title: Induction of CD8+ T-cell responses against subunit antigens by the novel cationic liposomal CAF09 adjuvant.
abstract: Vaccines inducing cytotoxic T-cell responses are required to achieve protection against cancers and intracellular infections such as HIV and Hepatitis C virus. Induction of CD8+ T cell responses in animal models can be achieved by the use of viral vectors or DNA vaccines but so far without much clinical success. Here we describe the novel CD8+ T-cell inducing adjuvant, cationic adjuvant formulation (CAF) 09, consisting of dimethyldioctadecylammonium (DDA)-liposomes stabilized with monomycoloyl glycerol (MMG)-1 and combined with the TLR3 ligand, Poly(I:C). Different antigens from tuberculosis (TB10.3, H56), HIV (Gag p24), HPV (E7) and the model antigen ovalbumin were formulated with CAF09 and administering these vaccines to mice resulted in a high frequency of antigen-specific CD8+ T cells. CAF09 was superior in its ability to induce antigen-specific CD8+ T cells as compared to other previously described CTL-inducing adjuvants, CAF05 (DDA/trehalose dibehenate (TDB)/Poly(I:C)), Aluminium/monophosphoryl lipid-A (MPL) and Montanide/CpG/IL-2. The optimal effect was obtained when the CAF09-adjuvanted vaccine was administered by the i.p. route, whereas s.c. administration primed limited CD8+ T-cell responses. The CD4+ T cells induced by CAF09 were mainly of an effector-memory-like phenotype and the CD8+ T cells were highly cytotoxic. Finally, in a mouse therapeutic skin tumor model, the HPV-16 E7 antigen formulated in CAF09 significantly reduced the growth of already established subcutaneous E7-expressing TC-1 tumors in 38% of the mice and in a corresponding prophylactic model 100% of the mice were protected. Thus, CAF09 is a potent new adjuvant which is able to induce CD8+ T-cell responses against several antigens and to enhance the protective efficacy of an E7 vaccine both in a therapeutic and in a prophylactic tumor model.
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: kkn@ssi.dk.
authors.forename: Karen Smith
authors.initials: KS
authors.lastname: Korsholm
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: joa@ssi.dk.
authors.forename: Jon
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: kasp@ssi.dk.
authors.forename: Kasper
authors.initials: K
authors.lastname: Karlsen
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: jtf@ssi.dk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Filskov
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: marianne.mikkelsen@dbac.dk.
authors.forename: Marianne
authors.initials: M
authors.lastname: Mikkelsen
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: thi@ssi.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lindenstrøm
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: sxs@ssi.dk.
authors.forename: Signe Tandrup
authors.initials: ST
authors.lastname: Schmidt
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: pa@ssi.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark. Electronic address: den@ssi.dk.
authors.forename: Dennis
authors.initials: D
authors.lastname: Christensen
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002412:Cations / Q000494:pharmacology; D005260:Female; D007111:Immunity, Cellular; D008081:Liposomes / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000276:immunology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D002412:Cations; D008081:Liposomes; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D011070:Poly I-C
keywords: Adjuvant; CAF09; CD8+ T cells; CTL; Cationic liposome; Vaccine