title: HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.
abstract: Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF) are potential adjuvants for adenoviral vector (Ad5) vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag) adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD27L constructed as soluble multi-trimeric proteins via fusion to Surfactant Protein D (SP-D) as a multimerization scaffold. Mice were vaccinated with Ad5-Gag combined with Ad5 expressing one of the SP-D-TNFSF constructs or single-chain IL-12p70 as adjuvant. To evaluate vaccine-induced protection, mice were challenged with vaccinia virus expressing Gag (vaccinia-Gag) which is known to target the female genital tract, a major route of sexually acquired HIV-1 infection. In this system, SP-D-4-1BBL or SP-D-BAFF led to significantly reduced vaccinia-Gag replication when compared to Ad5-Gag alone. In contrast, IL-12p70, SP-D-CD27L and SP-D-GITRL were not protective. Histological examination following vaccinia-Gag challenge showed a dramatic lymphocytic infiltration into the uterus and ovaries of SP-D-4-1BBL and SP-D-BAFF-treated animals. By day 5 post challenge, proinflammatory cytokines in the tissue were reduced, consistent with the enhanced control over viral replication. Splenocytes had no specific immune markers that correlated with protection induced by SP-D-4-1BBL and SP-D-BAFF versus other groups. IL-12p70, despite lack of anti-viral efficacy, increased the total numbers of splenic dextramer positive CD8+ T cells, effector memory T cells, and effector Gag-specific CD8+ T cells, suggesting that these markers are poor predictors of anti-viral immunity in this model. In conclusion, soluble multi-trimeric 4-1BBL and BAFF adjuvants led to strong protection from vaccinia-Gag challenge, but the protection was independent of standard immune markers. Soluble multi-trimeric SP-D-4-1BBL and SP-D-BAFF provide a novel technology to enhance adenoviral vector vaccines against HIV-1.
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Saravana
authors.initials: S
authors.lastname: Kanagavelu
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Termini
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Sachin
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Francesca N
authors.initials: FN
authors.lastname: Raffa
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fuller
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Yaelis
authors.initials: Y
authors.lastname: Rivas
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Sakhi
authors.initials: S
authors.lastname: Philip
authors.affiliation: Multimeric Biotherapeutics, Inc., La Jolla, California, United States of America.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kornbluth
authors.affiliation: Department of Microbiology and Immunology, Miami Center for AIDS Research, and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Stone
mesh_terms: D053330:4-1BB Ligand / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D053264:B-Cell Activating Factor / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D005260:Female; D015870:Gene Expression; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007110:Immunity, Active; D018655:Lymphocyte Count; D051379:Mice; D055503:Protein Multimerization; D014611:Vaccination; D022223:Vaccines, Subunit; D014616:Vaccinia virus / Q000276:immunology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D053330:4-1BB Ligand; D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D053264:B-Cell Activating Factor; D015683:Gene Products, gag; C505720:Tnfsf13b protein, mouse; D022223:Vaccines, Subunit