title: A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes.
abstract: There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders,p= 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen.
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London , London , UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Joseph
authors.affiliation: Department of Medicine, Imperial College London , London , UK.
authors.forename: Killian
authors.initials: K
authors.lastname: Quinn
authors.affiliation: Clinical Research Centre, University of Surrey , Guildford , UK.
authors.forename: Aldona
authors.initials: A
authors.lastname: Greenwood
authors.affiliation: Department of Medicine, Imperial College London , London , UK.
authors.forename: Alethea V
authors.initials: AV
authors.lastname: Cope
authors.affiliation: Department of Medicine, Imperial College London , London , UK.
authors.forename: Paul F
authors.initials: PF
authors.lastname: McKay
authors.affiliation: IAVI Human Immunology Laboratory, Imperial College London , London , UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hayes
authors.affiliation: IAVI Human Immunology Laboratory, Imperial College London , London , UK.
authors.forename: Jakub T
authors.initials: JT
authors.lastname: Kopycinski
authors.affiliation: IAVI Human Immunology Laboratory, Imperial College London , London , UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: ICTU, Department of Public Health, Imperial College London , London , UK.
authors.forename: Aleisha N
authors.initials: AN
authors.lastname: Miller
authors.affiliation: Department of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich, Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Geldmacher
authors.affiliation: Department of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich, Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nadai
authors.affiliation: Department of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich, Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany.
authors.forename: Mohamed I M
authors.initials: MI
authors.lastname: Ahmed
authors.affiliation: Duke University Medical Centre , Durham, NC , USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: The EMMES Corporation , Rockville, MD , USA.
authors.forename: Len
authors.initials: L
authors.lastname: Dally
authors.affiliation: ICTU, Department of Public Health, Imperial College London , London , UK.
authors.forename: George
authors.initials: G
authors.lastname: Bouliotis
authors.affiliation: Clinical Research Centre, University of Surrey, Guildford, UK; Clinical Research Facility, Imperial College Healthcare NHS Trust, London, UK.
authors.forename: David J M
authors.initials: DJ
authors.lastname: Lewis
authors.affiliation: Department of Medicine, Imperial College London , London , UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Tatoud
authors.affiliation: University of Regensburg and University Hospital Regensburg , Regensburg , Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Wagner
authors.affiliation: National Center for Biotechnology, CSIC , Madrid , Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
authors.affiliation: Department of Medicine, Imperial College London , London , UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.affiliation: MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London , London , UK.
authors.forename: Sheena
authors.initials: S
authors.lastname: McCormack
authors.affiliation: Department of Medicine, Imperial College London , London , UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weber
keywords: DNA; HIV vaccine; MVA; envelope protein; phase I trial