Immunization With BCG Vaccine to Prevent Tuberculosis Infection

A Proof-of Concept, Randomized, Controlled Study of Tuberculosis Immunization With BCG to Prevent Infection in Healthy Adults (TIPI Trial)

The purpose of this research is to find out if a single dose of pre-travel vaccination with BCG can lessen tuberculosis (TB) infection by producing an immune response when given to adults traveling to countries with a high or moderate burden of TB. BCG will be compared with a placebo (an inactive vaccine). BCG (Japan) is used globally but is not approved for use in the United States, therefore it is considered experimental. Participants choosing to take part in this research study, will be randomly assigned (this is like a coin flip) to BCG or placebo. 2000 eligible volunteers will be enrolled.

This study is a multi-center, prospective, randomized, placebo-controlled, participant and laboratory-blinded clinical trial to evaluate a single pre-travel vaccination with investigational freeze-dried glutamate BCG (Japan) to prevent Mycobacterium tuberculosis complex (Mtb) infection in healthy adult travelers, 18-65 years of age, exposed to persons with TB in high or moderate burden countries.

The goals of this study are both public health and scientific. The public health goal of this study is to offer possible protection against TB to US workers traveling abroad to work in countries with a high burden of TB where there is a risk for multidrug resistant/extensively drug resistant TB exposure and where effective TB infection control interventions are infrequently fully implemented. A long-term scientific goal is to test the hypothesis that TB vaccination prevents primary TB infection as measured by peripheral blood TB interferon gamma release assay (IGRA) conversion at return from travel visit, as well as sustained conversion at approximately 4-6 months post-return from travel. Rates of IGRA conversion in BCG-vaccinated recipients as compared to placebo recipients will be evaluated. Additionally, this study will collect information regarding exposure to and infection with TB, assessing risk factors for TB infection during the participant's travel.

This study will recruit health care workers (public health workers or students in training status) traveling to countries with a high or moderate burden of TB where there is a risk for multidrug resistant/extensively drug resistant (MDR/XDR) for a minimum of 10 days up through 6 months, with planned exposure to the local population such as patient care activities. Performance sites will not enroll anyone traveling for greater than 6 months or longer.

High or moderate TB burden countries for this study are defined as countries identified in the World Health Organization (WHO) Global Tuberculosis Report 2020 to have a TB incidence of ≥20/100,000. Targeted participant population of travelers at-risk for high TB exposure will work specifically in one or more of the 131 highest ranked TB burden countries as recognized by the WHO 2020 report.

Participants enrolled will be required to complete typically 4, but up to 6 study visits composed of: screening and eligibility assessments, vaccination with study vaccine (BCG or placebo), a subsequent post-vaccination follow-up assessment visit to identify potential adverse event occurrences, a post-travel follow-up visit to assess the risk factors for Mtb infection and assess the primary endpoint (IGRA conversion from negative to positive), and if applicable, an additional visit for those participants who are found to have a borderline IGRA result. For participants found to have post-travel IGRA conversion results, an additional visit will be requested for assessment of sustained TB IGRA conversion and reversion.

Different evaluations, tests and/or procedures to be performed during study visits include: interviews relevant to their medical history and general well-being between study visits; physical examinations and vital signs; completion of a pre-travel questionnaire and post-travel questionnaires to collect information regarding exposure to TB and risk factors for infection, as well as any information regarding development of active TB disease, both pulmonary and/or extrapulmonary and evaluation for the presence and severity of self-reported symptomatic all-cause respiratory infection occurrences while traveling abroad; keeping a record to assess for occurrence of local reactions at the injection site and incidence of selected symptoms for the first 14 days post-vaccination; and blood draws (2 up to 4 depending on what previous blood test results reveal).

The study design is endpoint driven; designed to observe 56 total IGRA conversions. Therefore, enrollment into this study will be stopped if the target endpoint (56 IGRA conversions) are met earlier than expected.

Inclusion Criteria:

• Participants will be eligible for study participation if they meet all of the following criteria:

  1. Participant is willing to participate in the study as evidenced by providing voluntary written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization prior to conducting any trial related procedures

  2. Participant is male or female, age ≥ 18 years and ≤ 65 years at time of consent

  3. Participant is in good general health, confirmed by medical history, laboratory screening, and physical examination

  4. Participant has no known history of Mtb infection

  5. Participant has no prior history of BCG vaccination, or previous receipt of an investigational Mtb vaccine

  6. Participant is assessed to be at risk for TB exposure (particularly drug resistant TB) during planned travel and has planned to work in high or moderate TB burden countries for a duration of a minimum of 10 days and not greater than 6 months for HCW

  7. Participant presents at least 4 weeks prior to travel departure

  8. Participant is willing to forego any periodic tuberculin skin test screening procedures for 6 months after receiving BCG/placebo vaccine

  9. Participant is willing to wait after receiving a COVID-19 vaccine for 7 days before receiving BCG/placebo vaccine

  10. Participant is willing to complete all study visits as required by the protocol and is reachable by telephone or email during the study

  11. Participant agrees to medical record access for purposes of relevant medical history collection

      For Females of Childbearing Potential Only:

  12. Participant has a negative urine pregnancy test prior to starting study treatment

  13. Participant is willing to use effective contraception for at least 30 days before and 6 weeks after BCG/placebo vaccination

  14. Lactating female that is willing to refrain from breast-feeding for 6 weeks post-vaccination

Exclusion Criteria:

• Participants will be ineligible for study participation if they meet any of the following criteria:

  1. Participant has known positive tuberculin skin test (>10 mm) or positive IGRA
  2. Participant has medical condition for which BCG vaccination is contraindicated (e.g., HIV or other immunocompromised conditions)
  3. Participant is currently receiving (within last 30 days) immune-compromising treatments, such as TNF-α blockade
  4. Participant has history of chronic (≥ 30 days) oral steroid use or intravenous (IV) steroids within the last 90 days
  5. Participant has received radiation therapy or chemotherapy within the last 180 days
  6. Participant has received BCG treatment for bladder cancer
  7. Participant is female and is pregnant (as defined by positive urine βHCG test) or intends to become pregnant in next 3 months, or is breast-feeding at screening or vaccination visit
  8. Participant is unwilling to complete all required study elements (e.g., HIV testing)
  9. Participant has received 2 or more live vaccinations (e.g., measles and yellow fever) within 30 days prior to receipt of BCG/placebo vaccine (Visit 2)
  10. Participant has known or suspected hypersensitivity to BCG vaccine or related products
  11. Participant has positive/borderline IGRA test at screening
  12. Participant has positive/indeterminate HIV test at screening unless has received prior HIV vaccine
  13. Participant has a history of life-threatening adverse event following receipt of any immunization
  14. Participant is known to have a behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand or cooperate with the requirements of the study protocol
  15. Participant has other concurrent condition(s) that in the opinion of the investigator would jeopardize the safety or rights of a participant participating in the trial or would render the participant unable to comply with the protocol and/or compromise study objectives
  16. Participant has had tuberculin skin testing performed within 1 month prior to Visit 1
  17. Participant has received a COVID-19 vaccine within 7 days prior to BCG/placebo vaccine
  18. Participant has had a probable exposure to TB (defined as to someone with suspected or confirmed pulmonary TB who is likely infectious) within 8-10 weeks of Visit 1
  19. Participant has prior history of nontuberculous mycobacterial disease, not colonization only