| Purpose: |
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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 (up to 80) healthy volunteers, 18-40 years old, for 24 months.
Study procedures will include 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).
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| Study summary: |
|
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.
Approximately 70 (up to 80) 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) Danish BCG vaccination plus oral (PO) placebo, ID
placebo plus PO Danish BCG vaccination, or a combination of ID and PO Danish BCG
vaccination, or to the open-label Group G to receive ID Connaught 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 Connaught 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 24
months. 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 and mucosal immunoglobulin-A
induced by BCG vaccination given intradermally, orally, and by both routes combined; and
comparison of safety and immunogenicity of Danish and Connaught 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; and
quantitation of BCG replication in ID BCG ulcerative lesions after primary and secondary ID
BCG vaccination. Exploratory objectives are: comparisons of intracellular killing activity
induced by BCG vaccinations given intradermally, orally, and by both routes combined; and
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. |
| Criteria: |
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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 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 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, 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 or equal to 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. |