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BCG Vaccine Oral Intradermal
This study is currently recruiting participants.
Verified by National Institute of Allergy and Infectious Diseases (NIAID), November 2008
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00396370
  Purpose

This study will assess the safety of a Bacillus Calmette-Guerin (BCG) vaccine against tuberculosis (TB) and will evaluate if giving the vaccine by mouth, injection, or by both methods produces greater results. BCG vaccine and/or placebo (substance containing no medication) will be given by mouth and/or by injection into the skin. A second vaccine and/or placebo will be given 12 months later. This study, conducted at Saint Louis University, will enroll 70 healthy volunteers, 18-40 years old, for up to 26 months, which includes a 60-day screening period. Study procedures will undergo a physical exam; review of TB exposure history and medical history; collection of multiple samples of blood, urine, stool, tears, and nose fluid; and skin and blood tests for TB. Some participants may volunteer to have a bronchoscopy (inserting a small viewing device into the lung passages) and bronchoalveolar lavage (washing out cells and fluid from the lung).


Condition Intervention Phase
Tuberculosis
Biological: BCG (ID)
Biological: BCG (PO)
Drug: Placebo (ID)
Biological: Connaught strain BCG
Drug: Placebo (PO)
Phase I

MedlinePlus related topics: Tuberculosis
Drug Information available for: Sodium chloride BCG Vaccine
U.S. FDA Resources
Study Type: Interventional
Study Design: Prevention, Randomized, Double Blind (Subject, Investigator), Active Control, Factorial Assignment, Safety Study
Official Title: 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

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Immunogenicity: post-vaccination mycobacteria-specific secretory IgA responses measured by ELISA. [ Time Frame: Harvested immediately before primary vaccination, and 1 week, 2, 6, 8, and 12 months after primary vaccination, and 1 week, 2, 6, 8, and 12 months after secondary vaccination. ] [ Designated as safety issue: No ]
  • Safety: incidence of adverse events. [ Time Frame: Duration of study. ] [ Designated as safety issue: Yes ]
  • Immunogenicity: post-vaccination increases in mycobacteria-specific Th1 responses measured by both 7 day whole blood IFN-gamma secretion and overnight IFN-gamma ELISPOT assays. [ Time Frame: Day of primary vaccination followed by day 7, 56, 180, and month 12. After second vaccine day 7, month 2, 6, and 12. ] [ Designated as safety issue: No ]
  • Immunogenicity: post-vaccination T cell-mediated killing of intracellular mycobacteria. [ Time Frame: Month 12 after secondary vaccination and repeated if needed at 12 + 2-3 days. ] [ Designated as safety issue: No ]
  • Microbiologic: variability of BCG replication in 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 (primary and secondary) ID BCG vaccination. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Immunogenicity: proliferation of mycobacteria-specific T cells induced by ID and/or PO vaccination with SSI BCG using dendritic cells as antigen-presenting cells, and stored PBMCs as a source for matched T cells collected. [ Time Frame: Day of primary vaccination followed by day 7, 56, 180, and month 12. After second vaccine day 7, month 2, 6, and 12. ] [ Designated as safety issue: No ]
  • Immunogenicity: percentage of inhibition of BCG growth as indicated by secondary lymphocyte inhibition (killing) assays with serum samples. [ Time Frame: Harvested immediately before primary vaccination, and 1 week, 2, 6, 8, and 12 months after primary vaccination, and 1 week, 2, 6, 8, and 12 months after secondary vaccination. ] [ Designated as safety issue: No ]
  • Microbiologic: Reduction in secondary BCG replication by preceding Sanofi Pasteur BCG vaccination. [ Time Frame: After primary and secondary BCG ID vaccination. ] [ Designated as safety issue: No ]
  • Immunogenicity: proportion of subjects in each treatment group achieving an immunologically significant increase in Mtb-specific immune responses (i.e., at least 2 standard deviations above mean for negative controls for above assays). [ Time Frame: Analysis. ] [ Designated as safety issue: No ]
  • Immunogenicity: presence or absence of cutaneous T cell trafficking, as indicated by 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. ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: December 2008
Estimated Study Completion Date: June 2010
Estimated Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Group A: BCG ID/Placebo PO; Placebo ID/Placebo PO: Experimental
Primary vaccination: BCG ID (Danish)/Placebo PO; secondary vaccination (1 year later): Placebo ID/Placebo PO.
Biological: BCG (ID)
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..
Drug: Placebo (ID)
Sauton medium for intradermal administration.
Drug: Placebo (PO)
Phosphate buffered saline (PBS) for oral administration.
Group B: BCG ID/Placebo PO; BCG ID/Placebo PO: Experimental
Primary vaccination: BCG ID (Danish)/Placebo PO; secondary vaccination (1 year later): BCG ID (Danish)/Placebo PO.
Biological: BCG (ID)
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..
Drug: Placebo (PO)
Phosphate buffered saline (PBS) for oral administration.
Group C: Placebo ID/BCG PO; Placebo ID/Placebo PO: Experimental
Primary vaccination: Placebo ID/BCG PO (Danish); secondary vaccination (1 year later): Placebo ID/Placebo PO.
Biological: BCG (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).
Drug: Placebo (ID)
Sauton medium for intradermal administration.
Drug: Placebo (PO)
Phosphate buffered saline (PBS) for oral administration.
Group D: Placebo ID/BCG PO; Placebo ID/BCG PO: Experimental
Primary vaccination: Placebo ID/BCG PO (Danish); secondary vaccination (1 year later): Placebo ID/BCG (Danish) PO.
Biological: BCG (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).
Drug: Placebo (ID)
Sauton medium for intradermal administration.
Group G: Connaught strain BCG ID; Connaught strain BCG ID: Experimental
Primary vaccination: Connaught strain BCG ID; secondary vaccination (1 year later); Connaught strain BCG ID.
Biological: Connaught strain BCG
Connaught strain Bacillus Calmette-Guerin (BCG), 8-32 x 10^5 CFU vaccine for intradermal administration.
Group F: BCG ID/BCG PO; BCG ID/BCG PO: Experimental
Primary vaccination: BCG ID/BCG PO (Danish); secondary vaccination (1 year later): BCG ID (Danish)/BCG PO (Danish).
Biological: BCG (ID)
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..
Biological: BCG (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).
Group E: BCG ID/BCG PO; Placebo ID/Placebo PO: Experimental
Primary vaccination: BCG ID (Danish)/BCG PO (Danish); secondary vaccination (1 year later): Placebo ID/Placebo PO.
Biological: BCG (ID)
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..
Biological: BCG (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).
Drug: Placebo (ID)
Sauton medium for intradermal administration.
Drug: Placebo (PO)
Phosphate buffered saline (PBS) for oral administration.

