title: Alphavirus replicon DNA expressing HIV antigens is an excellent prime for boosting with recombinant modified vaccinia Ankara (MVA) or with HIV gp140 protein antigen.
abstract: Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells and antibodies. Studies in humans have shown that DNA vaccines are safe, but their immunogenicity needs further improvement. As a step towards this goal, we have previously demonstrated that immunogenicity is increased with the use of an alphavirus DNA-launched replicon (DREP) vector compared to conventional DNA vaccines. In this study, we investigated the effect of varying the dose and number of administrations of DREP when given as a prime prior to a heterologous boost with poxvirus vector (MVA) and/or HIV gp140 protein formulated in glucopyranosyl lipid A (GLA-AF) adjuvant. The DREP and MVA vaccine constructs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three administrations of 0.2 μg DREP induced lower HIV-specific T cell and IgG responses than the equivalent number of immunizations with 10 μg DREP. However, the two doses were equally efficient as a priming component in a heterologous prime-boost regimen. The magnitude of immune responses depended on the number of priming immunizations rather than the dose. A single low dose of DREP prior to a heterologous boost resulted in greatly increased immune responses compared to MVA or protein antigen alone, demonstrating that a mere 0.2 μg DREP was sufficient for priming immune responses. Following a DREP prime, T cell responses were expanded greatly by an MVA boost, and IgG responses were also expanded when boosted with protein antigen. When MVA and protein were administered simultaneously following multiple DREP primes, responses were slightly compromised compared to administering them sequentially. In conclusion, we have demonstrated efficient priming of HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the priming effect depends on number of primes administered rather than dose.
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Maria L
authors: ML
authors: Knudsen
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Karl
authors: K
authors: Ljungberg
authors: Imperial College London, Department of Infectious Diseases, Division of Medicine, Norfolk Place, London, United Kingdom.
authors: Roger
authors: R
authors: Tatoud
authors: Imperial College London, Department of Infectious Diseases, Division of Medicine, Norfolk Place, London, United Kingdom.
authors: Jonathan
authors: J
authors: Weber
authors: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors: Mariano
authors: M
authors: Esteban
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Peter
authors: P
authors: Liljeström
mesh_terms: D000524:Alphavirus / Q000235:genetics*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002626:Chemistry, Pharmaceutical; D004274:DNA, Recombinant / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000276:immunology; D008050:Lipid A / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D012093:Replicon / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D004274:DNA, Recombinant; D004279:DNA, Viral; D015488:HIV Antigens; D007074:Immunoglobulin G; D008050:Lipid A; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1
references: Cancer Res. 1984 Nov;44(11):5127-31
references: 6435864
references: Viral Immunol. 2009 Oct;22(5):309-19
references: 19811088
references: J Virol. 1998 Feb;72(2):950-8
references: 9444987
references: Vaccine. 1998 Mar;16(5):439-45
references: 9491498
references: Nature. 1998 Mar 5;392(6671):86-9
references: 9510252
references: Nat Biotechnol. 1998 Jun;16(6):562-5
references: 9624688
references: J Virol. 1999 Sep;73(9):7524-32
references: 10438842
references: J Gen Virol. 2005 Feb;86(Pt 2):349-54
references: 15659754
references: Nature. 2005 Feb 24;433(7028):887-92
references: 15711573
references: J Virol. 2005 Aug;79(16):10376-85
references: 16051830
references: Vaccine. 2006 May 22;24(21):4524-6
references: 16174543
references: Blood. 2006 Jun 15;107(12):4781-9
references: 16467198
references: Virology. 2006 Jun 20;350(1):34-47
references: 16616287
references: J Virol. 2006 Jul;80(14):7100-10
references: 16809315
references: Immunol Rev. 2006 Jun;211:236-54
references: 16824132
references: J Virol. 2006 Dec;80(24):11991-7
references: 17005652
references: Vaccine. 2007 Mar 1;25(11):1969-92
references: 17224219
references: Immunity. 2007 Sep;27(3):370-83
references: 17892846
references: J Exp Med. 2007 Oct 1;204(10):2473-85
references: 17893201
references: J Virol. 2007 Dec;81(24):13412-23
references: 17913817
references: N Engl J Med. 2009 Dec 3;361(23):2209-20
references: 19843557
references: Ann Rheum Dis. 2010 Jan;69 Suppl 1:i92-96
references: 19995755
references: Expert Rev Vaccines. 2010 May;9(5):503-17
references: 20450325
references: J Virol. 2010 Jul;84(14):7369-77
references: 20427528
references: Expert Rev Vaccines. 2010 Sep;9(9):1055-69
references: 20822348
references: Virol J. 2011;8:36
references: 21261958
references: Immunol Cell Biol. 2011 Mar;89(3):367-74
references: 20956986
references: Curr Opin Immunol. 2011 Jun;23(3):421-9
references: 21530212
references: PLoS One. 2012;7(1):e29732
references: 22238645
references: J Virol. 2012 Apr;86(8):4082-90
references: 22318135
references: Clin Immunol. 2012 May;143(2):99-115
references: 22391152
references: PLoS One. 2012;7(7):e41144
references: 22829921
references: PLoS One. 2012;7(7):e42163
references: 22848738
references: PLoS One. 2013;8(6):e65964
references: 23785460
references: PLoS One. 2013;8(12):e84234
references: 24391921
references: PLoS One. 2014;9(1):e84707
references: 24465426
references: PLoS One. 2014;9(2):e87837
references: 24503579
references: Methods Mol Biol. 2014;1121:147-54
references: 24510820
references: Vaccine. 2014 Apr 11;32(18):2109-16
references: 24556505
references: Clin Vaccine Immunol. 2014 Aug;21(8):1023-36
references: 24920599
references: J Virol. 2014 Sep 1;88(17):10134-45
references: 24965450
references: Hum Vaccin Immunother. 2014;10(6):1734-46
references: 24637946
references: J Virol. 2014 Nov;88(21):12438-51
references: 25122792
references: J Virol. 2014 Nov;88(22):13333-43
references: 25210177
references: Expert Rev Vaccines. 2015 Feb;14(2):177-94
references: 25269775
references: PLoS One. 2011;6(1):e16333
references: 21298114
references: J Exp Med. 2008 Jan 21;205(1):63-77
references: 18195071
references: J Infect Dis. 2008 Nov 15;198(10):1482-90
references: 18808335
references: Nat Immunol. 2009 Jun;10(6):636-46
references: 19412183
references: J Gen Virol. 2009 Jun;90(Pt 6):1382-91
references: 19264662
references: J Gen Virol. 1997 Jul;78 ( Pt 7):1559-63
references: 9225029