title: Phase II randomized, double-blinded comparison of a single high dose (5×10(8) TCID50) of modified vaccinia Ankara compared to a standard dose (1×10(8) TCID50) in healthy vaccinia-naïve individuals.
abstract: BACKGROUND
  Reintroduction of Variola major as an agent of bioterrorism remains a concern. Time to seroconversion and plaque reduction neutralizing antibody titers (PRNT) of 1 or 2 standard doses (SD) were compared to a single high dose (HD) of modified vaccinia Ankara (MVA).
  
  
  METHODS
  Ninety subjects were randomized 1:1 to receive 1 HD or 2 SD of MVA subcutaneously on Days 0 and 28 in a placebo-controlled trial. Serum was collected for PRNT and ELISA. Subjects were followed for safety for the entire study.
  
  
  RESULTS
  The HD was well-tolerated. Using Bavarian Nordic's ELISA, subjects in both groups achieved seroconversion by Study Day 15 (HD) and Day 28 (SD). Before second vaccination, the hazard rate of seroconverting for the HD group was 1.7 times the SD group with a median time for seroconversion of 14 days for both groups. The peak titer of one HD vaccine was superior to one dose of SD vaccine but inferior to the peak titer after the second dose of the SD vaccination regimen. Using Saint Louis University's PRNT, peak titers were 95.8 and 65.2 for the HD and SD groups, respectively, prior to second vaccination. Non-inferiority of the SD group was not established. The proportions of positives were 93.3% (42/45) and 82.2% (37/45) for the HD and SD groups, respectively. The peak titer after two standard doses was superior to that of the HD.
  
  
  CONCLUSIONS
  HD MVA was safe and well-tolerated. While the hazard rate for seroconverting was significantly higher in the HD group before second dose, the effect was small as the median time to seroconversion was identical. When comparing PRNT, non-inferiority of one SD was not established and the peak titers were low for both groups. The HD peak response was inferior to the standard two-dose regimen response based on ELISA and PRNT.
authors.affiliation: Saint Louis University Medical School, Department of Internal Medicine, United States. Electronic address: freyse@slu.edu.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Frey
authors.affiliation: University of Iowa and Iowa City VA Medical Center Health Care System, Department of Internal Medicine, United States.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Winokur
authors.affiliation: EMMES Corporation, Rockville, MD, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Hill
authors.affiliation: EMMES Corporation, Rockville, MD, United States.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Goll
authors.affiliation: Bavarian Nordic GmbH, Martinsried, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Chaplin
authors.affiliation: Saint Louis University Medical School, Department of Internal Medicine, United States.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Belshe
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D009500:Neutralization Tests; D012899:Smallpox / Q000517:prevention & control*; D012900:Smallpox Vaccine / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D010948:Viral Plaque Assay; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D012900:Smallpox Vaccine
keywords: ELISA; IMVAMUNE; MVA; Plaque reduction neutralizing antibody; Smallpox; Vaccine; Variola