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Live attenuated bacterial vaccine / Immunostimulant

BCG vaccine

BCG (Bacillus Calmette-Guérin) vaccine is a live attenuated strain of Mycobacterium bovis used primarily to prevent severe forms of tuberculosis in children and as intravesical immunotherapy for non-muscle-invasive bladder cancer. The most testable fact is that BCG is contraindicated in immunocompromised patients because it contains live bacteria and can cause disseminated BCG infection.

Practice questionsHigh-yield facts
Drug classLive attenuated bacterial vaccine / Immunostimulant
MechanismStimulates cell-mediated immunity via Th1 response
Main usesTB prevention; intravesical therapy for bladder cancer
Key adverse effectLocal abscess; disseminated BCG in immunocompromised patients
5 min readFor medical studentsUpdated 2026-10-14

Mechanism of action

BCG vaccine contains live attenuated Mycobacterium bovis (substrain specifics vary by manufacturer). When administered, it stimulates both innate and adaptive immune responses.

As a vaccine (intradermal)

BCG induces a robust cell-mediated (Th1) immune response. It activates macrophages, dendritic cells, and CD4+ T lymphocytes, leading to formation of granulomas similar to those seen in natural tuberculosis infection. This primes the immune system to respond more effectively to subsequent exposure to Mycobacterium tuberculosis. The protection is strongest against severe disseminated forms of TB (miliary TB, TB meningitis) in children, with variable efficacy against pulmonary TB in adults.

As immunotherapy (intravesical)

When instilled into the bladder for non-muscle-invasive bladder cancer, BCG elicits a local inflammatory response. It attaches to the urothelium, is internalized by urothelial cells and immune cells, and triggers an immune cascade involving cytokine release (IL-2, IL-6, IL-8, TNF-α, IFN-γ), recruitment of granulocytes, macrophages, and T cells, and cytotoxic activity against tumor cells. The exact antitumor mechanism is multifactorial and not fully elucidated, but the Th1 immune activation is central.

High-yield for exams
  • BCG is a live attenuated Mycobacterium bovis vaccine; contraindicated in immunocompromised patients.
  • BCG causes false-positive TST for years; use IGRA (QuantiFERON) for latent TB screening in vaccinated individuals.
  • Most effective agent for carcinoma in situ and high-risk non-muscle-invasive bladder cancer.
  • BCG protects against severe disseminated TB (miliary, meningitis) in children, not reliably against pulmonary TB in adults.
  • Fever >39.5°C for >48 hours or sepsis after intravesical BCG: treat urgently with isoniazid + rifampin + ethambutol.
  • Avoid intravesical BCG within 2 weeks of transurethral resection or traumatic catheterization (risk of systemic dissemination).
  • Antimycobacterial antibiotics (rifampin, quinolones) reduce BCG efficacy; avoid during bladder cancer therapy.
  • Disseminated BCG infection (BCGosis) is rare but life-threatening; seen in immunodeficient patients.

Indications

Vaccination (intradermal)

  • Prevention of tuberculosis, particularly in infants and children in high-burden TB areas
  • Used in countries with high TB prevalence; not routinely used in the United States
  • Healthcare workers with high risk of exposure to multidrug-resistant TB (country-dependent)

Intravesical immunotherapy

  • Carcinoma in situ (CIS) of the urinary bladder
  • High-risk non-muscle-invasive bladder cancer (Ta/T1 high-grade) after transurethral resection, to reduce recurrence and progression
  • BCG is considered the gold standard for CIS and high-risk superficial bladder tumors

BCG vaccination is not recommended in the United States for routine use due to low TB prevalence, variable vaccine efficacy against pulmonary TB, and interference with tuberculin skin test (TST) interpretation.

Pharmacokinetics

BCG is not absorbed systemically in the traditional sense because it is a live organism administered locally.

Intradermal vaccination: The vaccine is given as a single intradermal injection. Live bacteria persist locally for weeks to months, stimulating prolonged immune activation. Viable BCG organisms can occasionally be cultured from regional lymph nodes. There is no systemic "distribution" or metabolism in the pharmacologic sense. Immunity develops over several weeks to months.

Intravesical instillation: BCG is instilled directly into the bladder via catheter and retained for approximately 2 hours before voiding. The bacteria attach to and are internalized by bladder mucosa. Systemic absorption is minimal, though systemic immune activation and rare dissemination can occur. Therapy typically involves an induction course followed by maintenance schedules as directed by the product label.

BCG is not metabolized by hepatic or renal pathways. Clearance involves immune-mediated destruction and local containment.

