A self-destructive vaccine administered intravenously provides additional safety and protection against tuberculosis (TB) in macaque monkeys, suggests new research from the University of Pittsburgh published today in nature microbiology.
Built-in safety mechanisms prevent the possibility of accidental autoinfection with weakened mycobacteria, offering a safe and effective way to combat the disease that was named the deadliest of 2024 by the World Health Organization.
“Although the idea of intravenous vaccination with a live vaccine may seem scary, it was very effective in our previous studies in non-human primates. In this case, we focused on the safety aspect of intravenous vaccination and used a strain of mycobacteria that once administered to the animals, to our surprise, it was equal to or slightly better than the regular tuberculosis vaccine in protecting the monkeys against infection, providing sterilizing immunity in almost all animals,” said JoAnne Flynn, Ph.D. 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 long to provide exceptional protection and with this strain there is essentially no chance of a vaccine-derived infection, even in an immunocompromised host.”
Despite the current global public health burden of tuberculosis, safe and effective protection strategies against infection are lacking. The Bacillus Calmette-Guérin (BCG) vaccine, named after its developers, contains inactivated mycobacteria that infect livestock and remains the only vaccination strategy against infection in humans. Injected into the skin, it provides only partial protection against tuberculosis in young children and no protection in adults.
To develop a more universally effective vaccination approach, Flynn teamed up with colleagues at Cornell University. In Flynn’s previous work in macaque monkeys with collaborators at the National Institutes of Health, researchers observed a 100,000-fold reduction in bacterial load in the lungs of animals that received the BCG vaccine intravenously compared to intradermally. standard. Nine out of 10 animals showed no inflammation in their lungs.
To improve the safety of intravenous BCG administration in the new study, the researchers designed two integrated mechanisms that instruct BCG particles to dissolve upon exposure to the antibiotic doxycycline or when chronic doxycycline treatment is discontinued. Experiments with mice demonstrated that BCG vaccine containing this double safety switch protects animals against tuberculosis comparably to a standard BCG vaccine, but has the added benefit of faster clearance and safety, even for immunocompromised mice.
In macaque monkeys, the updated self-destructive BCG vaccine elicited an even stronger immune response and better protection against tuberculosis than a standard intravenous 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. Additionally, six of eight monkeys had no trace of recoverable live M. tuberculosis compared to two of eight monkeys that received standard BCG intravenously.
Despite the additional challenges posed by the clinical trials needed to expand use of the updated BCG vaccine in humans, researchers are optimistic.
“We hope that this ‘inactivating’ BCG strain can limit safety concerns about intravenous vaccine administration and provide an option for a safer and more effective vaccination route for immunocompromised individuals,” Flynn said.
The other lead 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, MS, H. Jacob Borish, Ph.D., Caylin Winchell, Ph.D., Andrew Simonson, Ph.D., Philana Ling Lin, MD , Mark Rodgers, MS, 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.