The widely used tuberculosis vaccine also fends off a slew of unrelated infectious diseases, and its immune boost can protect newborns for more than a year, researchers in Australia have found.

The bacillus calmette-guérin (BCG) vaccine for tuberculosis causes front-line immune cells to make long-lasting biological “marks” on their DNA, changing how they read genetic instructions for fighting off viruses, the researchers say.

“The DNA is like the manual for the cell. It tells you what it can and can’t do,” study author and molecular immunologist Boris Novakovic of the University of Melbourne told VOA. “You might have a sentence that says, ‘If you see a virus, turn the following genes on.’ And what we’ve done with the BCG vaccine [is] sort of [change] that full stop at the end of that sentence to an exclamation mark.”

The findings were published in the Science Advances journal.

“What is new here is the durability, the long-lasting imprinting effects of BCG vaccine at birth in these Australian babies, and also [that] they can show [in detail] how that takes place,” vaccine epidemiologist Christine Stabell Benn, of the University of Southern Denmark, said in an interview with VOA. She was not involved in the study.

Developed more than a century ago, the BCG vaccine contains live, weakened bacteria. It is one of the oldest vaccines still used and is the most frequently administered vaccine in the world.

Decades ago, Benn and her colleagues noticed that children in Guinea-Bissau who received the tuberculosis shot were less likely to die from other, unrelated diseases. They later confirmed this in a randomized trial, showing that low-birthweight babies who got BCG at birth were about a third less likely to die in their first month of life than those who got BCG later on the normal schedule. Later trials in Guinea-Bissau and Uganda corroborated these findings.

Today, this “non-specific effect” of BCG vaccination has been observed in babies, healthy adults and elderly people. The vaccine’s immune boost is used to treat bladder cancer. Clinical trials are ongoing to see if it could help protect against COVID-19.

There is growing evidence that BCG trains the innate immune system — the non-specific, fast-acting response that activates to fight a wide range of threats.

But it wasn’t until recently that scientists started to figure out how this “trained immunity” that the BCG vaccine generates actually works.

Previous studies found marks of trained immunity a month to three months after BCG vaccination in adults. But the vaccine is typically administered to young babies, and scientists had not tested whether training could last for a long time.

Novakovic and his colleagues compared the immune cells of 63 newborns who received the BCG vaccine right after birth to those of 67 babies who didn’t get the vaccine. They found that exposure to BCG left marks on virus-fighting regions of the genome that tell cells to activate specific genes more or less often. Immune cells passed down these marks, generation to generation, as they divided to make new cells. The marks of trained immunity persisted for more than a year.

In lab tests using cultured human immune cells, the scientists were able to piece together the cellular machinery involved in making these marks more precisely than before.

“We were able to look at all these different levels to see, in a really comprehensive way, what happens to these cells when they directly get exposed to BCG,” said Novakovic.

In the future, Novakovic — who also works at the Murdoch Children’s Research Institute — said he’d like to see if the study’s findings hold in different populations — especially in places where infectious disease is more common than in Australia. And in the long term, he thinks scientists should design vaccines that specifically target the immune-boosting pathways BCG incidentally activates.

“The BCG vaccine is great — it’s safe, and it works. But it’s a bit of a dirty method because we don’t really know what it does. We just know it works,” he said. “Imagine you can just make a purely trained-immunity vaccine.”

Benn said future studies should consider factors such as sex and mother’s vaccination status, which epidemiologists have noticed can affect the immune boost from BCG. For instance, boys seem to benefit from the vaccine’s extra protection more than girls during the first weeks of life, she said.

But beyond more research, Benn hopes the new study will give public health officials more confidence in off-target immunity from BCG, a vaccine she says should be recommended as protection against death from infectious disease — not just as a tuberculosis vaccine.

“I feel that we’re sitting on our hands,” she said, “waiting for biological mechanisms while children could be saved.”
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