title: Safety and immunogenicity of new cell-cultured smallpox vaccine compared with calf-lymph derived vaccine: a blind, single-centre, randomised controlled trial.
abstract: BACKGROUND
  US government organisations have identified the need for a new smallpox vaccine to replenish limited stocks of the approved, calf-lymph derived vaccine, the manufacture of which is no longer acceptable. We aimed to compare the safety and immunogenicity of the new cell-cultured smallpox vaccine (CCSV) to that of the calf-lymph derived vaccine (as a positive control) in 350 healthy, adult volunteers.
  
  
  METHODS
  We did a randomised controlled study at the University of Kentucky Medical Center. We randomised 150 vaccinia-naive volunteers, aged 18-30 years, and 100 vaccinia-non-naive people, aged 32-65 years, to equivalent doses of either CCSV or test vaccine (2.5x10(5) plaque-forming units) by 15 puncture scarification in double-blind fashion. Immunogenicity was assessed by pock formation (take rate), humoral immune response by plaque-reduction neutralisation titres, and cellular immune response by vaccinia-specific, interferon-gamma T-cell quantification, cytotoxicity, and T-cell proliferation response. A further 100 vaccine-naive individuals, aged 18-30 years, received one of five doses of CCSV (undiluted, diluted 1 in 5, 1 in 10, 1 in 25, and 1 in 50) in single-blind fashion. Routine laboratory assessments, physical examinations, and recording of adverse events were done to assess vaccine safety. The primary endpoints were safety and reactogenicity (take rate) of CCSV.
  
  
  RESULTS
  349 (99.7%) of 350 volunteers developed pock lesions; one vaccinia-naive individual who received a 1 in 25 dilution of CCSV did not. The rate of adverse events related to vaccine and the extent of humoral and cellular immune responses did not differ between the vaccine groups in vaccinia-naive or non-naive people. CCSV was immunogenic in vaccine-naive volunteers at a dose 50 times lower than that approved for Dryvax.
  
  
  CONCLUSIONS
  CCSV seems to be a safe and immunogenic alternative to calf-lymph derived vaccine for both vaccinia-naive and non-naive people.
authors.affiliation: Medicine Service, Department of Veterans Affairs Medical Center, Lexington, KY, USA. RNgree01@uky.edu
authors.forename: Richard N
authors.initials: RN
authors.lastname: Greenberg
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kennedy
authors.forename: David J
authors.initials: DJ
authors.lastname: Clanton
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Plummer
authors.forename: Lynda
authors.initials: L
authors.lastname: Hague
authors.forename: John
authors.initials: J
authors.lastname: Cruz
authors.forename: Francis A
authors.initials: FA
authors.lastname: Ennis
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkins
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D004311:Double-Blind Method; D006801:Humans; D008213:Lymphocyte Activation; D008875:Middle Aged; D012900:Smallpox Vaccine / Q000009:adverse effects* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology; D010948:Viral Plaque Assay
chemical_list: D000914:Antibodies, Viral; C078786:DryVax vaccine; D012900:Smallpox Vaccine