BCG Vaccine for Tuberculosis Prevention

(TIPI Trial)

Recruiting at 5 trial locations

Overseen By Nancy M. Veit, NP

Age: 18+

Sex: Any

Trial Phase: Phase 3

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) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

2000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a single dose of the BCG vaccine can prevent tuberculosis (TB) in adults traveling to countries where TB is common. Researchers seek to understand if the vaccine can trigger an immune response to protect against TB. Participants will receive either the BCG vaccine or a placebo (a non-active shot) and will be randomly assigned to one of these groups. Those planning to work or stay in high TB-risk countries for more than four weeks may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking TB prevention strategy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the BCG (Tokyo 172) vaccine is generally safe and lacks obvious side effects. Many countries have used this vaccine to prevent tuberculosis (TB). However, it is not commonly used in the United States, where it is considered experimental.

Some studies have found that the vaccine can cause a false-positive result in TB skin tests, making it appear as though someone has TB when they do not. Serious side effects, however, are rare.

This trial is in Phase 3, indicating that earlier studies tested the treatment and found it safe for most people. The long history of BCG vaccine use further supports its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for tuberculosis, which often involve lengthy antibiotic courses, the BCG (Tokyo 172) vaccine offers a preventive approach. This vaccine uses a live attenuated strain of bacteria to boost the immune system, potentially stopping the disease before it starts. Researchers are excited about this treatment because it may provide long-lasting immunity, reducing the need for ongoing medication and combating the rise of antibiotic-resistant TB strains.

What evidence suggests that the BCG vaccine might be an effective treatment for tuberculosis?

In this trial, participants will receive either the BCG vaccine or a placebo. Research has shown that the BCG vaccine can help prevent tuberculosis (TB), with effectiveness ranging from 0% to 80% across different studies. In some instances, the vaccine was up to 95.5% effective in preventing severe TB. However, its effectiveness can vary significantly based on factors like location and population. Although the BCG vaccine is used worldwide, it does not work uniformly across all regions or age groups. Despite these variations, the vaccine is considered to provide some protection against TB, which is why it is commonly used in countries with high TB rates. ^{4 6 7 8 9}

Who Is on the 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

Are You a Good Fit for This Trial?

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 agree not to have any TB skin tests for 6 months after getting the BCG/placebo vaccine.

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• BCG (Tokyo 172) vaccine
• Placebo

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.

How Is the Trial Designed?

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 European Union, Canada, Japan, United Kingdom for the following indications:

Approved in European Union as BCG vaccine for:

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

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

Approved in United Kingdom as BCG vaccine for:

• Prevention of tuberculosis infection in high-risk individuals
• 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+

Published Research Related to This Trial

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 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]

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]

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 strain of the BCG vaccine, developed in Japan from the 172nd passage of the original culture, has been recognized as an International Reference Strain by the World Health Organization since 1965, highlighting its importance in vaccine research and standardization.

The introduction of a multiple puncture method for BCG vaccination in 1967 improved the administration technique, making it safer and more effective compared to traditional intradermal injections, while ongoing research continues to evaluate its efficacy and potential adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Historical review of BCG vaccine in Japan. Yamamoto, S., Yamamoto, T.[2022]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6879972/

Effectiveness of bacillus Calmette–Guerin vaccination ... The results of the present study indicated that BCG vaccine shows an overall effectiveness of 95.5% in the prevention of acute TB. Declaration ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10081113/

Bacillus Calmette–Guérin Tokyo-172 vaccine provides age ... Overall, BCG vaccine conferred neuroprotection in both the models, decreasing the incidence and severity of the disease, but failed to attenuate disease ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2666634021003809

Protection against tuberculosis by Bacillus Calmette ... Efficacy rates of BCG for protection against TB disease have ranged from an absence of clinically relevant effects to substantial protection. A ...

4. en.wikipedia.org en.wikipedia.org/wiki/BCG_vaccine

BCG vaccine The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for 15 years; however, its protective effect appears to vary according to ...

5. cell.com cell.com/med/fulltext/S2666-6340(21)00380-9

Protection against tuberculosis by Bacillus Calmette ... Efficacy rates of BCG for protection against TB disease have ranged from an absence of clinically relevant effects to substantial protection. A ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9320669/

Past, Present and Future of Bacillus Calmette-Guérin Vaccine ... Eventually, even though BCG administration was safe and had no obvious side effects, the BCG strain was lost, as it could not be preserved [23].

7. cdc.gov cdc.gov/tb/hcp/vaccines/index.html

Bacille Calmette-Guérin (BCG) Vaccine for Tuberculosis This vaccine is not generally used in the United States. The vaccine can cause a false-positive TB skin test reaction. Syringe and vials, ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0264410X22006727

Characteristics and incidence of vaccine adverse events ... Clinical features and outcomes of Bacille Calmette-Guerin (BCG)-induced diseases following neonatal BCG Tokyo-172 strain immunization. Vaccine ...

9. fda.gov fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert---BCG-Vaccine.pdf

BCG Vaccine Package Insert BCG VACCINE (TICE® strain) is indicated for the prevention of tuberculosis in persons not previously infected with M. tuberculosis who are at high risk for ...