title: Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1.
  
  
  METHODS
  Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789.
  
  
  RESULTS
  174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations.
  
  
  CONCLUSIONS
  The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies.
  
  
  BACKGROUND
  Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.
authors: Division of Infectious Diseases, UC Davis Medical Center, Sacramento, CA, USA.
authors: Richard B
authors: RB
authors: Pollard
authors: Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I, Immunologische Ambulanz, Bonn, Germany.
authors: Jürgen K
authors: JK
authors: Rockstroh
authors: Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
authors: Giuseppe
authors: G
authors: Pantaleo
authors: Division of Infectious Diseases, UC Davis Medical Center, Sacramento, CA, USA.
authors: David M
authors: DM
authors: Asmuth
authors: Harrison Wing, St Thomas' Hospital, London, UK.
authors: Barry
authors: B
authors: Peters
authors: Department of Infectious Diseases, Ospedale San Raffaele and Vita-Salute University, Milan, Italy.
authors: Adriano
authors: A
authors: Lazzarin
authors: Infectious Diseases and AIDS Units, Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain.
authors: Felipe
authors: F
authors: Garcia
authors: Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland.
authors: Kim
authors: K
authors: Ellefsen
authors: HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors: Daniel
authors: D
authors: Podzamczer
authors: Universitätsklinikum Hamburg Eppendorf, Ambulanzzentrum Infektiologie, Hamburg, Germany.
authors: Jan
authors: J
authors: van Lunzen
authors: EPIMED-Gesellschaft für Epidemiologische und Klinische Forschung in der Medizin mbH/Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany.
authors: Keikawus
authors: K
authors: Arastéh
authors: Department of Internal Medicine, Division of Infectious Diseases and Pulmonary Medicine, Charité-University Medicine Berlin, Berlin, Germany.
authors: Dirk
authors: D
authors: Schürmann
authors: Irsicaixa Foundation, UAB, UVic, Hospital Universitari "Germans Trias i Pujol", Badalona, Catalonia, Spain.
authors: Bonaventura
authors: B
authors: Clotet
authors: Division of Infectious Diseases Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: W David
authors: WD
authors: Hardy
authors: UCLA CARE Center, University of California, Los Angeles, CA, USA.
authors: Ronald
authors: R
authors: Mitsuyasu
authors: Kobler Clinic, Chelsea and Westminster Hospital, London, UK.
authors: Graeme
authors: G
authors: Moyle
authors: ifi-Institut, an der Asklepios-Klinik St Georg, Hamburg, Germany.
authors: Andreas
authors: A
authors: Plettenberg
authors: Brighton and Sussex University Hospital, HIV/GUM Research, Elton John Centre, Brighton, UK.
authors: Martin
authors: M
authors: Fisher
authors: Klinik I für Innere Medizin, Klinikum der Universität zu Köln, Cologne, Germany.
authors: Gerd
authors: G
authors: Fätkenheuer
authors: University of Miami School of Medicine AIDS Clinical Research Unit, Miami, FL, USA.
authors: Margaret
authors: M
authors: Fischl
authors: Division of Infectious Diseases, Northwestern University, Chicago, IL, USA.
authors: Babafemi
authors: B
authors: Taiwo
authors: Mericon AS, Skien, Norway.
authors: Ingebjørg
authors: I
authors: Baksaas
authors: Aptiv Solutions, Abingdon, UK.
authors: Darren
authors: D
authors: Jolliffe
authors: SP PharmaConsulting, Uppsala, Sweden.
authors: Stefan
authors: S
authors: Persson
authors: Bionor Laboratories, Skien, Norway.
authors: Oyvind
authors: O
authors: Jelmert
authors: Bionor Pharma ASA, Oslo, Norway.
authors: Arnt-Ove
authors: AO
authors: Hovden
authors: Bionor Pharma ASA, Oslo, Norway.
authors: Maja A
authors: MA
authors: Sommerfelt
authors: Bionor Pharma ASA, Oslo, Norway. Electronic address: post@bionorpharma.com.
authors: Vidar
authors: V
authors: Wendel-Hansen
authors: Bionor Pharma ASA, Oslo, Norway.
authors: Birger
authors: B
authors: Sørensen
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D049109:Cell Proliferation; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D016233:Immunotherapy, Active; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D019562:Viral Load; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D044966:Anti-Retroviral Agents; C494182:Vacc-4x