BCG Vaccine for Tuberculosis Prevention

(TIPI Trial)

Recruiting at 9 trial locations

Overseen By Marianne Spevak

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine

Must not be taking: Immunosuppressants, Steroids, Chemotherapy, others

Disqualifiers: HIV, Pregnancy, Immunocompromised, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing if a single dose of the BCG vaccine can help prevent TB in healthy adults traveling to countries where TB is common. The vaccine works by preparing the immune system to fight off TB bacteria. Participants will receive either the BCG vaccine or a non-active substance. BCG is currently the only available vaccine against TB, widely used but with variable efficacy in adults.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on immune-compromising treatments or have used oral or IV steroids recently, you may not be eligible to participate.

What data supports the effectiveness of the BCG (Tokyo 172) vaccine treatment for tuberculosis prevention?

The BCG vaccine, including the Tokyo 172 strain, is known to protect against serious forms of tuberculosis in children and some adult cases in certain regions, although its effectiveness varies globally. Additionally, research has shown that the Tokyo 172 strain has been used successfully in other medical contexts, such as treating skin lesions, indicating its potential effectiveness in stimulating the immune system. ^{1 2 3 4 5}

Is the BCG Tokyo 172 vaccine generally safe for humans?

The BCG Tokyo 172 vaccine is generally considered safe, with serious side effects being rare. However, there have been isolated cases of adverse reactions, such as skin lesions and osteomyelitis (a bone infection), especially when the vaccine is not administered correctly. ^{1 3 4 6 7}

How is the BCG Tokyo 172 vaccine treatment different from other tuberculosis treatments?

The BCG Tokyo 172 vaccine is unique because it is a high-concentration strain used primarily in Japan for percutaneous (through the skin) administration, unlike other BCG vaccines that are often given intradermally (into the skin). This strain has shown significant protective efficacy against tuberculosis with a low rate of side effects, although rare complications like osteomyelitis (bone infection) can occur. ^{1 3 4 7 8}

Research Team

Naomi E. Aronson, MD

Principal Investigator

Uniformed Services University of the Health Sciences

Merlin L. Robb, MD

Principal Investigator

Henry M. Jackson Foundation for the Advancement of Military Medicine

Eligibility Criteria

Adults aged 18-65 planning to travel to high TB risk countries, in good health, with no prior BCG vaccination or history of TB infection. They must agree to avoid pregnancy, breastfeeding for specific periods post-vaccination and forego certain skin tests for 6 months.

Inclusion Criteria

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

I am in good health as confirmed by recent medical exams.

I am between 18 and 65 years old.

Exclusion Criteria

I have had radiation or chemotherapy in the past 6 months.

I am currently on treatments that weaken my immune system.

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

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Vaccination

Participants receive a single dose of BCG or placebo vaccine before travel

1 day

1 visit (in-person)

Post-vaccination Follow-up

Participants are monitored for adverse events and local reactions at the injection site

2-6 weeks

1 visit (in-person)

Post-travel Follow-up

Participants are assessed for TB infection and risk factors after returning from travel

4-10 weeks

1 visit (in-person)

Extended Follow-up

Participants with IGRA conversion are monitored for sustained conversion or reversion

4-6 months

1 visit (in-person)

Treatment Details

Interventions

• BCG (Tokyo 172) vaccine (Vaccine)
• Placebo (Other)

Trial Overview The trial is testing if the BCG (Tokyo 172) vaccine can prevent tuberculosis in adults traveling to high-risk areas compared to a placebo. Participants will be randomly assigned either the vaccine or placebo before their travel.

Participant Groups

Group I: BCG vaccine Experimental Treatment 1 Intervention

Freeze-dried Glutamate Bacillus Calmette-Guérin (BCG) (Tokyo 172) vaccine

Group II: Placebo Placebo Group 1 Intervention

Vaccine diluent \[sodium glutamate\]

BCG (Tokyo 172) vaccine is already approved in Canada, Japan for the following indications:

Approved in Canada as BCG vaccine for:

• Prevention of tuberculosis infection
• Prevention of tuberculous meningitis and miliary disease in children

Approved in Japan as BCG vaccine for:

• Prevention of tuberculosis infection
• Prevention of tuberculous meningitis and miliary disease in children

Who Is Running the Clinical Trial?

Henry M. Jackson Foundation for the Advancement of Military Medicine

Lead Sponsor

Trials

103

Recruited

94,300+

Uniformed Services University of the Health Sciences

Collaborator

Trials

130

Recruited

91,100+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In a study of 156 patients with superficial bladder cancer, low-dose BCG (40 mg) was found to be as effective as standard-dose BCG (80 mg) in preventing tumor recurrence and progression, with no significant differences in outcomes.

The low-dose BCG treatment resulted in significantly fewer side effects, particularly less severe pollakisuria, indicating a safer profile compared to the standard dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose instillation therapy with bacille Calmette-Guérin Tokyo 172 strain after transurethral resection: historical cohort study. Yoneyama, T., Ohyama, C., Imai, A., et al.[2008]

The current tuberculosis vaccine, bacille Calmette Guerin (BCG), is effective against serious pediatric forms and some adult cases, but many populations in high-burden countries do not benefit, highlighting the need for new vaccines.

