Gibraltar Barbay Macaques. Credit: Berthold Werner, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons.

A self-destructing vaccine administered intravenously provides additional safety and protection against tuberculosis (TB) in macaque monkeys.

The in-built safety mechanisms circumvent the possibility of an accidental self-infection with weakened mycobacteria, offering a safe and effective way to combat the disease that was named as the deadliest of 2024 by the World Health Organization.

JoAnne Flynn, PhD, distinguished professor and chair of microbiology and molecular genetics at the University of Pittsburgh, said: “Although the idea of intravenous vaccination with a live vaccine may sound scary, it was very effective in our previous studies in non-human primates.

“Here, we focused on the safety aspect of IV vaccination and used a strain of mycobacteria that kills itself once administered to the animals.

“To our surprise, it was equal or slightly better than the regular TB vaccine in protecting monkeys against infection, providing sterilising immunity in almost all animals.”

She added: “The live-attenuated form of the mycobacteria does not need to be alive for very long to provide outstanding protection and with this strain there is essentially no chance for a vaccine-derived infection, even in an immunocompromised host.”

While unvaccinated macaque monkeys exhibited signs of severe lung inflammation and disease following the Mycobacterium tuberculosis infection (warm colours indicate inflammation and disease, bottom row), monkeys that received the intravenously administered Kill-Switch BCG vaccine (middle row) were equally or better protected against the infection as those immunised with the standard BCG vaccine (top row). Credit: Pauline Maiello.

Universally effective approach

Despite the ongoing global public health burden of TB, safe and effective protection strategies against the infection are lacking.

Bacillus Calmette-Guérin (BCG) vaccine – named for its developers – contains inactivated mycobacteria that infect cattle and remains the only vaccination strategy against the infection in humans.

Injected into the skin, it provides only partial protection against TB in young children and no protection in adults.

To develop a more universally effective vaccination approach, Flynn partnered with colleagues at Cornell University.

In Flynn’s earlier work in macaque monkeys with collaborators at the National Institutes of Health, researchers saw a 100,000-fold reduction in bacterial burden in the lungs of animals who were given the BCG vaccine intravenously compared with the standard intradermal route.

Nine out of ten animals showed no inflammation in their lungs.

Dual safety switch

To improve the safety of IV BCG delivery in the new study, researchers engineered two built-in mechanisms that instruct the BCG particles to dissolve either upon exposure to the antibiotic doxycycline or when chronic doxycycline treatment is stopped.

Mouse experiments showed that the BCG vaccine containing this dual safety switch protects the animals against TB comparable to a standard BCG vaccination but has the added benefit of faster elimination and safety, even for mice that were immunocompromised.

In macaque monkeys, the updated self-destructing BCG vaccine caused an even stronger immune response and better protection against TB than a standard IV BCG injection.

None of the monkeys that received the updated BCG vaccine had any detectable level of lung inflammation eight weeks after being infected with live Mycobacterium tuberculosis.

In addition, six out of eight monkeys had no traces of recoverable live M tuberculosis compared to two out of eight monkeys that received the standard BCG intravenously.

Despite the additional challenges of clinical testing required for expanding the use of the updated BCG vaccine in humans, researchers are optimistic.

Flynn said: “We hope that this ‘kill switch’ BCG strain could limit safety concerns over intravenous vaccine administration and provide an option for a safer and more effective vaccination route for individuals who are immunocompromised.”

The study is published in Nature Microbiology.