Every year, tuberculosis kills over a million people. Can a new vaccine turn the tide?

It’s 2024, and people are still dying from ... consumption.

This ancient disease, known today as tuberculosis or TB, has plagued humanity for thousands of years, and as recently as a few hundred years ago, was thought to be responsible for some 25 percent of all deaths in Europe and North America.

Today, TB is both preventable and treatable — there’s a century-old vaccine, effective antibiotics, and known behavioral and sanitation safeguards that disrupt transmission. Yet in 2022, more than 10 million people globally still fell ill from TB and 1.3 million died, making it the second deadliest infectious disease that year. (More people die from TB generally, but Covid-19 temporarily outpaced it.) More than 80 percent of those TB cases and deaths occur in low- and middle-income countries.

That’s largely because people in those countries are more likely to suffer from contributing risk factors to TB, such as malnourishment and HIV.

But beyond those factors, when it comes to preventing illness and death in these regions, physicians, researchers, and public health officials say that the available vaccine and treatments don’t do enough: The vaccine is given to infants and only offers protection in the first few years of life, leaving large swaths of people at risk, while antibiotic treatments take months to cure the disease.

“TB is a disease of poverty,” explained Helen McShane, professor of vaccinology at the University of Oxford, where she and her team are developing a new TB vaccine among other TB research. “There have been decades of neglect where there was no funding for new drugs or new vaccines for TB.”

But for the first time, promising new vaccines are now in the pipeline and may help prevent TB in adolescents and adults who currently have no such protection. These vaccines might also be more effective than what we have right now. Several are undergoing phase 3 trials — the last step before vaccine makers can apply to international and national agencies for approval.

“It is excellent news,” said Matteo Zignol, unit head of the WHO’s Global Tuberculosis Programme. The success of the first wave of vaccines has helped usher in more support and funding to the field, but many researchers say we will need more than just a few effective vaccines. “We all wish [the M72/AS01E vaccine trial] is going to be a successful trial, but in any case, this is going to be like a first generation sort of new vaccine, and we really need more candidates to be able to help the epidemic.”

It’ll likely still take years for the vaccines to be rolled out, but if approved, the new vaccines have the potential to save hundreds of thousands of lives, making an enormous dent in a disease that has killed humans for millennia.

Why do we need another TB vaccine?

One of the strange things about tuberculosis is that having the bacterium that causes TB doesn’t mean you have the disease. In a 2016 paper published in PLOS Medicine, researchers estimated that nearly 25 percent of the world’s population has a latent TB infection. For most people, though, the bacteria remain dormant and never go on to cause disease.

Basic preventative measures — such as improving sanitation, ensuring proper ventilation in hospitals and laboratories, and proactively identifying and treating high-risk patients — helped greatly reduce TB cases in developed countries like the US, where there were around 8,000 TB cases reported in 2022. Many lower-income countries, unfortunately, still have underdeveloped public health systems and lack the resources to implement the multipronged approach necessary to stamp out TB. That is where vaccination can be a critical tool.

The world’s first and only available TB vaccine, the Bacille Calmette-Guérin (BCG) vaccine, was created in 1921. Given the low burden of TB in the US, BCG is not routinely given to infants, but it is commonly used in many other countries. In Africa and Southeast Asia — the regions with the highest TB burden — 80 and 91 percent of 1-year-olds received the BCG vaccine in 2022, respectively, according to estimates by the WHO.

The BCG vaccine is considered safe with rare side effects, but it’s not very effective. One meta-analysis of 26 studies reported that when the BCG vaccine was given during infancy, it was 37 percent effective against all forms of TB during the first five years of life, but did not offer protection among adolescents and adults.

The way TB infects someone also plays a role in how contagious the disease can be and limits the vaccine’s ability to prevent disease. Usually, TB infects the lungs — that’s pulmonary TB. But Mycobacterium tuberculosis can infect the liver, bones, spinal cord, brain, urinary tract, bladder, kidneys, and even the intestines. When TB infects organs other than the lungs, it’s called extrapulmonary TB. Individuals with extrapulmonary disease don’t usually infect others, while those with TB in their lungs can more easily spread the bacterium to others by breathing, coughing, or sneezing.

Pulmonary infections account for the majority of TB morbidity and mortality. Exact percentages vary by country, but globally around 63 percent of all TB cases were pulmonary in 2021, according to the WHO. BCG vaccine efficacy against pulmonary TB infections still remains a bit of a mystery as studies have reported efficacy rates ranging from 0 to 80 percent and efficacy tends to be lowest in high-burden countries close to the equator.

