“The disease is still around, it's still contagious, and despite the fact that the vaccine costs approximately sixteen cents to produce, and $3.13 to buy, tuberculosis continues to ravage periphery countries. Millions of people die from tuberculosis every year - and it's totally treatable. This is a disease we can eradicate in our lifetime.” - Jennifer Wright, American author
“From my numerous observations, I conclude that these tubercle bacilli occur in all tuberculous disorders, and that they are distinguishable from all other microorganisms.” - Robert Koch
On July 18, 1921, BCG, a vaccine that prevents tuberculosis (TB), was first given to a human. In the ensuing 100 years, it has become the most widely used vaccine in the world. In 2013, it was estimated that over 4 billion people had received BCG with a safety record described as “astonishing.” Yet, many, if not most, Americans have never heard of BCG. This is due to the fact that the disease it prevents—TB—is predominantly a threat in poor countries. Therefore, the vaccine is not recommended for routine use in the U.S. In this week’s Germ Gems post, you will read about this remarkable vaccine and its track record not only in preventing TB, but also its use in treating other diseases such as bladder cancer and, potentially, COVID-19.
A brief history of TB. Before the emergence of COVID-19 in 2019, TB was the leading cause of death globally by an infectious agent. In 2018, there were an estimated 10 million cases of TB worldwide and 1.5 million TB-related deaths. By comparison, more than 78 million cases and 1.7 million deaths were attributed to COVID-19 in the first year of the pandemic. Historically, however, TB has been responsible for the death of more people than any other infectious disease, causing over a billion deaths in the past 200 years alone.
When the tubercle bacillus is inhaled a lower respiratory tract infection develops. About 50% of patients with active TB succumb to the infection most of whom have advanced disease of the lungs or involvement of other organs, such as, the brain (meningitis), kidneys, or gastrointestinal tract. In the 19th century, TB was referred to as the “White Plague” not only because it killed a mass number of people but also because the people who had it were anemic and thus very pale. In fact, at this time it killed about a quarter of the adult population of Europe and terrorized the rest of the world including America. In 1882, Robert Koch discovered the cause of TB—Mycobacterium tuberculosis. Given the impact of TB on Homo sapiens, it is easy to understand why Koch’s discovery is considered one of the all-time greatest achievements in microbiology.
The late 19th century was, to say the very least, a heady time in the field of microbiology. Many microbial pathogens in addition to M. tuberculosis were discovered. Also, Louis Pasteur and Elie Metchnikoff founded the field of immunology. As a result, an understanding of the underlying mechanisms responsible for vaccine-induced prevention of infections began to be elucidated.
Origin of the BCG vaccine. Following the discovery that M. tuberculosis caused TB, scientists raced to develop an effective vaccine. In 1908, Albert Calmette and Jean-Marie Camille Guerin working in the Pasteur Institute in France initiated their research with a virulent strain of Mycobacterium bovis from a cow with mastitis. After 13 years and more than 200 passages of the bacterium in laboratory culture medium, the bacillus was sufficiently attenuated (weakened) to be used in the vaccine that was named after them, Bacillus Calmette-Geurin (BCG). And on July 18, 1921, an oral dose of BCG was given to a newborn, whose mother had died of TB a few hours after giving birth. Following this landmark inoculation, as they say, “the rest is history.”
Over the next 100 years, BCG was developed further and used more widely to prevent TB. A multitude of studies carried out in many countries over the past century (mainly with intradermal injection) has demonstrated that when BCG is administered in neonates after birth it is 70-80% effective against the most severe forms of TB, such as meningitis. It is less effective, however, in adults and in protecting against pulmonary TB, which is the most common form of the disease.
BCG is on the “List of Essential Medicines” of the World Health Organization (WHO). As of 2004, the vaccine was given to about 100 million children globally per year. Its routine use, however, varies with the prevalence of TB in different countries. In the U.S., for example, the Center for Disease Control and Prevention does not recommend BCG because of the relatively low risk of TB in America. Also, because the BCG vaccine contains live, albeit attenuated bacteria, it should not be given to people who are clinically immunosuppressed either due to drug treatment or underlying illness because they are at risk of developing bovine TB.
BCG and bladder cancer. The Federal Drug Administration (FDA) has approved use of BCG vaccine for two things: the prevention of TB; and, in 1990, as immunotherapy for people with early-stage bladder cancer. In fact, BCG was the first ever cancer immunotherapy to be FDA approved — yet scientists still don't fully understand why the treatment works.
