title: Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: a randomized trial.
abstract: OBJECTIVE
  We evaluated an alternative administration route, reduced schedule priming series, and increased intervals between booster doses for anthrax vaccine adsorbed (AVA). AVA's originally licensed schedule was 6 subcutaneous (SQ) priming injections administered at months (m) 0, 0.5, 1, 6, 12 and 18 with annual boosters; a simpler schedule is desired.
  
  
  METHODS
  Through a multicenter randomized, double blind, non-inferiority Phase IV human clinical trial, the originally licensed schedule was compared to four alternative and two placebo schedules. 8-SQ group participants received 6 SQ injections with m30 and m42 "annual" boosters; participants in the 8-IM group received intramuscular (IM) injections according to the same schedule. Reduced schedule groups (7-IM, 5-IM, 4-IM) received IM injections at m0, m1, m6; at least one of the m0.5, m12, m18, m30 vaccine doses were replaced with saline. All reduced schedule groups received a m42 booster. Post-injection blood draws were taken two to four weeks following injection. Non-inferiority of the alternative schedules was compared to the 8-SQ group at m2, m7, and m43. Reactogenicity outcomes were proportions of injection site and systemic adverse events (AEs).
  
  
  RESULTS
  The 8-IM group's m2 response was non-inferior to the 8-SQ group for the three primary endpoints of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer, and proportion of responders with a 4-fold rise in titer. At m7 anti-PA IgG GMCs for the three reduced dosage groups were non-inferior to the 8-SQ group GMCs. At m43, 8-IM, 5-IM, and 4-IM group GMCs were superior to the 8-SQ group. Solicited injection site AEs occurred at lower proportions in the IM group compared to SQ. Route of administration did not influence the occurrence of systemic AEs. A 3 dose IM priming schedule with doses administered at m0, m1, and m6 elicited long term immunological responses and robust immunological memory that was efficiently stimulated by a single booster vaccination at 42 months.
  
  
  CONCLUSIONS
  A priming series of 3 intramuscular doses administered at m0, m1, and m6 with a triennial booster was non-inferior to more complex schedules for achieving antibody response.
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States. Electronic address: jgwright@cdc.gov.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Wright
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Plikaytis
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Rose
authors.affiliation: Alabama Vaccine Research Clinic, University of Alabama at Birmingham, 908 20th Street South, Birmingham, AL 35294-2050, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Parker
authors.affiliation: Walter Reed Army Institute for Research, 503 Robert Grant Avenue, Silver Springs, MD 20910-7500, United States.
authors.forename: Janiine
authors.initials: J
authors.lastname: Babcock
authors.affiliation: Departments of Molecular Virology & Microbiology and Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Keitel
authors.affiliation: Departments of Molecular Virology & Microbiology and Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States.
authors.forename: Hana
authors.initials: H
authors.lastname: El Sahly
authors.affiliation: Mayo Clinic and Foundation, 611C Guggenheim Building, 200 First Street SW, Rochester, MN 55905, United States.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
authors.affiliation: Mayo Clinic and Foundation, 611C Guggenheim Building, 200 First Street SW, Rochester, MN 55905, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jacobson
authors.affiliation: Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, GA 30322, United States.
authors.forename: Harry L
authors.initials: HL
authors.lastname: Keyserling
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Vera A
authors.initials: VA
authors.lastname: Semenova
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Jarad
authors.initials: J
authors.lastname: Schiffer
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Hanan
authors.initials: H
authors.lastname: Dababneh
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Martin
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Stacey W
authors.initials: SW
authors.lastname: Martin
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Marano
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Messonnier
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, United States.
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Quinn
mesh_terms: D000328:Adult; D000881:Anthrax / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage*; D000907:Antibodies, Bacterial / Q000097:blood; D000917:Antibody Formation; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000097:blood; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D007074:Immunoglobulin G
keywords: AE; AVA; AVRP; Adverse events; Anthrax Vaccine Research Program; Anthrax vaccines; Bacillus anthracis; Bacterial vaccines; CDC; Centers for Disease Control and Prevention; Department of Defense; DoD; FDA; Food and Drug Administration; GCP; Good Clinical Practices; IM; IND; Investigational New Drug; LTx; PA; SQ; USAMMA; United States Army Medical Materiel Agency; Vaccination; adverse event; anthrax vaccine adsorbed; intramuscularly; lethal toxin; protective antigen; subcutaneous