BCG Vaccination Delivered Intradermally, Orally and by Combined Routes
BCG Vaccination Delivered Intradermally, Orally and by Combined Routes
This study will assess the safety of a Bacillus Calmette-Guérin (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. This study, conducted
 at Saint Louis University, will enroll 60 (up to 80) healthy volunteers, 18-40 years old, who
 are negative for a TB test (QuantiFERON®-Gold) and human immunodeficiency virus (HIV). 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. Volunteers may participate for about 24 months.
Vaccination with Bacillus Calmette-Guérin (BCG) is used as part of tuberculosis (TB) control
 strategies in most of the world outside of the United States and constitutes the most widely
 implemented vaccination strategy worldwide. However, despite widespread use of BCG, TB
 remains a leading infectious cause of death worldwide and it is estimated that one-third of
 the world's population is chronically and asymptomatically (latently) infected with
 Mycobacterium tuberculosis (Mtb), the causative agent of TB. This is a phase I,
 single-center, randomized, vaccine trial including six double-blind, placebo-controlled
 groups and one open-label group. Approximately 68 (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 be enrolled. The expected total duration of the volunteer
 enrollment, vaccination, and follow-up (volunteer participation) for this study is 30 months.
 All volunteers are expected to be enrolled over a period of 9 months and on study for 24
 months. Detailed immune studies with frozen samples will be expected to continue after
 collection of all samples and after the protocol has been completed. Eligibility will be
 determined by volunteer's health at prescreening and eligible subjects will give study
 specific main study informed consent for enrollment in the study. Subjects randomized to
 Groups A-F will receive, at Day 0 and 1 year later, BCG intradermally, orally, or by both
 routes. PBS (PO) and Sauton medium (injectable) placebo will be used to blind the study.
 Subjects randomized to Group G will receive BCG intradermally at Day 0 only. The primary
 study objectives are the assessment of the safety of combined and individual intradermal (ID)
 and oral (PO) vaccination with Statens Serum Institut (SSI) BCG in healthy, immunologically
 naïve volunteers; comparisons of mycobacteria-specific interferon-gamma responses and mucosal
 immunoglobulin-A induced by SSI 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 the assessment of purified protein
 derivative skin test responses as an indication of cutaneous T cell trafficking after
 vaccination with SSI BCG; and quantitation of BCG replication in Sanofi Pasteur ID BCG
 ulcerative lesions after ID BCG vaccination. The exploratory study objectives are comparisons
 of intracellular killing activity induced by SSI BCG vaccination given intradermally, orally,
 and by both routes combined; and characterization of mycobacteria-specific T cells induced
 intradermally, orally, or both routes by vaccination with SSI 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. Parent protocol to sub-study 12-0110
 and 10-0026.
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.