Tuberculosis may seem like a relic of the past in wealthy countries, yet it still kills more people worldwide than any other infectious disease besides COVID – with about 1.6 million people dying from TB annually. And the one approved vaccine – invented more than a century ago – is only reliably protective when given to children.

Now, scientists at South Africa's University of Cape Town have taken a major step toward creating an mRNA vaccine against TB that could work for people of all ages. The key to their breakthrough: An unusual set of blood samples that were kept in deep freeze for nearly two decades – until the vital information they contained could finally be unlocked thanks to some new technology.

To explain, one of the researchers behind the effort, Munyaradzi Musvosvi, ushers me into a room with several enormous metal vats. "These are our cryotanks," he says. "The cells are kept here in liquid nitrogen." He pulls the lid off one of the tanks and plumes of white vapor spill out. "It's kind of hazy," he says, pointing deep inside. "But you just might be able to see a little box there."

Blood samples from high school students

The samples were collected from about 6,000 South African high school students beginning in 2005. And they were originally intended – and used – for a range of other research on TB. But Musvosvi says the researchers soon realized that the cells contained some rare clues for how the human immune system can kill the bacterium.

That's because follow-up samples had been taken repeatedly over a two year period – and because of one of the particularities of TB: The bacterium that causes it is so widespread that more than 80 percent of South Africans have been exposed to it; Yet only about one in ten of those people actually develop the disease – often months or even years after exposure.

This meant that when the researchers analyzed the first round of blood samples they could identify a subset who had immune cells indicating that they had been exposed to TB but had not gotten sick. Then, says Musvosvi, "as we follow them up, we could document that some of these adolescents were [subsequently] diagnosed with active TB disease. They had symptoms and we could actually measure the bacteria in the sputum that they were coughing up."

In other words, says Musvosvi, the researchers could set up a comparison. "It allowed us to ask the question: Of those adolescents who progressed to disease during this two-year period, what was different between them and those who managed to control infection during the two year follow-up?"

Specifically, he and his collaborators wondered: Did the exposed students who never got sick have a different set of immune cells. And, if so, were those immune cells – they're called T-cells – latching on to different, presumably more vulnerable, parts of the TB bacteria? As Musvosvi puts it, "Out of all the proteins that TB makes, what do these T-cells recognize?"

Except there was a snag. Scientists didn't actually have a good way of doing that kind of analysis of T-cells. At least not one that wasn't prohibitively expensive.

And so the cells were left sitting in the cryotanks for more than a decade. "Yeah," says Musvosvi, with a wry smile. "They were kept nicely frozen for quite a long time."

A breakthrough in 2019

Then in 2019, a researcher at Stanford named Huang Huang came up with a new – and far more affordable – method to determine what proteins a given T-cell is reacting to.

Huang, now with the pharmaceutical company Gilead Sciences, says the moment he realized the technique was going to work was somewhat eerie. "It was about four in the morning. The lab was empty. No persons around – only myself," he says. "Then I see the machine give this positive result, and it was very, very exciting for me. Because this had not been done previously."

But Huang says he didn't appreciate just how useful the technique – and several related ones developed with collaborators – might prove until the researchers in South Africa found out about the work and proposed teaming up.

Huang's reaction: "This is a great opportunity to explore these very precious samples."

So they thawed them out and got to work.

This year the team was able to publish their findings in the journal Nature Medicine. Just as they'd hoped, they discovered several T-cells that were far more common to people who are able to control TB. And they've been able to determine several TB proteins that these T-cells focus on.

Back in his office, Musvosvi pulls them up on his computer. "So here you can see that so far we've identified three proteins."

This would have been helpful information under any circumstances, he says. The research group he's part of is called the South African Tuberculosis Vaccine Initiative, "and what we're trying to do here is to identify priority targets that vaccine developers could then use to develop a TB vaccine that is more efficacious."

The mRNA twist

But it's particularly handy in light of the final twist to this tale: The recent development of a whole new class of vaccines — the highly effective "mRNA" shots like those made against COVID by Pfizer and Moderna.

With traditional vaccines, notes Musvosvi, even if you know what proteins on a virus or bacterium a person's immune system can latch on to to kill it, you still have to find a way to manufacture and then insert those proteins into the body as part of the vaccine – so that the body can prepare defenses against them.

By contrast, mRNA vaccines are more like a plug and play system: You just insert the genetic code for the proteins into the vaccine, and the body uses that code to make them. Or as Musvosvi puts it, "the body does [the manufacturing] for you." This, in turn, means that "in terms of scaling up, it's quite easy."

Indeed, several vaccine developers are already working on prototype mRNA vaccines against TB based on the proteins identified by Musvosvi and his collaborators, in order to check if they work in animals. These include both for-profit companies like Pfizer as well as a separate team in South Africa that's part of an mRNA research and manufacturing "hub" launched by the World Health Organization and other partners.

If any of those prototypes prove successful, it will likely still take several more years before a version for humans is finalized.

But Musvosvi says he's optimistic that after decades of failed efforts to make a better TB vaccine, scientists may finally have hit on a winning approach. And given how many people suffer from TB he adds, "It would be a game changer."

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