title: Therapeutic vaccination with TNF-Kinoid in TNF antagonist-resistant rheumatoid arthritis: a phase II randomized, controlled clinical trial.
abstract: OBJECTIVE
  Active immunization, or vaccination, with tumor necrosis factor (TNF)-Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA.
  
  
  METHODS
  This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 µg TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection.
  
  
  RESULTS
  The highest anti-TNF antibody response was detected in patients immunized with 360 µg TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not.
  
  
  CONCLUSIONS
  TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01040715.
authors.affiliation: Service et Pole de Rhumatologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Experimentale et Clinique, Universite catholique de Louvain, Rheumatology, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Durez
authors.affiliation: Neovacs S.A., Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vandepapeliere
authors.affiliation: Centro de Estudios Reumatológicos, Santiago de Chile, Chile.
authors.forename: Pedro
authors.initials: P
authors.lastname: Miranda
authors.affiliation: National Multiprofile Transport Hospital "Tzar Boris III", Sofia, Bulgaria.
authors.forename: Antoaneta
authors.initials: A
authors.lastname: Toncheva
authors.affiliation: Centro Medico Privado de Reumatologia, San Miguel de Tucuman, Argentina.
authors.forename: Alberto
authors.initials: A
authors.lastname: Berman
authors.affiliation: Thalassotherapia Opatija, Opatija, Croatia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kehler
authors.affiliation: Emergency County Hospital "Dr Constantin Opris", Baia Mare, Romania.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Mociran
authors.affiliation: UPMC, GRC 08 (EEMOIS), Institut Pierre Louis d'Epidémiologie et Santé Publique, Paris, France; AP-HP, Pitié Salpêtrière University Hospital, Dept of Rheumatology, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fautrel
authors.affiliation: Université Paris-Sud, Hôpitaux Universitaires Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.affiliation: Neovacs S.A., Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dhellin
authors.affiliation: Neovacs S.A., Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fanget
authors.affiliation: Neovacs S.A., Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Ouary
authors.affiliation: Neovacs S.A., Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Grouard-Vogel
authors.affiliation: INSERM U1125, Bobigny, France; Université Paris 13, Sorbonne Paris Cité, Bobigny, France; AP-HP, Avicenne University Hospital, Department of Rheumatology, Bobigny, France.
authors.forename: Marie-Christophe
authors.initials: MC
authors.lastname: Boissier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology*; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000517:prevention & control*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology*; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*; D055815:Young Adult
chemical_list: D000906:Antibodies; D018501:Antirheumatic Agents; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors