BCG Vaccination Delivered Intradermally, Orally and by Combined Routes
Phase I Studies of the Safety and Immunogenicity of Primary and Secondary BCG Vaccination Delivered Intradermally, Orally and by Combined Routes of Administration in Healthy and Previously Immunologically Naïve Volunteers
Study Overview
Status
Conditions
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Missouri
-
Saint Louis, Missouri, United States, 63104-1015
- Saint Louis University - Center for Vaccine Development
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
-Demonstrate adequate understanding of the study and its requirements for participation, as demonstrated by the responses on a written assessment tool, discussions with the study staff, and ability to provide written informed consent to participate in the research study. -Be 18 to 40 years of age, inclusive. -Be available for a total of up to 36 months of follow-up (for those volunteers interested in the leukapheresis procedure). -Weigh at least 110 pounds. -Male or female. Females must not be pregnant, as determined by negative serum pregnancy test at screening, have a negative urine pregnancy test on the day of vaccination, and must be non-lactating. -Women will use an effective method of contraception (licensed hormonal treatment, monogamous relationship with vasectomized partner, surgical sterilization, barrier method such as diaphragm or condom with contraceptive foam or total abstinence) for 30 days prior to immunization and for the 2-year period of study follow-up. -Be in good health as judged by a physician on the basis of reported medical history and physical examination including blood pressure (BP) and respiratory evaluation. -Have a negative human immunodeficiency virus (HIV)-1 enzyme-linked immunosorbent assay (ELISA) test. -Have negative serology tests for hepatitis B surface antigen and hepatitis C virus antibody. -Have a negative QuantiFERON®-tuberculosis (TB) Gold test, defined as early secretory antigenic target (ESAT)-6 response minus nil response < 0.35 IU/ml, CFP-10 response minus nil response <0.35 IU/ml, nil response less than or equal to 0.7 IU/ml, and mitogen response greater than or equal to 0.5 IU/ml. -Have clinical hematologic and chemistry laboratory results within normal values for age and gender. For creatinine and aspartate aminotransferase (AST) levels, the applicable cut-offs for determination of normal are the upper limits of normal only, as there is no clinical significance associated with results below the lower limits of normal for these laboratory values. -Have a urine dipstick test negative for glucose and </=1 plus for protein. -Access to a telephone.
Exclusion Criteria:
-Have a history of suspected or confirmed active tuberculosis (symptoms may include recurrent fever, fatigue, night sweats, weight loss, oral ulcers, diarrhea, nausea or vomiting, bleeding). -Have any systemic symptoms including fever, malaise, fatigue, chills, night sweats, weight loss, nausea, vomiting or bleeding, diarrhea, abdominal pain, rhinorrhea, cough, wheezing, or shortness of breath within 72 hr before vaccination or signs of mucosal ulceration, lymphadenitis, gastrointestinal, or pulmonary disease by physical examination on day of vaccination. -Note: Systemic symptoms occurring prior to secondary vaccination will result in the secondary vaccination being delayed until at least 72 hr after resolution of any of these symptoms that were not considered indicative of active tuberculosis (TB). -Have lymphadenopathy, hepatosplenomegaly, or other abnormalities on physical examination. -Have oropharyngeal or skin ulceration, or history of chronic/recurrent peptic ulcer disease or gastritis. -Note: Self-limited ulceration at intradermal (ID) vaccination site healing within 3 months or other mild to moderate complaints lasting less than 1-2 weeks, as documented in the memory aids (used for 2 weeks after each vaccination) or other source documents used to capture results of clinical assessments at any time point during the trial, will not be reasons to exclude a volunteer from receiving the secondary vaccination. -History of any significant acute or chronic medical conditions including, but not limited to, disorders of the liver, kidney, lung, heart, or nervous system, or other metabolic or autoimmune/inflammatory conditions. -Have any history of scarring badly or keloid formation. -Have identifiable intermediate or high-risk behavior for HIV