepatitis B Vaccines / Q000008:administration & dosage*; D018928:Immunity, Mucosal; D007252:Influenza Vaccines / Q000008:administration & dosage*; D007273:Injections, Intramuscular; D008081:Liposomes; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000235:genetics*; D009975:Orthomyxoviridae / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; C408982:CPG-oligonucleotide; D006510:Hepatitis B Antibodies; D017325:Hepatitis B Vaccines; D007252:Influenza Vaccines; D008081:Liposomes; D009838:Oligodeoxyribonucleotides