The effort to develop a TB vaccine dates back to 1882, when a German microbiologist named Dr. Robert Koch identified the Mycobacterium Tuberculosis—the bacteria that causes TB—in infected tissue samples. Thanks to this crucial discovery, scientists finally knew what to target in their efforts to develop a solution. A vaccine was the obvious best-case scenario, and many set off to try to create one. One slightly bungled effort in the 1890s yielded the tuberculin skin test, which didn’t provide any immunity but nonetheless proved to be an innovative diagnostic tool. It is nearly the same test that is widely used today that scans for infection by sparking a red, irritated reaction at the injection site when TB antibodies are present. But being infected with TB is different than being sick with it—some estimate that around one-third of the world is infected with TB bacteria, which can lurk quietly in the body for years without ever activating and causing disease. Up to 95 percent of these people will never develop the illness.

Many other vaccine development efforts were similarly unsuccessful, except for one. The BCG, or Bacillus Calmette-Guérin vaccine, has been on the market for nearly a century. BCG is the most widely used vaccine in the world, and is given to babies in many countries shortly after birth. However, it is not used in the United States, and some TB specialists—like Dr. Lee Reichman in his 2001 book Timebomb—go so far as to call BCG practically useless. The vaccine offers limited protection against types of TB most common in babies and young children, but does not seem to last past puberty. Most countries with the highest TB rates do indeed vaccinate babies against the disease. Besides being relatively weak, BCG comes with another major disadvantage—it creates a lifelong false-positive skin test. This makes TB tougher to diagnose among the vaccinated, unless their symptoms are severe.

It’s a misconception that global TB rates fell due to vaccines or even antibiotics, which didn’t even appear until TB was already on the decline. Instead, improved health, sanitation, quarantine, and screening measures combined to prevent cases before they ever happened. After a few decades of decreasing numbers of cases, the disease’s 1990s comeback—fueled largely by HIV and other geopolitical catastrophes—reignited research and encouraged researches to revisit the white whale of a safe, affordable vaccine.

Any would-be TB vaccine faces serious roadblocks. For one thing, scientists still don’t fully understand the way that TB hibernates in the body. Among people with latent infections, it is difficult to pinpoint why one person never develops an active disease, why another develops it within a year, and why yet another develops it decades later. This not only makes clinical trials difficult, but it also makes it hard to say whether a patient was protected by the vaccine or simply wouldn’t have developed the disease in the first place. Similarly, there are no biomarkers scientists can look for that flag immunity to TB—the only evidence is whether the person gets it or not. And TB tends to behave differently in animals than in people—vaccines that have seemed promising during initial animal trials have been disappointed in human testing.