Adverse effects

Intradermal vaccine

Common

  • Local reaction at injection site (papule, ulceration, regional lymphadenitis) — expected and indicates immune response
  • Low-grade fever
  • Axillary or cervical lymphadenopathy

Serious (rare)

  • Disseminated BCG infection (BCGosis): occurs in immunocompromised patients; can involve liver, lung, bone marrow, and CNS; potentially fatal
  • Osteomyelitis (BCG osteitis), often delayed (months to years)
  • Lupus vulgaris (chronic skin infection)

Intravesical therapy

Common

  • Dysuria, urinary frequency, hematuria (mild cystitis symptoms)
  • Flu-like symptoms (malaise, fever, myalgia) — seen in ~25% after instillation
  • Granulomatous prostatitis

Serious

  • BCG sepsis: high fever, hypotension, confusion; requires immediate anti-tuberculous therapy
  • Contracted bladder
  • Renal or ureteral obstruction (granulomatous inflammation)
  • Pneumonitis, hepatitis (rare systemic hypersensitivity)
  • Disseminated BCG infection

Key point: Persistent fever >39.5°C for >48 hours after intravesical BCG or signs of sepsis warrant urgent evaluation and empiric anti-tuberculous treatment.

Contraindications and warnings

Absolute contraindications

  • Immunodeficiency or immunosuppression: HIV/AIDS, congenital immunodeficiency, malignancy (especially hematologic), chronic corticosteroid therapy, immunosuppressive drugs (anti-TNF agents, chemotherapy)
  • Active tuberculosis (vaccine form)
  • Febrile illness at time of vaccination (defer until resolved)
  • Pregnancy (live vaccine)
  • Traumatic catheterization or gross hematuria (for intravesical use; delay until healed)
  • Active urinary tract infection (for intravesical use)

Warnings

  • TST and IGRA interference: BCG vaccination causes false-positive tuberculin skin tests for years to decades. Interferon-gamma release assays (IGRAs) are preferred for latent TB screening in BCG-vaccinated individuals.
  • Bladder perforation or recent TUR: intravesical BCG must be delayed ≥2 weeks after resection or traumatic catheterization to avoid systemic dissemination.
  • Antimicrobial therapy: avoid concurrent antibiotics with activity against mycobacteria (fluoroquinolones, rifampin) during intravesical BCG therapy, as they reduce efficacy.
  • Do not administer other live vaccines within 4 weeks of BCG.

Pregnancy and lactation

BCG is contraindicated in pregnancy (live vaccine; theoretical risk to fetus). Lactation: no data; generally avoided.

Drug interactions

  • Immunosuppressive agents (corticosteroids, azathioprine, methotrexate, anti-TNF biologics, checkpoint inhibitors): increased risk of disseminated BCG infection. These are contraindications, not merely interactions.
  • Antimycobacterial antibiotics (isoniazid, rifampin, fluoroquinolones, aminoglycosides): reduce BCG viability and efficacy. Avoid during intravesical BCG therapy unless treating BCG infection.
  • Other live vaccines: space ≥4 weeks apart to avoid immune interference.
  • Antiviral agents: no significant interactions reported.

Clinical note: If a patient on intravesical BCG develops BCG sepsis, treat with isoniazid + rifampin + ethambutol (and sometimes fluoroquinolone) — the same drugs that would undermine BCG therapy are life-saving in BCG infection.

Clinical pearls

  • BCG protects best against severe pediatric TB (miliary, meningitis), not adult pulmonary TB. Efficacy varies by geography and strain.
  • Intravesical BCG is the most effective agent for CIS and reduces progression to muscle-invasive disease.
  • Distinguish BCG cystitis from BCG sepsis: mild dysuria and low-grade fever are expected; high fever (>39.5°C), hypotension, or altered mental status require urgent anti-TB treatment.
  • TST is unreliable after BCG vaccination; use IGRA (QuantiFERON, T-SPOT) for latent TB screening in vaccinated individuals.
  • BCG scar: a small papule or scar at the injection site (deltoid region) is a normal finding and can help confirm vaccination status.
  • Do not give BCG to HIV-positive infants, even if asymptomatic, due to risk of disseminated BCG.
  • Bladder cancer recurrence: BCG reduces recurrence by ~40% and progression by ~30% compared to resection alone.
  • BCG shortage: global supply shortages have occurred; alternate strains and reduced-dose regimens are sometimes used.
  • Treatment of BCG complications: standard anti-TB drugs (isoniazid, rifampin, ethambutol) as directed by clinical guidelines, sometimes with fluoroquinolones. Corticosteroids may be used for severe hypersensitivity reactions under antimycobacterial cover.

Practice questions

1. A 3-month-old infant born to a mother with untreated pulmonary tuberculosis is brought to the clinic. The child has been living with the mother and has had close contact. The infant is asymptomatic and a tuberculin skin test is negative. The mother's TB isolate is sensitive to all first-line drugs. Which of the following is the most appropriate next step?

