Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial
Guy de Bruyn, Jamshid Saleh, David Workman, Richard Pollak, Victor Elinoff, Neil J Fraser, Gigi Lefebvre, Mark Martens, Richard E Mills, Richard Nathan, Miguel Trevino, Martin van Cleeff, Ginamarie Foglia, Ayca Ozol-Godfrey, Dhaval M Patel, Patricia J Pietrobon, Richard Gesser, H-030-012 Clinical Investigator Study Team, A Arslanian, P Gagianas, K Reisinger, A Brookmyre, S Christensen, R Cook, J Earl, F Eder, V Elinoff, P Evans, N Fraser, R Glover 2nd, R Haselby, D Henry, J Hoekstra, G Lefebvre, M Martens, R E Mills, R Nathan, M Patel, D Radin, J Rosen, J Rubino, J Saleh, N Segall, M Trevino, M van Cleeff, A White, D Workman, B Yangco, S Zakko, J Ervin, R Casanova, C Griffin, G Weiner, C Barish, O Kapoor, M Fernandez, R Pollak, R Epstein, T Poling, K Lesh, V Challa, C Farrington, T Bauch, M Chen, S Arora, Sinead Rudden, Christel Guillaume, Eric Gerchman, Ronald Blisard, Guy de Bruyn, Jamshid Saleh, David Workman, Richard Pollak, Victor Elinoff, Neil J Fraser, Gigi Lefebvre, Mark Martens, Richard E Mills, Richard Nathan, Miguel Trevino, Martin van Cleeff, Ginamarie Foglia, Ayca Ozol-Godfrey, Dhaval M Patel, Patricia J Pietrobon, Richard Gesser, H-030-012 Clinical Investigator Study Team, A Arslanian, P Gagianas, K Reisinger, A Brookmyre, S Christensen, R Cook, J Earl, F Eder, V Elinoff, P Evans, N Fraser, R Glover 2nd, R Haselby, D Henry, J Hoekstra, G Lefebvre, M Martens, R E Mills, R Nathan, M Patel, D Radin, J Rosen, J Rubino, J Saleh, N Segall, M Trevino, M van Cleeff, A White, D Workman, B Yangco, S Zakko, J Ervin, R Casanova, C Griffin, G Weiner, C Barish, O Kapoor, M Fernandez, R Pollak, R Epstein, T Poling, K Lesh, V Challa, C Farrington, T Bauch, M Chen, S Arora, Sinead Rudden, Christel Guillaume, Eric Gerchman, Ronald Blisard
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.
Keywords: Clostridium difficile; Formulation; Schedule; Vaccine.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
Source: PubMed