Detailed Description:

The purpose of this phase I, single-center, double-blind, randomized, placebo-controlled vaccine trial is to investigate the safety and immunogenicity of primary and secondary Bacillus Calmette-Guérin (BCG) vaccination delivered intradermally, orally, and by combined routes of administration in healthy and previously immunologically naïve volunteers. Seventy healthy male and female subjects, 18-40 years old, inclusive, who are negative for QuantiFERON®-TB Gold and human immunodeficiency virus will participate in this study conducted at Saint Louis University for Vaccine Development. Volunteers will be enrolled into 7 groups of 10 subjects to receive 1 or 2 BCG vaccinations intradermally, orally, or by both routes combined. Volunteers will be randomized in a double-blind fashion to groups A-F to receive intradermal (ID) BCG vaccination plus oral (PO) placebo, ID placebo plus PO BCG vaccination, or a combination of ID and PO BCG vaccination, or to the open-label Group G to receive ID BCG vaccination only. One year later, Groups A, C and E will receive both ID and PO placebos, while Groups B, D and F will receive the same combinations of vaccinations that they received 1 year earlier for primary vaccination. Group G will receive ID BCG (Connaught strain, all other BCG vaccinations are Danish BCG) vaccination again 12 months after the primary vaccination. Groups A-F will be followed in a double blind fashion until the end of the study. Group G will be followed in an open-label fashion throughout the study. The placebo will be injectable Sauton medium for ID administration and phosphate buffered saline (PBS) for oral administration. Each volunteer will participate in the study for up to 26 months, which includes the 60-day screening period. The primary study objectives are assessment of the safety of combined and individual ID and PO vaccination with BCG in healthy, immunologically naïve volunteers; comparisons of mycobacteria-specific interferon-gamma responses, mucosal immunoglobulin-A, and intracellular killing activity induced by BCG vaccination given intradermally, orally, and by both routes combined; and comparison of safety and immunogenicity BCG given intradermally. The secondary study objectives are assessment of purified protein derivative skin test responses as an indication of cutaneous T-cell trafficking after vaccination with BCG; characterization of mycobacteria-specific T cells induced intradermally, orally, or both routes by vaccination with BCG using dendritic cells as antigen-presenting cells and stored peripheral blood mononuclear cells as a source for matched T cells collected before and after vaccination; and quantitation of BCG replication in ID BCG ulcerative lesions after primary and secondary ID BCG vaccination. Safety is one of the primary endpoints of this Phase I trial.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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 24 months of follow-up.
  • Weigh at least 110 pounds.
  • Male or female. Females must not be pregnant, as determined by negative serum pregnancy test at pre-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, and 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 and respiratory evaluation.
  • Have a negative 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 ESAT-6 response minus nil response less than 0.35 IU/ml, CFP-10 response minus nil response less than 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 blood chemistry and hematologic laboratory values within normal values for age and gender according to the current normal ranges for testing vendor.
  • Have a urine dipstick test negative for glucose and less than 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 hours 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 hours 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 Human Immunodeficiency Virus (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, 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, occupational, 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 Tuberculosis (TB) patients.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00396370

Contacts
Contact: Daniel F Hoft (314) 577-8648 hoftdf@slu.edu

Locations
United States, Missouri
Saint Louis University Recruiting
St. Louis, Missouri, United States, 63104
Sponsors and Collaborators
  More Information

Responsible Party: HHS/NIAID/DMID ( Robert Johnson )
Study ID Numbers: 01-351, Concept 904-004
Study First Received: November 3, 2006
Last Updated: January 8, 2009
ClinicalTrials.gov Identifier: NCT00396370  
Health Authority: United States: Federal Government;   United States: Food and Drug Administration;   United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
tuberculosis, Bacillus Calmette-Guérin

Study placed in the following topic categories:
BCG Vaccine
Bacterial Infections
Gram-Positive Bacterial Infections
Neoplasm Metastasis
Mycobacterium Infections
Tuberculosis
Healthy

Additional relevant MeSH terms:
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic
Pharmacologic Actions
Actinomycetales Infections

ClinicalTrials.gov processed this record on January 14, 2009