In the June 15, 2021 issue of Nature Reviews Urology, “100 years of Bacillus Calmette-Guerin immunotherapy: from cattle to COVID-19,” British urologist Niyata Lobo and a group of international colleagues provide an outstanding review of BCG biology, its clinical applications, and an excellent history of the “non-specific” or “off target” effects of BCG, that is, effects that are unrelated to TB. A number of provocative studies of BCG are cited in this article. For example, the authors discuss a Dutch clinical trial of BCG vaccination with a 60-year follow-up, in which it was found that BCG-vaccinated children had a significantly reduced risk of lung cancer development than those who received placebo. This finding merits additional research to determine whether BCG immunotherapy has a role in the treatment or prevention of this or other types of cancer.
While the exact mechanism(s) underlying the immunotherapeutic effects of BCG are unknown, it appears that BCG vaccination is able to endow cells of the innate immune system, called monocytes or macrophages, with characteristics of “trained immunity,” that traditionally was considered to be associated with adaptive immunity (conferred by B and T lymphocytes). That is, BCG induces in trained monocytes/macrophages the capacity to respond to unrelated stimuli, like cancer cells, as well as to infectious agents other than M. tuberculosis.
BCG and COVID-19. One of the more remarkable applications of the off-target effects of BCG immunotherapy is its potential use in the prevention and treatment of COVID-19. The idea that BCG could be beneficial in this viral respiratory tract infection was based on earlier observations of BCG’s favorable effects in the treatment of other respiratory tract infections.
Strong evidence for the non-specific effects of BCG vaccination comes from a series of randomized controlled trials in Guinea-Bissau, a country with a high childhood mortality rate. In one study it was found that low-birth-weight neonates vaccinated with BCG at birth had a >40% reduction in neonatal mortality compared with low-birth-weight neonates who had delayed vaccination to 6 weeks. The benefit appeared to be due to protection against sepsis and respiratory tract infections. Also, in a double-blind, randomized trial of BCG in an elderly population, BCG was found to have similar protective effects against respiratory tract infections. Recently, BCG vaccination was also found to protect against a variety of other viral infections, including influenza virus, yellow fever virus, herpes simplex virus, and human papilloma virus.
In the review article of BCG by Lobo and colleagues, 17 randomized controlled trials of BCG vaccination are listed as underway or recruiting patients to determine whether this form of immunotherapy can prevent or protect against severe COVID-19. In the spring of 2020, Australia’s Murdoch Children’s Research Institute initiated the BRACE study, one of the first of these trials. At the end October 2020, 10,000 healthcare workers in the Netherlands and Spain had been enrolled in the study.
Like the BRACE study, many of these clinical trials were initiated, however, before highly effective specific vaccines against COVID-19 became available in late 2020. Nonetheless, as was pointed out in an article in Frontiers in Immunology in March 2021, “The BCG Vaccine for COVID-19: First Verdict and Future Directions,” if the BCG vaccine is found effective, its use will be most valuable in countries with insufficient supplies of COVID-19 vaccines.
The next generation of specific TB vaccines. The attention that is now focused on the potential use of BCG for the treatment of COVID-19 is in some ways a distraction from the much bigger picture—the need for a vaccine that is more effective than BCG in preventing TB. Once the COVID-19 pandemic subsides, TB is likely to regain its former title as the leading cause of death globally from a single infectious agent.
As was highlighted in my February 5, 2020 Germ Gems post “TB or Not TB: Is Tuberculosis Finally on Its Way Out?”, the WHO in 2016 launched an ambitious “End TB Strategy,” targeting TB’s demise by 2035. Reaching this goal calls for a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide. This would require a new vaccine that would be effective across all age groups, particularly adults and adolescents.
In my 2020 Germ Gems post on TB, I mentioned four promising new vaccine candidates. Recently, an additional investigational TB vaccine candidate (M72/AS01E) was found significantly protective against reactivation of latent TB. This is important because one out of every four people on planet Earth is latently infected with M. tuberculosis and reactivation of latent infection is a major source of active TB. Therefore, adding this vaccine to the pipeline of new vaccines against our old “Public Health Enemy No. 1” could move the world closer to the goal of ending TB in the next 15 years. If this extraordinary feat is accomplished, it will be akin to the eradication of smallpox.
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