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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 Random... Full description

Journal Title: Vaccine 2016, Vol.34 (19), p.2170-2178
Main Author: de Bruyn, Guy
Other Authors: Saleh, Jamshid , Workman, David , Pollak, Richard , Elinoff, Victor , Fraser, Neil J , Lefebvre, Gigi , Martens, Mark , Mills, Richard E , Nathan, Richard , Trevino, Miguel , van Cleeff, Martin , Foglia, Ginamarie , Ozol-Godfrey, Ayca , Patel, Dhaval M , Pietrobon, Patricia J , Gesser, Richard
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Netherlands: Elsevier Ltd
ID: ISSN: 0264-410X
Link: https://www.ncbi.nlm.nih.gov/pubmed/27013431
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title: Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial
format: Article
creator:
  • de Bruyn, Guy
  • Saleh, Jamshid
  • Workman, David
  • Pollak, Richard
  • Elinoff, Victor
  • Fraser, Neil J
  • Lefebvre, Gigi
  • Martens, Mark
  • Mills, Richard E
  • Nathan, Richard
  • Trevino, Miguel
  • van Cleeff, Martin
  • Foglia, Ginamarie
  • Ozol-Godfrey, Ayca
  • Patel, Dhaval M
  • Pietrobon, Patricia J
  • Gesser, Richard
subjects:
  • Adjuvants, Immunologic - administration & dosage
  • Adult
  • Aged
  • Allergy and Immunology
  • Aluminum hydroxide
  • Antibodies, Bacterial - blood
  • Antigens
  • Bacterial Vaccines - administration & dosage
  • Bacterial Vaccines - adverse effects
  • Bacterial Vaccines - immunology
  • Clinical trials
  • Clostridium difficile
  • Clostridium Infections - prevention & control
  • Communicable diseases
  • Diarrhea
  • Environmental
  • Enzymes
  • Formulation
  • Health aspects
  • Hepatitis
  • Humans
  • Immunization Schedule
  • Immunoglobulin G - blood
  • Immunology
  • Infectious Diseases
  • Laboratories
  • Medical research
  • Medicine, Experimental
  • Microbiology(all)
  • Middle Aged
  • Molecular Medicine
  • Nosocomial infections
  • Occupational Health
  • Product development
  • Public Health
  • Rankings
  • Schedule
  • Seroconversion
  • Toxins
  • Toxoids - administration & dosage
  • Toxoids - adverse effects
  • Toxoids - immunology
  • Vaccine
  • Vaccines
  • veterinary(all)
ispartof: Vaccine, 2016, Vol.34 (19), p.2170-2178
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0264-410X
fulltext: fulltext
issn:
  • 0264-410X
  • 1873-2518
url: Link


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titleDefining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial
sourceAlma/SFX Local Collection
creatorde Bruyn, Guy ; Saleh, Jamshid ; Workman, David ; Pollak, Richard ; Elinoff, Victor ; Fraser, Neil J ; Lefebvre, Gigi ; Martens, Mark ; Mills, Richard E ; Nathan, Richard ; Trevino, Miguel ; van Cleeff, Martin ; Foglia, Ginamarie ; Ozol-Godfrey, Ayca ; Patel, Dhaval M ; Pietrobon, Patricia J ; Gesser, Richard
creatorcontribde Bruyn, Guy ; Saleh, Jamshid ; Workman, David ; Pollak, Richard ; Elinoff, Victor ; Fraser, Neil J ; Lefebvre, Gigi ; Martens, Mark ; Mills, Richard E ; Nathan, Richard ; Trevino, Miguel ; van Cleeff, Martin ; Foglia, Ginamarie ; Ozol-Godfrey, Ayca ; Patel, Dhaval M ; Pietrobon, Patricia J ; Gesser, Richard ; On behalf of the H-030-012 Clinical Investigator Study Team ; H-030-012 Clinical Investigator Study Team
descriptionAbstract 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.
