- Researchers at Texas A&M University and five other academic institutions have begun a phase 4 clinical trial re-purposing a live attenuated tuberculosis vaccine to treat COVID-19.
- The researchers believe that the TICE® BCG vaccine, which is licensed to prevent and treat bladder cancer, may help mitigate the severity of COVID-19.
- The research team is recruiting 1,800 healthcare workers to participate in the trial.
Researchers at Texas A&M University have initiated a Phase 4 clinical trial to test whether a type of tuberculosis (TB) vaccine, TICE® BCG, manufactured by a subsidiary of Merck & Co., will mitigate the severity of the COVID-19 infection in healthcare workers.1 Unlike BCG Live, known as Bacillus Calmette–Guérin (BCG) vaccine, which has been used for more than 100 years in countries around the world to prevent tuberculosis, TICE® BCG has been licensed in the U.S. to treat and prevent bladder cancer.2
Texas A&M Health Science Center is leading the trials in collaboration with scientists and doctors at Harvard T.H Chan School of Public Health in Boston, Massachusetts, the University of Texas MD Anderson Cancer Center in Houston, Texas, Cedars Sinai Medical Center in Los Angeles, California and the Baylor College of Medicine in Houston, Texas.3 Texas A&M System Chancellor John Sharp provided the research team with a $2.5 million grant from the Chancellor Research Initiative in order to begin the clinical trial.4
In a Texas A&M Apr. 29, 2020 press release, Dr. Jeffrey D. Crillo, a Regent’s Professor of Microbial Pathogenesis and Immunology at the Texas A&M Health Science Center, said, “It’s not going to prevent people from getting infected. This vaccine has the very broad ability to strengthen your immune response. We call it ‘trained immunity.”5
The research team is recruiting 1,800 healthcare workers on the front lines to participate in the clinical trial; however, the BCG vaccine will only be tested on people who have not yet been exposed to the SARS-CoV-2 virus.6
BCG Live Vaccine Licensed for Use In U.S. to Prevent TB
The U.S. Food and Drug Administration (FDA) has licensed two tuberculosis vaccines for use in the U.S, BCG Live and TICE® BCG. Both vaccines are manufactured by Organon Teknika Corporation, LLC in Durham, North Carolina, a subsidiary of Merck &Co.7
The FDA licensed the use of BCG Live for the prevention of tuberculosis in persons who have not previously been infected with bacterium M. tuberculosis and are at high risk for exposure.8 This attenuated live virus vaccine is administered by intradermal injection and is not generally recommended for use in the U.S because of the low risk of infection with Mycobacterium tuberculosis, the variable effectiveness of the vaccine against adult pulmonary TB, and the vaccine’s potential interference with tuberculin skin test reactivity.9
According to the U.S. Centers for Disease Control and Prevention (CDC), BCG Live should be considered only for certain people who meet specific criteria and in consultation with a TB expert.10
TICE® BCG “Vaccine” Licensed in U.S. to Treat and Prevent Bladder Cancer
Although listed as a vaccine on the FDA’s website, TICE® BCG has been licensed by the FDA to be used as an immunotherapy treatment for patients diagnosed with urinary bladder cancer and to prevent the reoccurrence of Stage Ta and T1 papillary tumors of the bladder that have a high risk of reoccurrence.11 2
TICE® BCG is approved for intravesical use and is an attenuated, live culture preparation of the BCG strain of the Mycobacterium bovis (M.Bovis) bacterium.13 M.Bovis can cause tuberculosis in humans. It is also a bacterium commonly found in cattle and other animals like elk, bison and deer.14
Intravesical administration of this treatment means that it is infused into the bladder through a urethral catheter after completely draining the bladder.15 The TICE® strain was developed at the University of Illinois from a strain originated at the Pasteur Institute.16
Researchers Are Experimenting with Re-Purposing the TICE® BCG Vaccine to Treat COVID-19
According to Jeffery Cirillo, PhD, a Regent’s Professor of Microbial Pathogenesis and Immunology at the Texas A&M Health Science Center and a lead scientist in the clinical trial, repurposing the existing TICE® BCG, also used as a treatment for bladder cancer, could quickly offer the American people an approved treatment for COVID-19 infections.17 Since the FDA has already approved TICE® BCG for use in the U.S, the research team is allowed to skip the first three phases of clinical trials usually required before testing it on human subjects.18
The clinical trial participants’ health will be monitored over the next six months. Dr. Cirillo said that if the BCG vaccine is working as a treatment for COVID-19, they expect to observe a difference in the overall health of those vaccinated compared with a group that will receive a placebo treatment. Information about the placebo being used in the clinical trial has not been released to the public.19
The researchers are expecting that many of the BCG clinical trial participants will be exposed to the virus in the next few weeks given the nature of their jobs working with COVID-19 patients.20 While there will still be COVID-19 patients that need to be hospitalized, researchers are hopeful that TICE® BCG could help reduce the number of patients who need to be admitted to intensive care units.21
Andrew DiNardo, MD, assistant professor at the Baylor College of Medicine and an investigator on the clinical trial of the TICE® BCG vaccine commented that the BCG vaccine should be studied given in combination with a new COVID-19 vaccine:
It is a very well-known and safe vaccine available now that might be able to work as a buffer until a COVID-19 vaccine is developed, which could take 18 months.” He adds, “When a COVID-19 vaccine comes out, the BCG vaccine should be tested with it to see if it improves the efficacy.22
Mechanism of Action of TICE® BCG
The researchers of the study acknowledge that the vaccine will not prevent people from contracting COVID-19; however, they have hypothesized that since the human body fights the COVID-19 infection in a similar manner to how it would attack cancer cells in the bladder, the treatment could potentially strengthen the immune response to the virus and lead to an effective and quickly developed treatment for COVID-19.23
According to the TICE® BCG manufacturer insert and previous research, the exact biological mechanism of action to treat bladder cancer is not fully understood, but what is known is that TICE® BCG has a recognized effect on the stimulation of the immune system.24 25
Discrepancy in Information on Route of Administration
Although Texas A&M University’s has specified that TICE® BCG is the treatment used in the trial and the manufacturer’s insert on the FDA’s website states that TICE® BCG is only approved for intravesical use (via a urethral catheter),26 27 the details of the clinical trial listed on ClinicalTrials.gov suggests there is a discrepancy in the route of administration to treat cancer patients and the proposed route to treat COVID-19 patients. ClinicalTrials.gov states that participants will be randomized between administration by “slow intradermal injection” (into the skin) using a syringe in the deltoid (muscle in the upper arm) section or a placebo in a 1:1 ratio.28 The exact detail on how this treatment is administered is not clear.
