title: Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial.
abstract: BACKGROUND
  Clostridium difficile, a major cause of nosocomial and antibiotic-associated diarrhea, carries a significant disease and cost burden. This study aimed to select an optimal formulation and schedule for a candidate toxoid vaccine against C. difficile toxins A and B.
  
  
  METHODS
  Randomized, placebo-controlled, two-stage, Phase 2 study in a total of 661 adults aged 40-75 years. Stage I: low (50 μg antigen) or high (100 μg antigen) dose with or without aluminum hydroxide (AlOH) adjuvant, or placebo, administered on Days 0-7-30. Stage II: Days 0-7-30, 0-7-180, and 0-30-180, using the formulation selected in Stage I through a decision tree defined a priori and based principally on a bootstrap ranking approach. Administration was intramuscular. Blood samples were obtained on Days 0, 7, 14, 30, 60 (Stage I and II), 180, and 210 (Stage II); IgG to toxins A and B was measured by ELISA and in vitro functional activity was measured by toxin neutralizing assay (TNA). Safety data were collected using diary cards.
  
  
  RESULTS
  In Stage I the composite immune response against toxins A and B (percentage of participants who seroconverted for both toxins) was highest in the high dose+adjuvant group (97% and 92% for Toxins A and B, respectively) and was chosen for Stage II. In Stage II the immune response profile for this formulation through Day 180 given on Days 0-7-30 ranked above the other two administration schedules. There were no safety issues.
  
  
  CONCLUSIONS
  The high dose+adjuvant (100 μg antigen+AlOH) formulation administered at 0-7-30 days elicited the best immune response profile, including functional antibody responses, through Day 180 and was selected for use in subsequent clinical trials.
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA. Electronic address: guy.debruyn@sanofipasteur.com.
authors.forename: Guy
authors.initials: G
authors.lastname: de Bruyn
authors.affiliation: Northern California Research Center, Redding, CA, USA.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Saleh
authors.affiliation: Jean Brown Research, Salt Lake City, UT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Workman
authors.affiliation: Endeavor Clinical Trials, San Antonio, TX, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pollak
authors.affiliation: Regional Clinical Research Inc., Endwell, NY, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Elinoff
authors.affiliation: Troy Internal Medicine P.C./Research, Troy, MI, USA.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Fraser
authors.affiliation: Meridien Research, St Petersburg, FL, USA.
authors.forename: Gigi
authors.initials: G
authors.lastname: Lefebvre
authors.affiliation: Meridian Health, Neptune, NJ, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Martens
authors.affiliation: PMG Research of Charleston, Mt Pleasant, SC, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mills
authors.affiliation: Idaho Falls Infectious Diseases PLC, Idaho Falls, ID, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Nathan
authors.affiliation: Innovative Research of West Florida Inc., Clearwater, FL, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Trevino
authors.affiliation: PMG Research of Cary, Cary, NC, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: van Cleeff
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Ginamarie
authors.initials: G
authors.lastname: Foglia
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Ayca
authors.initials: A
authors.lastname: Ozol-Godfrey
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Dhaval M
authors.initials: DM
authors.lastname: Patel
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Pietrobon
authors.affiliation: Sanofi Pasteur, Swiftwater, PA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gesser
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D016360:Clostridioides difficile; D003015:Clostridium Infections / Q000517:prevention & control*; D006801:Humans; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000097:blood; D008875:Middle Aged; D000069078:Seroconversion; D014121:Toxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D014121:Toxoids
keywords: Clostridium difficile; Formulation; Schedule; Vaccine