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A new study suggests that a simple tweak could make a century-old vaccine for tuberculosis far more effective — but that shift could prove difficult in practice.

Researchers found that increasing the dose of a TB vaccine and delivering it intravenously better protected monkeys against the infection than the standard method, of injecting the vaccine into the skin. The scientists reported their findings Wednesday in Nature.

“By just changing the route of vaccination, we see an incredible protection against TB,” said Dr. Maziar Divangahi, who studies TB and vaccines at McGill University and was not involved in the new research.


“The question is can we ever do IV vaccination [with the TB vaccine] in humans? That’s a little bit tricky,” he added. Experts said there are questions about the safety of delivering the live — though weakened — bacteria in a TB vaccine into the bloodstream. There would also practical hurdles to delivering an IV vaccine in low-resource areas, where health providers often have difficulty reaching people to provide even simpler vaccinations, like the polio vaccine given through drops in the mouth.

There were 1.5 million deaths due to TB worldwide in 2018, making it the leading cause of death from a single infectious pathogen. One in four people worldwide has what’s known as latent TB infection, which means they’re infected but haven’t yet developed the disease. Those infected have between a 5% and 15% risk of getting sick from TB. Researchers say there’s an urgent need for a way to better protect against TB infection — and prevent an infection from turning into disease.


“The burden is high. And it’s not just the people who die — it’s also a disease that takes an enormous toll on a person,” said Joanne Flynn, a tuberculosis researcher at the University of Pittsburgh and an author of the new study.

There is only one licensed vaccine for TB, created from a strain of bacteria known as Bacille Calmette-Guerine, or BCG. It is given in the skin to infants around the world and can prevent deadly forms of TB that strike in early childhood. But its protection against pulmonary tuberculosis — which spreads through airborne particles and is the primary form of TB in adolescents and adults — varies wildly.

The scientists behind the new study wanted to see whether delivering the vaccine by a different route might provide better protection. The idea: The vaccine activates the immune system’s T cells, but delivering it through an injection might not generate enough T cells in the lungs to protect against pulmonary TB. They suspected that administering the vaccine through an IV or an aerosol might produce more T cells in the lungs.

The idea of IV vaccination for TB has come up before. There are papers stretching back to the 1970s that suggest IV vaccination provides the best protection against TB. And research in recent years on a malaria vaccine has suggested that the delivery route can make a significant difference in how well a vaccine works.

Dr. Robert Seder, an NIAID immunologist and an author of the new Nature paper, helped lead that malaria research. Seder, Flynne and and their colleagues wanted to see whether the same finding would prove true for the TB vaccine. They tested the hypothesis in a study with rhesus macaques, a type of monkey that’s particularly susceptible to TB. They immunized the monkeys by delivering the vaccine — through an injection, IV, or aerosol — and monitored the immune response by testing blood and lung fluid for the next six months.

They saw a promising sign for their hypothesis: Monkeys vaccinated through an IV had substantially higher levels of T cells in their blood and lungs. After six months, the researchers introduced the bacteria that causes TB directly into the lungs of the vaccinated monkeys and a group of unvaccinated monkeys. They tracked the infection and progression over three months.

The IV vaccine appeared to offer nearly total protection. Three of the 10 monkeys vaccinated through an IV had only low counts of TB bacteria in their lung tissue. Six had no detectable infection in any of the tissue researchers tested, which suggests the infection had been cleared or prevented entirely.

The monkeys vaccinated with aerosol or skin injections had significantly more infection than the monkeys vaccinated via IV, but had modestly improved lung infections compared to the monkeys that weren’t vaccinated at all.

“We were very surprised — in fact stunned — at how well it worked,” said Flynne. “It’s really a remarkable level of protection.”

The researchers are now conducting studies to test whether lower doses of BCG given via IV can still provide protection. They’re also testing whether T cells are required for the vaccine to provide protection.

“We have to start with very careful analysis in the animals before we start any phase 1 studies,” Seder said. They’ve also started clinical development on a different form of the BCG vaccine — what’s known as a recombinant vaccine — which would be delivered through IV. They hope to launch a phase 1 study in the U.S. in 18 months, Seder said.

Any phase 1 trials will have to answer a looming question: Is it safe to send the bacteria in the BCG vaccine straight into a person’s bloodstream?

The BCG vaccine contains live bacteria that has been attenuated, which means it is weakened in a way that makes it possible to create immunity without leading to illness. There are concerns about inundating the circulatory system with live bacteria — particularly at such a high dose as was used in the study — because the bacteria can replicate and potentially cause problems. That’s less of a concern when the BCG vaccine is injected under the skin.

Seder said in both animal studies and clinical trials, “we will be very careful and slow and methodical to make sure that the vaccine is safe.”

Even if the studies do show that IV vaccination is both safe and more effective, it could still prove difficult to carry out widespread IV vaccinations, particularly in low-resource areas where TB is more common. For a vaccine to be delivered intravenously, staff would need specialized medical training and the vaccine would need to be kept cold.

Experts acknowledged those challenges, but said they believed IV vaccinations could one day be feasible.

“If we had a highly effective vaccine and it costs 10 cents, but has to be given intravenously, then training people to deliver it would be very reasonable,” Seder said. “I have full confidence in my colleagues [in other countries] that if this works well and it’s safe, they will be able to do it.”