Over the past decade, numerous new tuberculosis vaccine candidates have been developed and tested in animal models, with one promising candidate currently in Phase I human trials, indicating significant progress in vaccine research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress in the development and testing of vaccines against human tuberculosis. McMurray, DN.[2019]

The 'Tokyo 172' BCG vaccine, which is used in Japan and has a higher concentration of M. bovis BCG, can cause ulcerous skin lesions when administered intradermally, as seen in a patient case.

The patient's ulcer was successfully treated with systemic corticosteroids and anti-tuberculous drugs, indicating that while the vaccine is effective, it can lead to adverse effects that require medical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of ulcerous skin lesion caused by mistaken intradermal injection of BCG (Bacille de Calmette et Guerin) vaccine with anti-tuberculous drugs and systemic administration of corticosteroid. Watanabe, K., Teruya, K., Kikuchi, Y., et al.[2019]

The recombinant BCG Tokyo vaccine with the Ag85A gene insert showed better protective efficacy against Mycobacterium tuberculosis compared to the Ag85A DNA vaccine, significantly reducing lung pathology and bacterial counts in guinea pigs.

Using an immunogenic synthetic Ag85A peptide as a booster alongside the recombinant BCG Tokyo or Ag85A DNA vaccine further improved lung health and reduced bacterial counts, highlighting the importance of peptide boosting for enhancing vaccine efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective efficacy of recombinant (Ag85A) BCG Tokyo with Ag85A peptide boosting against Mycobacterium tuberculosis-infected guinea pigs in comparison with that of DNA vaccine encoding Ag85A. Sugawara, I., Udagawa, T., Taniyama, T.[2009]

The Bacillus Calmette-Guérin (BCG) vaccine is generally safe, with serious adverse events being rare, but common side effects reported in Victoria, Australia, included abscesses and lymphadenopathy, particularly in males.

The incidence of adverse events following immunization (AEFI) was similar for the Connaught and Denmark-SSI BCG strains, but the reported AEFI rate for the Denmark-SSI strain was significantly higher when considering doses administered, highlighting the need for effective surveillance systems in vaccination programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bacillus Calmette-Guérin (BCG) vaccine adverse events in Victoria, Australia: analysis of reports to an enhanced passive surveillance system. Clothier, HJ., Hosking, L., Crawford, NW., et al.[2018]

A rare case of BCG osteomyelitis occurred in a 9-month-old girl after receiving the BCG Tokyo-172 vaccine, highlighting that even vaccines with a good safety profile can have serious side effects in rare instances.

The child required multiple surgeries and antituberculosis treatment, but after 2 years of follow-up, she showed no lasting effects, indicating that while complications can arise, they may be manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe osteomyelitis as a complication of Tokyo-172 BCG vaccination. Kwon, HJ., Chung, BH., Choi, BM., et al.[2021]

The BCG Tokyo 172 strain demonstrated significant protective efficacy against pulmonary tuberculosis in guinea pigs, showing lower bacterial counts in the lungs and spleens compared to non-vaccinated controls.

Both BCG Tokyo 172 and BCG Copenhagen 1331 strains provided similar levels of protection, indicating that the BCG Tokyo 172 strain is an effective vaccine option against M. tuberculosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Protective efficacy of BCG Tokyo 172 in the guinea pig model of pulmonary tuberculosis]. Yamamoto, T., Phalen, S., Uchida, K., et al.[2006]

References

1. United States pubmed.ncbi.nlm.nih.gov

Low-dose instillation therapy with bacille Calmette-Guérin Tokyo 172 strain after transurethral resection: historical cohort study. [2008]

2. England pubmed.ncbi.nlm.nih.gov

Recent progress in the development and testing of vaccines against human tuberculosis. [2019]

3. Japan pubmed.ncbi.nlm.nih.gov

Successful treatment of ulcerous skin lesion caused by mistaken intradermal injection of BCG (Bacille de Calmette et Guerin) vaccine with anti-tuberculous drugs and systemic administration of corticosteroid. [2019]

4. Japan pubmed.ncbi.nlm.nih.gov

Historical review of BCG vaccine in Japan. [2022]

5. Scotland pubmed.ncbi.nlm.nih.gov

Protective efficacy of recombinant (Ag85A) BCG Tokyo with Ag85A peptide boosting against Mycobacterium tuberculosis-infected guinea pigs in comparison with that of DNA vaccine encoding Ag85A. [2009]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Bacillus Calmette-Guérin (BCG) vaccine adverse events in Victoria, Australia: analysis of reports to an enhanced passive surveillance system. [2018]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Severe osteomyelitis as a complication of Tokyo-172 BCG vaccination. [2021]

8. Japan pubmed.ncbi.nlm.nih.gov

[Protective efficacy of BCG Tokyo 172 in the guinea pig model of pulmonary tuberculosis]. [2006]