title: Deletion of specific immune-modulatory genes from modified vaccinia virus Ankara-based HIV vaccines engenders improved immunogenicity in rhesus macaques.
abstract: Modified vaccinia virus Ankara (MVA) is a safe, attenuated orthopoxvirus that is being developed as a vaccine vector but has demonstrated limited immunogenicity in several early-phase clinical trials. Our objective was to rationally improve the immunogenicity of MVA-based HIV/AIDS vaccines via the targeted deletion of specific poxvirus immune-modulatory genes. Vaccines expressing codon-optimized HIV subtype C consensus Env and Gag antigens were generated from MVA vector backbones that (i) harbor simultaneous deletions of four viral immune-modulatory genes, encoding an interleukin-18 (IL-18) binding protein, an IL-1β receptor, a dominant negative Toll/IL-1 signaling adapter, and CC-chemokine binding protein (MVAΔ4-HIV); (ii) harbor a deletion of an additional (fifth) viral gene, encoding uracil-DNA glycosylase (MVAΔ5-HIV); or (iii) represent the parental MVA backbone as a control (MVA-HIV). We performed head-to-head comparisons of the cellular and humoral immune responses that were elicited by these vectors during homologous prime-boost immunization regimens utilizing either high-dose (2 × 10(8) PFU) or low-dose (1 × 10(7) PFU) intramuscular immunization of rhesus macaques. At all time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates.
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. david.garber@cdc.hhs.gov
authors.forename: David A
authors.initials: DA
authors.lastname: Garber
authors.forename: Leigh A
authors.initials: LA
authors.lastname: O'Mara
authors.forename: Sailaja
authors.initials: S
authors.lastname: Gangadhara
authors.forename: Monica
authors.initials: M
authors.lastname: McQuoid
authors.forename: Xiugen
authors.initials: X
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Zheng
authors.forename: Kiran
authors.initials: K
authors.lastname: Gill
authors.forename: Meena
authors.initials: M
authors.lastname: Verma
authors.forename: Tianwei
authors.initials: T
authors.lastname: Yu
authors.forename: Brent
authors.initials: B
authors.lastname: Johnson
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.forename: Chris
authors.initials: C
authors.lastname: Ibegbu
authors.forename: John D
authors.initials: JD
authors.lastname: Altman
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.forename: Mark B
authors.initials: MB
authors.lastname: Feinberg
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D005822:Genetic Vectors / Q000276:immunology*; D007273:Injections, Intramuscular; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008253:Macaca mulatta; D019707:Receptors, Chemokine / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA; D014765:Viral Vaccines / Q000235:genetics* / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D036341:Intercellular Signaling Peptides and Proteins; C560489:MVA vaccine; D019707:Receptors, Chemokine; D017472:Receptors, Interleukin-1; D019444:Vaccines, DNA; D014765:Viral Vaccines; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus; C118370:interleukin-18 binding protein