title: Heterologous prime-boost regimens with a recombinant chimpanzee adenoviral vector and adjuvanted F4 protein elicit polyfunctional HIV-1-specific T-Cell responses in macaques.
abstract: HIV-1-specific CD4+ and CD8+ T lymphocytes are important for HIV-1 replication control. F4/AS01 consists of F4 recombinant fusion protein (containing clade B Gag/p24, Pol/RT, Nef and Gag/p17) formulated in AS01 Adjuvant System, and was shown to induce F4-specific polyfunctional CD4+ T-cell responses in humans. While replication-incompetent recombinant HIV-1/SIV antigen-expressing human adenoviral vectors can elicit high-frequency antigen-specific CD8+ T-cell responses, their use is hampered by widespread pre-existing immunity to human serotypes. Non-human adenovirus serotypes associated with lower prevalence may offer an alternative strategy. We evaluated the immunogenicity of AdC7-GRN ('A'), a recombinant chimpanzee adenovirus type 7 vector expressing clade B Gag, RT and Nef, and F4/AS01 ('P'), when delivered intramuscularly in homologous (PP or AA) and heterologous (AAPP or PPAA) prime-boost regimens, in macaques and mice. Vaccine-induced HIV-1-antigen-specific T cells in peripheral blood (macaques), liver, spleen, and intestinal and genital mucosa (mice) were characterized by intracellular cytokine staining. Vaccine-specific IgG antibodies (macaques) were detected using ELISA. In macaques, only the heterologous prime-boost regimens induced polyfunctional, persistent and balanced CD4+ and CD8+ T-cell responses specific to each HIV-1 vaccine antigen. AdC7-GRN priming increased the polyfunctionality of F4/AS01-induced CD4+ T cells. Approximately 50% of AdC7-GRN-induced memory CD8+ T cells exhibited an effector-memory phenotype. HIV-1-specific antibodies were detected with each regimen. In mice, antigen-specific CD4+ and CD8+ T-cell responses were detected in the mucosal and systemic anatomical compartments assessed. When administered in heterologous prime-boost regimens, AdC7-GRN and F4/AS01 candidate vaccines acted complementarily in inducing potent and persistent peripheral blood HIV-1-specific CD4+ and CD8+ T-cell responses and antibodies in macaques. Besides, adenoviral vector priming modulated the cytokine-expression profile of the protein-induced CD4+ T cells. Each regimen induced HIV-1-specific T-cell responses in systemic/local tissues in mice. This suggests that prime-boost regimens combining adjuvanted protein and low-seroprevalent chimpanzee adenoviral vectors represent an attractive vaccination strategy for clinical evaluation.
authors: GSK Vaccines, Rixensart, Belgium.
authors: Clarisse
authors: C
authors: Lorin
authors: GSK Vaccines, Rixensart, Belgium.
authors: Yannick
authors: Y
authors: Vanloubbeeck
authors: GSK Vaccines, Rixensart, Belgium.
authors: Sébastien
authors: S
authors: Baudart
authors: GSK Vaccines, Rixensart, Belgium.
authors: Michaël
authors: M
authors: Ska
authors: GSK Vaccines, Rixensart, Belgium.
authors: Babak
authors: B
authors: Bayat
authors: GSK Vaccines, Rixensart, Belgium.
authors: Geoffroy
authors: G
authors: Brauers
authors: GSK Vaccines, Rixensart, Belgium.
authors: Géraldine
authors: G
authors: Clarinval
authors: GSK Vaccines, Rixensart, Belgium.
authors: Marie-Noëlle
authors: MN
authors: Donner
authors: GSK Vaccines, Rixensart, Belgium.
authors: Martine
authors: M
authors: Marchand
authors: GSK Vaccines, Rixensart, Belgium.
authors: Marguerite
authors: M
authors: Koutsoukos
authors: GSK Vaccines, Rixensart, Belgium.
authors: Pascal
authors: P
authors: Mettens
authors: GSK Vaccines, Rixensart, Belgium.
authors: Joe
authors: J
authors: Cohen
authors: GSK Vaccines, Rixensart, Belgium.
authors: Gerald
authors: G
authors: Voss
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015751:Genes, pol / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D015488:HIV Antigens / Q000235:genetics; D016655:HIV Core Protein p24 / Q000235:genetics; D015497:HIV-1 / Q000276:immunology*; D007273:Injections, Intramuscular; D008251:Macaca; D051379:Mice; D002679:Pan troglodytes; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D015488:HIV Antigens; D016655:HIV Core Protein p24; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C054858:p17 protein, Human Immunodeficiency Virus Type 1