Bacillus Calmette and Guerin (BCG) is an attenuated strain of Mycobacterium bovis, the pathogen responsible for bovine tuberculosis. Calmette and Guérin cultivated this stable, non-virulent substrain during the development of their tuberculosis vaccine, which was first administered to humans in 1921. As there was no method of preserving viable mycobacterium at that time, BCG required continuous culture. By 1961, the original BCG strain had been serially passaged 1,173 times, resulting in the development of several daughter strains. These strains were then named after the manufacturer and place of origin.

As a result, BCG is not a well-defined pharmacological agent. Rather, it is a term applied to a pool of BCG strains that have acquired phenotypic and genotypic variations due to in vitro culturing in different laboratories under different conditions. These strains can be grouped as shown in Table 1.

Table 1. Groups of BCG substrains

Group Description Names
1 Early strains – closest genetically to original strain BCG Russia

BCG Moreau

BCG Japan

2 Deletion of IS6110 gene upstream of phoP BCG Sweden

BCG Birkhaug

3 Established after 1931 BCG Glaxo

BCG Prague

BCG Danish

4 Late strains BCG TICE

BCG Frappier

BCG Phipps

BCG Connaught

BCG Pasteur 1173

Comparison of substrains

The various substrains have noted differences in immunogenicity, antibiotic susceptibility, and adverse effects. Some studies suggest that these distinctions translate into only small differences in the efficacy of BCG vaccines against tuberculosis. However, head-to-head studies looking at different substrains in bladder cancer are limited. This makes it difficult to compare the clinical efficacy of different strains in this setting.

One study compared the in vitro anti-tumour effects of eight different strains. This study demonstrates that BCG Russia and BCG Connaught are the most effective in inhibiting cell proliferation and inducing cytokine production, while BCG Glaxo was the least effective.

Boehm et al. (2017) conducted a systematic review and meta-analysis to examine whether different BCG strains are associated with different clinical responses in bladder cancer. Their analysis demonstrated that BCG significantly reduced disease recurrence compared to chemotherapy and surgery. However, no BCG strain was found to be significantly superior in preventing disease recurrence.

Supply issues

In recent years, manufacturing issues have led to global shortages of BCG products. Australia currently has a shortage of OncoTICE® (BCG Tice), the Australian-registered BCG product for bladder irrigation. This long-term supply interruption is expected to continue until at least the end of December 2024.

The Therapeutic Goods Administration (TGA) has authorised the supply of an internationally registered alternative under Section 19A of the Therapeutic Goods Act 1989. The alternative product, VesiCulture BCG, is registered in Denmark. The package insert and product labelling is in English.

It is important to appreciate that the strengths of these two products are expressed differently. An OncoTICE vial contains 2-8 × 108 colony-forming units (CFU), which may also be expressed as 500 million CFU. In contrast, the strength of VesiCulture is typically stated as 30mg per vial but may also be referred to as 2.5 x 108 CFU.

In clinical trials, a standard dose is often defined as 120mg for the Danish strain and 5 × 108 CFU for the TICE strain. This equates to four vials of VesiCulture or one vial of OncoTICE.

Some of the other key differences between VesiCulture and OncoTICE® are summarised in Table 2.

Table 2. Comparison of OncoTICE and VesiCulture (adapted from Link Communication 2023)

  OncoTICE® VesiCulture
Strain Tice BCG BCG Danish strain 1331
Contents of one vial 500 million CFU

(2-8 × 108 CFU)

30mg per vial

(Approx. 2.5 x 108 CFU)

Pack size One or three glass vials Four glass vials
Dosage Each instillation comprises 2-8 × 108 CFU (the contents of one reconstituted and diluted vial

of OncoTICE suspended in 0.9% sodium chloride up to a total volume of 50 mL)

Normal dose (120 mg) = 4 reconstituted vials. The required dose is resuspended in 50 ml sterile preservative-free 0.9% sodium chloride.
Standard dose 1 vial 4 vials
Storage of reconstituted product 2 hours at 2-8 °C. Protect from light Up to 4 hours at 2-8 °C. Protect from light

BCG Efficacy

The anti-tumour activity of BCG is thought to be related to local modulation of immune responses, leading to inflammation and the subsequent elimination of malignant cells. Interaction of BCG with urothelial cells may result in immunological effects, such as the induction of chemokines (e.g. interleukin-8), pro-inflammatory cytokines (e.g. granulocyte-macrophage colony-stimulating factor, tumour necrosis factor α, interleukin-6), and the upregulation of adhesion-molecule expression.

There are a number of conditions that should be met to improve the likelihood of treatment success with BCG. These include:

  • The patient must be immunocompetent to ensure a robust immune response;
  • The tumour burden should be small;
  • BCG must come into direct contact with the tumour; and
  • The dose must be adequate to stimulate an immune reaction.

The current evidence suggests that the use of an established BCG strain from another country does not disadvantage patients with bladder cancer. However, healthcare professionals are advised to take additional care when dispensing and administering any product that they are not familiar with.

Further information:


  1. Babaian KN, Adams PG, McClure C, Tompkins B, McMurray M. Bacillus Calmette-Guérin immunotherapy for bladder cancer overview of BCG immunotherapy. Medscape; 2022.
  2. Boehm BE, Cornell JE, Mukherjee N, Oppenheimer JS, Svatek RS. Efficacy of Bacillus Calmette-Guerin Strains for the Treatment of Non-Muscle Invasive Bladder Cancer: A systematic review and network meta-analysis. J Urol. 2017; 198(3), 503.
  3. Horwitz MA, Harth G, Dillon BJ, Masleša-Galić S. Commonly administered BCG strains including an evolutionarily early strain and evolutionarily late strains of disparate genealogy induce comparable protective immunity against tuberculosis. Vaccine, 2009; 27(3): 441-445.
  4. Miyazaki J, Onozawa M, Takaoka E, Yano I. Bacillus Calmette–Guérin strain differences as the basis for immunotherapies against bladder cancer. International Journal of Urology 2018; 25(5), 405-413.
  5. OncoTice® (Mycobacterium bovis (Bacillus Calmette and Guerin (BCG) strain) Australian approved product information. Macquarie Park: Merck Sharp & Dohme. Approved May 2023.
  6. Secanella-Fandos S, Luquin M, Julian E. Connaught and Russian strains showed the highest direct antitumor effects of different Bacillus Calmette-Guerin substrains. J Urol. 2013; 189: 711–8.
  7. Sharma A. Communication to Healthcare Professionals; Link Healthcare: 2023.
  8. Tan GH, Kuk C, Zlotta AR. Are there differences among bacillus Calmette-Guérin (BCG) strains regarding their clinical efficacy in the treatment of non-muscleinvasive bladder cancer? The jury is still out but the answer is likely no. Can Urol Assoc J. 2020; 14(2): E54.
  9. VesiCulture® (Mycobacterium bovis (BCG), Danish strain 1331) Instructions for Use. Copenhagen: AJVaccines. Approved April 2021.

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