Researchers are not quite sure why this is. One theory is that those who live closer to the equator are more likely to be exposed to non-tuberculous mycobacteria, which are similar to the pathogen that causes TB. This exposure confers preexisting immunity which may actually hinder the BCG vaccine from doing its job, McShane said.

All in all, researchers estimate that the BCG vaccine prevents only 5 percent of all vaccine-preventable deaths due to TB. For comparison, vaccines for measles, smallpox, and polio are 93, 95, and 90 percent effective in preventing disease, respectively.

So why now? What can a new TB vaccine actually accomplish?

Despite the limitations of the BCG vaccine, no new vaccine candidates have emerged in the past 100 years. M. tuberculosis is notoriously difficult to make a vaccine for because the bacterium has an adept ability to evade the human immune system. As Vox’s Dylan Matthews reported last year, “TB is a hard disease to vaccinate against. While most vaccines target viruses, TB is a bacterium, and one with a strange lifecycle.”

Economic and political factors play a role as well. After many high-income countries made huge strides in reducing TB in the late 1990s and early 2000s, they allocated few resources to further research and development of new vaccines and treatments, focusing instead on other health threats such as cancer and cardiovascular disease. TB fell into the category of neglected diseases.

McShane recalled when her team conducted the first trials of a new generation TB vaccine in 2002. “At the time, there were about 50 candidate vaccines being tested for malaria and about 50 for HIV,” she said. “Of course, for both of those pathogens, there is a Western market. There is no Western market for a TB vaccine.”

Since then, however, there have been renewed efforts to eradicate TB. The emergence of drug-resistant TB has threatened to reverse what global gains against TB have been made and may even cause a TB resurgence in the US and other low-burden countries, spurring more attention and funding to the disease. The Global Fund and the Stop TB Partnership have also launched major advocacy campaigns to bring more attention to the epidemic.

Additionally, in 2016, the World Health Organization set a goal to end the TB epidemic by 2030. The US government has also ramped up investments in global TB eradication efforts. In the 2023 fiscal year, the US contributed more than $400 million to the cause, nearly double its total investments for global TB in fiscal year 2013.

As of last year, there are 16 new TB vaccine candidates in development, four of which are in phase 3 clinical trials — which, if successful, would likely be the last phase of trials before FDA or WHO approval. Some vaccines aim to replace the BCG vaccine altogether while other candidates will serve as boosters to the BCG vaccine among adolescents and adults, McShane explained.

One vaccine, M72/AS01E, seems to be the most promising candidate, buoyed by support and funding from the Bill and Melinda Gates Foundation. In a phase 2B clinical trial conducted in South Africa, Kenya, and Zambia, more than 3,500 adults with latent TB were randomly assigned to receive either two doses of the M72/AS01E vaccine or a placebo. Initial vaccine efficacy was 54 percent. Three years later, a follow-up analysis revealed that the vaccine had prevented active TB cases in 49.7 percent of people who received the vaccine.

Most other TB vaccine candidates have demonstrated similar efficacy rates. “It’s unlikely that we’re going to get a vaccine against tuberculosis that is 100 percent effective anytime soon,” McShane said.

But even a TB vaccine with low efficacy can have profound global implications. If the M72/AS01E vaccine demonstrates safety and efficacy in the ongoing phase 3 trial, then for the first time, the world could prevent at least a good portion of infections among adolescents and adults.

“One of the big issues is that even if we’ll have a vaccine, it’ll be a game changer, but the effectiveness is around 50 percent. So it’s not one of the best, but it is something,” said Eliud Wandwalo, head of TB at the Global Fund to Fight AIDS, Tuberculosis and Malaria.

Given the relatively low efficacy rates, these new TB vaccines are not a silver bullet for eradicating TB globally. For most of the world, improvements in sanitation, infrastructure, and medication are also urgently needed. Currently, it takes six months of ongoing therapy to cure TB, and as drug-resistant strains of TB become more common, existing antibiotics will become less and less useful. The vaccine will be just one of the tools in the toolbox, Wandwalo said.

“If you look at the trajectory and projections, if we continue the same pace with the same tools, we’ll be ending TB in the next 180 years,” he said. “It’s a dire projection. But I think with a vaccine, we are likely to be able to end TB in our lifetime.”