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1EISSN: 1873-2518
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languageeng
publisherNetherlands: Elsevier Ltd
subjectAdjuvants, Immunologic - administration & dosage ; Adult ; Aged ; Allergy and Immunology ; Aluminum hydroxide ; Antibodies, Bacterial - blood ; Antigens ; Bacterial Vaccines - administration & dosage ; Bacterial Vaccines - adverse effects ; Bacterial Vaccines - immunology ; Clinical trials ; Clostridium difficile ; Clostridium Infections - prevention & control ; Communicable diseases ; Diarrhea ; Environmental ; Enzymes ; Formulation ; Health aspects ; Hepatitis ; Humans ; Immunization Schedule ; Immunoglobulin G - blood ; Immunology ; Infectious Diseases ; Laboratories ; Medical research ; Medicine, Experimental ; Microbiology(all) ; Middle Aged ; Molecular Medicine ; Nosocomial infections ; Occupational Health ; Product development ; Public Health ; Rankings ; Schedule ; Seroconversion ; Toxins ; Toxoids - administration & dosage ; Toxoids - adverse effects ; Toxoids - immunology ; Vaccine ; Vaccines ; veterinary(all)
ispartofVaccine, 2016, Vol.34 (19), p.2170-2178
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1Saleh, Jamshid
2Workman, David
3Pollak, Richard
4Elinoff, Victor
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7Martens, Mark
8Mills, Richard E
9Nathan, Richard
10Trevino, Miguel
11van Cleeff, Martin
12Foglia, Ginamarie
13Ozol-Godfrey, Ayca
14Patel, Dhaval M
15Pietrobon, Patricia J
16Gesser, Richard
17On behalf of the H-030-012 Clinical Investigator Study Team
18H-030-012 Clinical Investigator Study Team
title
0Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial
1Vaccine
addtitleVaccine
descriptionAbstract 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.
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1Adult
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3Allergy and Immunology
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5Antibodies, Bacterial - blood
6Antigens
7Bacterial Vaccines - administration & dosage
8Bacterial Vaccines - adverse effects
9Bacterial Vaccines - immunology
10Clinical trials
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12Clostridium Infections - prevention & control
13Communicable diseases
14Diarrhea
15Environmental
16Enzymes
17Formulation
18Health aspects
19Hepatitis
20Humans
21Immunization Schedule
22Immunoglobulin G - blood
23Immunology
24Infectious Diseases
25Laboratories
26Medical research
27Medicine, Experimental
28Microbiology(all)
29Middle Aged
30Molecular Medicine
31Nosocomial infections
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39Toxoids - administration & dosage
40Toxoids - adverse effects
41Toxoids - immunology
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10Trevino, Miguel
11van Cleeff, Martin
12Foglia, Ginamarie
13Ozol-Godfrey, Ayca
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titleDefining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial
authorde Bruyn, Guy ; Saleh, Jamshid ; Workman, David ; Pollak, Richard ; Elinoff, Victor ; Fraser, Neil J ; Lefebvre, Gigi ; Martens, Mark ; Mills, Richard E ; Nathan, Richard ; Trevino, Miguel ; van Cleeff, Martin ; Foglia, Ginamarie ; Ozol-Godfrey, Ayca ; Patel, Dhaval M ; Pietrobon, Patricia J ; Gesser, Richard
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7Bacterial Vaccines - administration & dosage
8Bacterial Vaccines - adverse effects
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11Clostridium difficile
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13Communicable diseases
14Diarrhea
15Environmental
16Enzymes
17Formulation
18Health aspects
19Hepatitis
20Humans
21Immunization Schedule
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23Immunology
24Infectious Diseases
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30Molecular Medicine
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36Schedule
37Seroconversion
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39Toxoids - administration & dosage
40Toxoids - adverse effects
41Toxoids - immunology
42Vaccine
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11van Cleeff, Martin
12Foglia, Ginamarie
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7Martens, Mark
8Mills, Richard E
9Nathan, Richard
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atitleDefining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial
jtitleVaccine
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date2016
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pages2170-2178
issn0264-410X
eissn1873-2518
abstractAbstract 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.
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pmid27013431
doi10.1016/j.vaccine.2016.03.028
orcididhttps://orcid.org/0000-0002-8028-4474
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