A new tuberculosis vaccine that self-destructs to enhance safety has shown promising results in macaque monkeys, providing better protection than traditional vaccines and eliminating the risks of vaccine-derived infections.
A new study from the University of Pittsburgh, published today (January 10) in Nature Microbiology, reveals that a self-destructing vaccine given intravenously offers enhanced safety and protection against tuberculosis (TB) in macaque monkeys.
This innovative vaccine includes built-in safety mechanisms that prevent accidental infections with weakened mycobacteria, providing a secure and effective method to fight TB, which the World Health Organization (WHO) identified as the deadliest disease of 2024.
Achieving Sterilizing Immunity in Monkeys
“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 sterilizing immunity in almost all animals,” said JoAnne Flynn, Ph.D., distinguished professor and chair of microbiology and molecular genetics at Pitt.
“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.”
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.
Pioneering a More Effective TB Vaccine
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 10 animals showed no inflammation in their lungs.
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.
Stronger Immune Responses in Monkeys
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.
Future Prospects for Human Trials
Despite the additional challenges of clinical testing required for expanding the use of the updated BCG vaccine in humans, researchers are optimistic.
“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,” Flynn said.
Reference: “A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity’” 10 January 2025, Nature Microbiology.
DOI: 10.1038/s41564-024-01895-4
The other senior authors of this research are Dirk Schnappinger, Ph.D., and Sabine Ehrt, Ph.D. of Weill Cornell Medicine. Other authors of this research are Alexander Smith, Ph.D., Pauline Maiello, M.S., H. Jacob Borish, Ph.D., Caylin Winchell, Ph.D., Andrew Simonson, Ph.D., Philana Ling Lin, M.D., Mark Rodgers, M.S., Daniel Fillmore and Jennifer Sakal, all of Pitt; and Hongwei Su, Ph.D., Joshua Wallach, Yao Liu, Ph.D., Kan Lin, Ph.D., Valerie Vinette, Ph.D., all of Weill Cornell Medicine.
