“I was very influenced by The Magic Mountain. It's a book that had a huge impact on me. I loved that as a shape for a novel: put a bunch of people in a beautiful place, give them all tuberculosis, make them all stay in a fur sleeping bag for several years and see what happens.” Ann Patchett
“A vaccine that prevented tuberculosis would merit a Nobel Prize, but it's just very difficult to develop.” Tom Frieden
My favorite book in college was Thomas Mann’s The Magic Mountain. It tells the story of patients with tuberculosis (TB) who, at the turn of the 19th century, were living in a luxurious sanatorium on a mountaintop in Davos, Switzerland. The story is more about the search for the meaning of life than TB, a disease that in those days killed about half of the people it sickened. (In the 19th century, TB—the White Plague—was the leading cause of death.) Thus when I was a third year medical student and a revered teacher, a professor of Pulmonary Medicine, stated that The Magic Mountain was the best book ever written about TB, I was duly impressed.
In this germgems post, I’ll cover three things you may not know about TB: 1) the bacterium that causes TB, Mycobacterium tuberculosis, is public health enemy number 1; 2) BCG, a vaccine with a checkered past, is the most widely used vaccine in the world; and 3) a new vaccine is on the horizon that could be a game changer.
Putting TB in perspective. Today, nobody knows for sure where 2019-nCoV, the novel coronavirus that emerged in Wuhan, China last December, is headed. So far it has afflicted about 25,000 people, killed 490, and been detected in 24 countries. Chaos and panic are following in its tracks.
But we do know is that M. tuberculosis is predicted to sicken 10 million people this year, 1.7 million of whom will die, making TB the deadliest of all communicable diseases. On top of these mind-numbing statistics on those directly impacted by TB, about one of every four people on our planet is latently infected with the tubercle bacillus—a zombie-like state of the bacterium that has the propensity to reactivate if immunity wanes. Yet, despite all these frightening numbers there is little sense of urgency. One wonders why?
One likely reason is that social determinants, such as poverty, discrimination, and overcrowding typically have played a major role in who contracts TB. A large majority of those affected live in developing countries where anti-tuberculous drugs cost too much and infrastructure for management of patients is spread thin.
Dating back about 5,000 years, the history of TB is extraordinary. So too are the immunology, microbiology, clinical features, and psychosocial aspects of the disease. Countless articles and books have been written about TB. (In addition to The Magic Mountain, I highly recommend Thomas Goetz’s book The Remedy: Robert Koch, Arthur Conan Doyle, and the Quest to Cure Tuberculosis. It recounts how the reputation of the discoverer of M. tuberculosis, Robert Koch, was sullied by his false claims of a cure with tuberculin. As the title of the book suggests, the story has an element of mystery involving the creator of Sherlock Holmes.)
BCG Vaccine. Immunotherapy as a defense against TB was first proposed in 1890 by Robert Koch. Today, the only effective TB vaccine in common use is bacilli Calmette Guerin (BCG). First used in humans in 1921, it is the most widely used vaccine in the world. More than 100 million children in developing countries, where TB is most prevalent, are vaccinated with BCG per year. (It is not used as a preventative strategy in the United States). The vaccine is 70 to 80% effective against the most severe forms of TB, such as TB meningitis in children. But it’s far less effective in preventing pulmonary disease, which is the more common form of TB in adults.
Researchers have known for a long time that the number of tubercle bacilli varies considerably between batches of BCG from different manufacturers. They’ve also known that the international standards for variance between different kinds of BCG are looser than they would be for a newer vaccine. While the different formulations appear to be just as safe as each other if you have a healthy immune system, they might not be equally safe or effective if your immune system is compromised. (The vaccine is composed of an attenuated, or weakened, TB strain, and shouldn’t be given to immunocompromised patients.)
A recent study in Rhesus macaque monkeys published in the journal Nature showed that intravenous administration of the BCG vaccine was significantly more effective in protection against pulmonary TB than was conventional intradermal administration. As monkey models of TB are the most relevant to humans, these findings are very promising. But it is unclear if and when these findings are slated for human trials. To my knowledge, this would be the first intravenous vaccine for humans, and it would add a level of complexity in implementation.
Antibiotic resistance. Growing demand for improvement of TB immunotherapy is fueled by increasing antibiotic resistance of M. tuberculosis. In fact, multi-drug-resistant M. tuberculosis (MDR-TB) should be considered the most serious of all superbugs. (The term “superbug” refers to microbes that are resistant to at least two of the commonly used antibiotics.) MDR-TB, strains that are resistant to the two most commonly used antibiotics (isoniazid and rifampin), and extensively drug-resistant (XDR-TB), strains that are resistant to these two and two or more additional drugs, have increased in prevalence over the past two decades.
MDR-TB caused an estimated 240,000 deaths in 2016. Sadly, three out of four of the 480,000 cases of MDR-TB that occur around the world annually go untreated. It is estimated that MDR-TB could cost the world a shocking $16.7 trillion by 2050. As for XDR-TB, it has now appeared in over ten countries. If this strain takes off, we may see a return to the pre-antibiotic era, when half of all TB patients died. However, some good news came in August 2019, when the US Food and Drug Administration approved a new antibiotic called pretomanid for treatment of XDR-TB. This was only the third new TB drug in nearly half a century to reach the market.
New TB Vaccines. As mentioned earlier, the biggest hurdle to vaccine development is economic—despite the huge numbers of people in need, most of them live in countries with limited resources, where drug companies are reluctant to venture. Thus, philanthropists and non-profit organizations play a key role in addressing this crisis. The Bill & Melinda Gates Foundation is a standout in this regard. They earmark $100 million per year for TB tools, about half of which is for vaccine development.
On January 27, 2020, GlaxoSmithKline licensed a promising TB vaccine to the Bill & Melinda Gates Medical Research Institute in a move the drug maker said will help bring prevention of the deadly disease to poor countries. The vaccine contains an engineered protein that’s modeled on those of M. tuberculosis plus the company’s adjuvant, which is designed to heighten the body’s immune response. The Gates group will lead development of the vaccine candidate and sponsor future clinical tests. Mid-stage testing had shown the vaccine to be effective in about half of people who got it for as long as three years. In addition to the GSK vaccine, three additional TB vaccines are under development: MVA85A, rBCG30, and 72F fusion protein.
Ambitious goals. In 2014 the World Health Assembly adopted a “Global strategy and targets for tuberculosis prevention, care and control after 2015.” This twenty year strategy (2016-2035) aims to end the global TB epidemic and is unsurprisingly called the "End TB Strategy." The main targets in the strategy are: to reduce TB deaths by 95%, to cut new cases of TB by 90%, and to ensure that no family is burdened with catastrophic expenses due to TB. A number of global health and academic alliances have signed on as partners.
Because HIV infection impairs immunity thereby fostering the progression of TB, as well as promoting reactivation of latent TB, addressing the HIV/AIDS epidemic needs to be part of the End TB strategy. You may recall reading in the January 29 Germ Gems post (Ending the HIV/AIDS Syndemic) that stopping HIV/AIDS is this another aspirational goal of the World Health Organization. If this goal is reached by its 2030 target date, it would help eliminate TB—two for the price of one.
There is little question, however, that putting an end to TB will depend on finding a more effective TB vaccine—an accomplishment most certainly worthy of a Nobel Prizes.