infection (defined as having had unprotected intercourse with multiple partners in the past year prior to enrollment, including men having sex with men). -Lives with someone with HIV, acquired immune deficiency syndrome (AIDS) or active cancer. -Have chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the vaccine dose. (For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 0.5 mg/kg/day. Inhaled and topical steroids are allowed.) -Have a history of smoking, alcoholism requiring medical attention, substance abuse, and/or intravenous drug use within the past 1 year prior to enrollment in the study. -Has a history or physical findings to suggest asthma or any chronic pulmonary condition. -Has a history of epilepsy. -Has a pacemaker or implantable cardiac devices. -Has a prosthetic valve. -Has a history of bleeding disorder. -Known allergy to any vaccine components. -Is currently taking anticoagulant or anti-platelet drugs and/or insulin. -Is currently under a physician's care for asthma or any chronic pulmonary condition. -Received blood products or immunoglobulin within 6 months of the first vaccination. -Vaccinated previously with Bacillus Calmette-Guérin (BCG) at study entry. -Received live attenuated vaccines within 4 weeks of vaccination. -Received inactivated vaccines within 2 weeks of vaccination. (Medically indicated inactivated vaccines should be given at least 2 weeks away from BCG immunization, or any sampling time point after vaccination.) -Participated in another research study that includes receiving an experimental agent or drug 30 days prior to vaccination. -Have a history of the use of a systemic antibiotic within the 14 days prior to vaccination or planned use of a systemic antibiotic during this study. -Have any medical, psychiatric, occupa tional, or behavioral problems that make it unlikely the volunteer will comply with the protocol as determined by the principal investigator (PI). -Be a health care provider at the highest risk of acquiring Mycobacterium tuberculosis (Mtb) infection, such as pulmonologists performing bronchoscopies on TB patients.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Group A: BCG ID/Placebo PO; Placebo ID/Placebo PO
Primary vaccination: BCG ID (Danish)/Placebo PO; secondary vaccination (1 year later): Placebo ID/Placebo PO.
|
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
1.2 X 10^8 colony-forming units (CFU) oral (PO) in 60 mililiters phosphate buffered saline (PBS).
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
2-8 X 10^5 colony-forming units (CFU) intradermal in 100 microliters diluent.
0.1 mL of sterile Sauton medium for intradermal administration.
60 mL of sterile phosphate buffered saline (PBS) for oral administration.
|
|
Experimental: Group B: BCG ID/Placebo PO; BCG ID/Placebo PO
Primary vaccination: BCG ID (Danish)/Placebo PO; secondary vaccination (1 year later): BCG ID (Danish)/Placebo PO.
|
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
1.2 X 10^8 colony-forming units (CFU) oral (PO) in 60 mililiters phosphate buffered saline (PBS).
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
2-8 X 10^5 colony-forming units (CFU) intradermal in 100 microliters diluent.
0.1 mL of sterile Sauton medium for intradermal administration.
60 mL of sterile phosphate buffered saline (PBS) for oral administration.
|
|
Experimental: Group C: Placebo ID/BCG PO; Placebo ID/Placebo PO
Primary vaccination: Placebo ID/BCG PO (Danish); secondary vaccination (1 year later): Placebo ID/Placebo PO.
|
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
1.2 X 10^8 colony-forming units (CFU) oral (PO) in 60 mililiters phosphate buffered saline (PBS).
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
2-8 X 10^5 colony-forming units (CFU) intradermal in 100 microliters diluent.
0.1 mL of sterile Sauton medium for intradermal administration.
60 mL of sterile phosphate buffered saline (PBS) for oral administration.
|
|
Experimental: Group D: Placebo ID/BCG PO; Placebo ID/BCG PO
Primary vaccination: Placebo ID/BCG PO (Danish); secondary vaccination (1 year later): Placebo ID/BCG PO (Danish).
|
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
1.2 X 10^8 colony-forming units (CFU) oral (PO) in 60 mililiters phosphate buffered saline (PBS).
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
2-8 X 10^5 colony-forming units (CFU) intradermal in 100 microliters diluent.
0.1 mL of sterile Sauton medium for intradermal administration.
