title: A new intranasal influenza vaccine based on a novel polycationic lipid--ceramide carbamoyl-spermine (CCS) I. Immunogenicity and efficacy studies in mice.
abstract: Although most pathogens use the mucosal routes for invasion, the majority of currently available vaccines are administered parenterally. Injectable vaccines induce good systemic immunity but often unsatisfactory mucosal immunity. A non-injectable mucosal vaccine, which can be self-administered intranasally, may provide both effective systemic and mucosal immunity and can be used for vaccination of large populations within a short period of time in case of a sudden epidemic. Here, we report on a new intranasal (i.n.) influenza vaccine, based on a novel polycationic sphingolipid, N-palmitoyl D-erythro-sphingosyl carbamoyl-spermine (ceramide carbamoyl-spermine = CCS), having combined carrier and adjuvant activities, which elicits, in mice, strong systemic (serum) and local (lung and nasal) humoral and cellular responses, and provides protective immunity. In a comparative study, we show that both unmodified commercial vaccine and vaccine formulated with neutral or anionic liposomes were poorly immunogenic upon i.n. administration. Of five vaccine formulations based on well-established monocationic lipids in the form of unsized liposomes, three (DC-Chol, DDAB, and DSTAP-based) resulted in low serum and local responses, while two others (DMTAP and DOTAP-based vaccines) induced both systemic and local vigorous Th1+Th2 immune responses. However, only the vaccine formulated with CCS was equivalent or superior to the commercial vaccine co-administered with cholera toxin as an adjuvant. Furthermore, the CCS-based influenza vaccine was highly efficacious following a single or a repeated (x2) i.n. or a single i.m. administration, without an added adjuvant, in both young (2 months) and old (18 months) mice. It elicited high titers of strain cross-reactive hemagglutination inhibition (HI) antibodies, and the high antibody titers and protective immunity persisted for at least 9 months. No systemic adverse effects, and only a mild local inflammatory response, were observed in mice and rabbits vaccinated i.n. with the CCS vaccine formulation. A similar approach may prove efficacious for i.n. vaccination against other pathogens.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Joseph
authors.forename: Noga
authors.initials: N
authors.lastname: Itskovitz-Cooper
authors.forename: Sarit
authors.initials: S
authors.lastname: Samira
authors.forename: Orli
authors.initials: O
authors.lastname: Flasterstein
authors.forename: Hagit
authors.initials: H
authors.lastname: Eliyahu
authors.forename: Dmitri
authors.initials: D
authors.lastname: Simberg
authors.forename: Itzik
authors.initials: I
authors.lastname: Goldwaser
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 / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D049109:Cell Proliferation; D002518:Ceramides; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006385:Hemagglutination Inhibition Tests; D018928:Immunity, Mucosal; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D008081:Liposomes / Q000737:chemistry; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D017817:Nasal Lavage Fluid / Q000276:immunology; D011073:Polyamines; D000071228:Polyelectrolytes; D011817:Rabbits; D013096:Spermine; D013154:Spleen / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D002518:Ceramides; D002772:Cholera Toxin; D016207:Cytokines; D007252:Influenza Vaccines; D008081:Liposomes; D011073:Polyamines; D000071228:Polyelectrolytes; D013096:Spermine