TICE® BCG Vaccine Adverse Reactions
The adverse effects of intravesical TICE® BCG treatment are characterized as local or systemic and range from minor to severe. Local complications are the result of BCG-contaminated urine and can occur anywhere along the genitourinary tract. Systemic effects manifest when BCG disseminates to other sites via the bloodstream.29
According to the manufacturer’s vaccine insert, some of the listed adverse affects of TICE® BCG vaccine include bladder irritability and “flu-like” symptoms (malaise, fever, and chills), which may accompany “the localized, irritative toxicities.” In addition, M. bovis infections have been reported in lung, liver, bone, bone marrow, kidney, regional lymph nodes and prostate in patients who have received intravesical BCG.30
Other serious complications resulting from this treatment include male genitourinary (genital and urinary organs) tract infections such as orchitis, which is inflammation of the testicles caused by a bacteria or virus, and epididymitis, which is inflammation of the tube at the back of the testicle that stores and carries the sperm. Both of these types of infections have been resistant to multiple drug anti-tuberculous therapy and some men have required orchiectomy (removal of the testicles).31
The adverse affects of TICE® BCG administered intradermally is not yet known.
WHO Warns on the Use of BCG Vaccine for COVID-19
On Apr. 12, 2020, the World Health Organization (WHO) released a scientific brief stating, “There is no evidence that the Bacille Calmette-Guérin vaccine (BCG) protects people against infection with COVID-19 virus. Two clinical trials addressing this question are underway, and WHO will evaluate the evidence when it is available. In the absence of evidence, WHO does not recommend BCG vaccination for the prevention of COVID-19.”32
The WHO statement goes on to say, “There is experimental evidence from both animal and human studies that the BCG vaccine has non-specific effects on the immune system. These effects have not been well characterized and their clinical relevance is unknown.”33
1 Oder M. Texas A&M starts COVID-19 vaccine clinical trial, looking for volunteers. KBTX May 6, 2020.
2 Organon Teknika Corp. TICE® BCG Vaccine Insert. U.S. Food and Drug Administration.
3 See Footnote 1.
5 Texas A&M University System Staff. Texas A&M Researchers To Lead Testing Of Tuberculosis Vaccine To Fight COVID-19. Today.Tamu.edu Apr. 29, 2020.
6 U.S. Food and Drug Administration. Vaccines Licensed for Use in the United States. Apr. 24, 2020.
7 FDA. BCG Vaccine. Feb. 21, 2018.
8 U.S. Centers for Disease Control and Prevention. Fact Sheet – BCG Vaccine. May. 4, 2016.
9 CDC. Fact Sheet – BCG Vaccine. May. 4, 2016.
11 See Footnote 2.
12 Alhunaidi O, Zlotta A. The use of intravesical BCG in urothelial carcinoma of the bladder ECancerMedicalScience 2019; 13.
13 See Footnote 2.
14 CDC. Mycobacterium bovis (Bovine Tuberculosis) in Humans. Sept. 1, 2012.
15 See Footnote 12.
16 See Footnote 2.
17 See Footnote 5.
20 Knowles S. Texas A&M researchers hope tuberculosis vaccine might prevent coronavirus deaths. Texas Tribune May 6, 2020.
21 Rodriguez M. Texas A&M researchers vaccinate 50-plus in COVID-19 clinical trial. TheEagle May. 6, 2020.
22 Marrow H. Baylor recruiting for clinical trial to test tuberculosis vaccine on COVID-19. Community Impact May. 4, 2020.
23 See Footnote 5.
24 See Footnote 12.
25 Fuge O. at el. Immunotherapy for Bladder Cancer. Research and Reports in Urology 2015; 7: 65-79.
26 See Footnote 5.
27 See Footnote 12.
28 ClinicalTrials.gov. BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS). May. 8, 2020.
29 Green D. et al. Complications of Intravesical BCG Immunotherapy for Bladder Cancer. Radiographics 2019; 39: 80-94.
30 See Footnote 2.
31 See Footnote 2.
32 World Health Organization. Bacille Calmette-Guérin (BCG) vaccination and COVID-19. Apr. 12, 2020.