60 mL of sterile phosphate buffered saline (PBS) for oral administration.
|
|
Experimental: Group E: BCG ID/BCG PO; Placebo ID/Placebo PO
Primary vaccination: BCG ID (Danish)/BCG PO (Danish); secondary vaccination (1 year later): Placebo ID/Placebo PO.
|
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
1.2 X 10^8 colony-forming units (CFU) oral (PO) in 60 mililiters phosphate buffered saline (PBS).
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
2-8 X 10^5 colony-forming units (CFU) intradermal in 100 microliters diluent.
0.1 mL of sterile Sauton medium for intradermal administration.
60 mL of sterile phosphate buffered saline (PBS) for oral administration.
|
|
Experimental: Group F: BCG ID/BCG PO; BCG ID/BCG PO
Primary vaccination: BCG ID (Danish)/BCG PO (Danish); secondary vaccination (1 year later): BCG ID (Danish)/BCG PO (Danish).
|
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
1.2 X 10^8 colony-forming units (CFU) oral (PO) in 60 mililiters phosphate buffered saline (PBS).
Bacillus Calmette-Guerin (BCG) strain Danish from the Statens Serum Institute (SSI BCG).
2-8 X 10^5 colony-forming units (CFU) intradermal in 100 microliters diluent.
|
|
Experimental: Group G: Connaught strain BCG ID
Primary vaccination: Connaught strain BCG ID; secondary vaccination (1 year later): none.
|
Connaught strain Bacillus Calmette-Guerin (BCG), 8-32 x 10^5 CFU vaccine for intradermal administration.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Immunogenicity: post-vaccination increases in mycobacteria-specific Th1 responses measured by both 7 day whole blood interferon (IFN)-gamma secretion and overnight IFN-gamma enzyme linked immunospot (ELISPOT) assays.
Time Frame: Harvested immediately before primary vaccination, and 1 week, 2, 6, and 12 months after primary vaccination, and 1 week, 2, 6, and 12 months after secondary vaccination.
|
Harvested immediately before primary vaccination, and 1 week, 2, 6, and 12 months after primary vaccination, and 1 week, 2, 6, and 12 months after secondary vaccination.
|
|
Immunogenicity: post-vaccination mycobacteria-specific secretory immunoglobulin A (IgA) responses measured by enzyme-linked immunosorbent assay (ELISA).
Time Frame: Harvested immediately before primary vaccination, and 1 week, 2, 6, and 12 months after primary vaccination, and 1 week, 2, 6, and 12 months after secondary vaccination.
|
Harvested immediately before primary vaccination, and 1 week, 2, 6, and 12 months after primary vaccination, and 1 week, 2, 6, and 12 months after secondary vaccination.
|
|
Microbiologic: variability of Bacillus Calmette-Guérin (BCG) replication in intradermal (ID) ulcerative lesions in Group G.
Time Frame: Days 7, 13-15, 20-22, 27-29, 34-36 and 41-43, and 2 months following ID BCG vaccination.
|
Days 7, 13-15, 20-22, 27-29, 34-36 and 41-43, and 2 months following ID BCG vaccination.
|
|
Safety: incidence of adverse events.
Time Frame: Solicited symptoms Days 0-14 after each vaccination, unsolicited adverse events collected for 2 months after each vaccination, serious adverse events collected through 12 months after the last vaccination.
|
Solicited symptoms Days 0-14 after each vaccination, unsolicited adverse events collected for 2 months after each vaccination, serious adverse events collected through 12 months after the last vaccination.
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Immunogenicity: presence or absence of cutaneous T cell trafficking, as indicated by purified protein derivative (PPD) skin test responses as an indication of cutaneous T cell trafficking after vaccination with SSI BCG.
Time Frame: Assessed in the study 2 years after primary vaccination with SSI BCG.
|
Assessed in the study 2 years after primary vaccination with SSI BCG.
|
|
Immunogenicity: proportion of subjects in each treatment group achieving an immunologically significant increase in primary endpoint Mtb-specific immune responses (i.e., at least 2 standard deviations above mean for negative controls for above assays).
Time Frame: Analysis.
|
Analysis.
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 01-351
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.