title: Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects.
abstract: BACKGROUND
  Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration.
  
  
  METHODS
  524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination.
  
  
  RESULTS
  Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group.
  
  
  CONCLUSIONS
  Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses).
authors.affiliation: Saint Louis University School of Medicine, Department of Internal Medicine, St. Louis, MO, USA. Electronic address: freyse@slu.edu.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Frey
authors.affiliation: University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wald
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Atlanta, GA, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Edupuganti
authors.affiliation: Group Health Cooperative, Seattle, WA, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Jackson
authors.affiliation: University of Iowa and Iowa City VA Medical Center, Department of Internal Medicine, Iowa City, IA, USA.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Stapleton
authors.affiliation: Baylor College of Medicine, Departments of Molecular Virology and Microbiology and Medicine, Houston, TX, USA.
authors.forename: Hana
authors.initials: H
authors.lastname: El Sahly
authors.affiliation: University of Maryland School of Medicine, Department of Epidemiology and Public Health, Center for Vaccine Development, Baltimore, MD, USA.
authors.forename: Samer S
authors.initials: SS
authors.lastname: El-Kamary
authors.affiliation: Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Edwards
authors.affiliation: Emory University, Emory Children's Center, Department of Pediatrics, Atlanta, GA, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Keyserling
authors.affiliation: University of Iowa and Iowa City VA Medical Center, Department of Internal Medicine, Iowa City, IA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Winokur
authors.affiliation: Baylor College of Medicine, Departments of Molecular Virology and Microbiology and Medicine, Houston, TX, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Keitel
authors.affiliation: EMMES Corporation, Rockville, MD, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Hill
authors.affiliation: EMMES Corporation, Rockville, MD, USA.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Goll
authors.affiliation: Saint Louis University School of Medicine, Department of Internal Medicine, St. Louis, MO, USA.
authors.forename: Edwin L
authors.initials: EL
authors.lastname: Anderson
authors.affiliation: Saint Louis University School of Medicine, Department of Internal Medicine, St. Louis, MO, USA.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Graham
authors.affiliation: University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Johnston
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Atlanta, GA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mulligan
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Atlanta, GA, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rouphael
authors.affiliation: Baylor College of Medicine, Departments of Molecular Virology and Microbiology and Medicine, Houston, TX, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Atmar
authors.affiliation: Baylor College of Medicine, Departments of Molecular Virology and Microbiology and Medicine, Houston, TX, USA.
authors.forename: Shital
authors.initials: S
authors.lastname: Patel
authors.affiliation: University of Maryland School of Medicine, Center for Vaccine Development, Baltimore, MD, USA.
authors.forename: Wilbur
authors.initials: W
authors.lastname: Chen
authors.affiliation: University of Maryland School of Medicine, Center for Vaccine Development, Baltimore, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kotloff
authors.affiliation: Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: Bavarian Nordic GmbH, Martinsried, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Chaplin
authors.affiliation: Saint Louis University School of Medicine, Department of Internal Medicine, St. Louis, MO, USA.
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*; D002626:Chemistry, Pharmaceutical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D006801:Humans; D007271:Injections, Intradermal; D007279:Injections, Subcutaneous; D008297:Male; D012900:Smallpox Vaccine / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D012900:Smallpox Vaccine
keywords: ELISA; IMVAMUNE; Intradermal; Lyophilized; MVA; NCT00914732; Plaque reduction neutralizing antibody; Smallpox; Subcutaneous; Vaccinia-naïve; Variola