Answer: B. An infant exposed to active pulmonary TB should receive isoniazid prophylaxis immediately, even if TST is negative, because infants can develop severe disseminated TB rapidly and TST may not yet be positive (window period). The TST is repeated in 8–12 weeks; if still negative and exposure has ended, prophylaxis can be stopped. BCG is not given to infants with known TB exposure or those already infected. Full therapy is reserved for active disease, which this infant does not have.

2. A 68-year-old man with high-grade non-muscle-invasive bladder cancer undergoes transurethral resection followed by intravesical BCG therapy. Two days after his third weekly instillation, he develops fever to 40°C, confusion, and hypotension. Blood cultures are pending. Which of the following is the most appropriate immediate management?

Answer: C. This patient has BCG sepsis, a life-threatening complication characterized by high fever, systemic toxicity, and signs of sepsis after intravesical BCG. Immediate treatment with anti-tuberculous therapy (isoniazid, rifampin, ethambutol, sometimes a fluoroquinolone) is critical. Mild cystitis symptoms and low-grade fever are common after BCG, but high fever (>39.5°C), altered mental status, and hypotension are not expected and require urgent treatment. Delaying therapy or using fluoroquinolones alone is inadequate for BCG sepsis. Corticosteroids may be added later under antimycobacterial cover for severe inflammation.

3. A 10-year-old boy recently immigrated from a country with high tuberculosis prevalence. He received BCG vaccination as an infant and has a visible scar on his left deltoid. He is asymptomatic. A tuberculin skin test is performed for school entry and shows 12 mm induration. Chest X-ray is normal. Which of the following is the most appropriate interpretation?

Answer: B. BCG vaccination causes false-positive tuberculin skin tests that can persist for years, making TST unreliable in vaccinated individuals. An interferon-gamma release assay (IGRA) such as QuantiFERON or T-SPOT does not cross-react with BCG and is the preferred test to distinguish true TB infection from vaccine effect. The child is asymptomatic with normal chest X-ray, so active TB is unlikely. Starting treatment without confirming true infection risks unnecessary therapy and side effects. Revaccination is not indicated, and repeating TST will not clarify the cause of positivity.

Frequently asked questions

How does the BCG vaccine work?

BCG vaccine contains live attenuated Mycobacterium bovis that stimulates a strong cell-mediated (Th1) immune response. When given intradermally, it primes macrophages and T lymphocytes to recognize and respond to Mycobacterium tuberculosis, providing protection especially against severe disseminated forms of TB like miliary TB and TB meningitis in children. When instilled into the bladder for cancer treatment, BCG triggers local immune activation with cytokine release and cytotoxic activity against tumor cells.

What are the side effects of BCG vaccine?

Common side effects of intradermal BCG include a local papule or ulcer at the injection site, regional lymphadenopathy, and low-grade fever. For intravesical BCG, patients often experience dysuria, urinary frequency, mild hematuria, and flu-like symptoms. Serious but rare complications include disseminated BCG infection (especially in immunocompromised patients), BCG sepsis (high fever, hypotension), osteomyelitis, and granulomatous inflammation of the bladder or prostate. Persistent high fever after intravesical BCG requires urgent evaluation.

Is BCG vaccine given in the United States?

BCG vaccination is not routinely recommended in the United States for the general population due to low TB prevalence, variable vaccine efficacy against pulmonary TB, and interference with tuberculin skin test interpretation. It is considered only in select cases such as children with unavoidable exposure to multidrug-resistant TB. However, intravesical BCG is widely used in the US as immunotherapy for non-muscle-invasive bladder cancer, where it is the gold standard treatment for carcinoma in situ and high-risk tumors.

BCG vaccine vs tuberculin skin test — what is the difference?

BCG vaccine is a live attenuated bacterial vaccine that actively immunizes against tuberculosis, while the tuberculin skin test (TST, Mantoux test) is a diagnostic test that detects immune response to TB antigens to identify latent or active infection. BCG vaccination causes false-positive TST results for years because the vaccine antigens cross-react with those used in the test. This is why interferon-gamma release assays (IGRAs like QuantiFERON) are preferred for TB screening in BCG-vaccinated individuals, as they do not cross-react with BCG.

What cancers is BCG used to treat?

BCG is used as intravesical immunotherapy specifically for non-muscle-invasive bladder cancer, particularly carcinoma in situ (CIS) and high-risk Ta/T1 high-grade tumors. It is instilled directly into the bladder after transurethral resection to reduce tumor recurrence and prevent progression to muscle-invasive disease. BCG is considered the most effective agent for CIS and significantly improves outcomes in high-risk superficial bladder cancer. It is not used for other cancer types.

Conditions it is used for

TuberculosisBladder cancerCarcinoma in situ of bladderNon-muscle-invasive bladder cancer
IsoniazidRifampinMitomycinInterferon alfaGemcitabineEthambutolPyrazinamide

Sources and further reading

DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: J07AN01WHO ATC/DDD index: L03AX03

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.