The built-in safety features provide a more secure and efficient method to fight against the most lethal disease of 2024.
A vaccine designed to self-destruct and given through an intravenous method offers extra safety and defense against tuberculosis (TB) in macaque monkeys, according to a recent study from the University of Pittsburgh, published today in Nature Microbiology.
The integrated safety systems prevent the chance of accidental self-infection with weakened mycobacteria, presenting a reliable and effective strategy to tackle the disease that the World Health Organization identified as the deadliest in 2024.
“Although the concept of using a live vaccine for intravenous vaccination might be concerning, our previous research in non-human primates demonstrated its effectiveness. In this study, we prioritized safety in IV vaccination, utilizing a strain of mycobacteria that self-eliminates once given to the animals. To our astonishment, it performed equally well or slightly better than standard TB vaccines in safeguarding monkeys from infection, offering sterilizing immunity to nearly all subjects,” stated JoAnne Flynn, Ph.D., a distinguished professor and chair of microbiology and molecular genetics at Pitt. “This live-attenuated mycobacterium does not need to live for an extended period to ensure exceptional protection, and with this specific strain, there is virtually no risk of vaccine-derived infection, even in those with weakened immune systems.”
Despite the persistent global public health issue posed by TB, effective and safe protection methods against the infection are in short supply. The Bacillus Calmette-Guérin (BCG) vaccine — named after its developers — contains inactive mycobacteria used in cattle and remains the only vaccination method against the infection in humans. Administered through the skin, it only offers limited protection against TB in young children, with no defense for adults.
In an effort to create a more universally effective vaccine approach, Flynn collaborated with colleagues at Cornell University. In previous research with macaque monkeys alongside partners at the National Institutes of Health, the team discovered a 100,000-fold decrease in the bacterial load in the lungs of animals that received the BCG vaccine intravenously, compared to using the standard intradermal method. Nine out of ten animals exhibited no lung inflammation.
To enhance the safety of intravenous BCG delivery in this recent study, researchers devised two safety mechanisms that prompt the BCG particles to dissolve either when exposed to the antibiotic doxycycline or upon halting chronic doxycycline treatment. Experiments with mice showed that this dual safety switch BCG vaccine provides TB protection similar to traditional BCG vaccination, while also facilitating faster clearance and enhanced safety, including for immunocompromised mice.
In macaque monkeys, the newly modified self-destructing BCG vaccine prompted an even more robust immune response and superior TB protection compared to a conventional IV BCG injection. None of the monkeys receiving the new BCG vaccine exhibited any detectable lung inflammation eight weeks post-exposure to live Mycobacterium tuberculosis. Additionally, six out of eight monkeys showed no signs of recoverable live M. tuberculosis, compared to just two out of eight that received the standard IV BCG vaccine.
Despite the extra hurdles of clinical trials needed to broaden the updated BCG vaccine’s application in humans, researchers remain hopeful.
“We anticipate that this ‘kill switch’ BCG strain could alleviate safety concerns regarding intravenous vaccine administration and present a safer, more effective vaccination option for individuals with compromised immune systems,” said Flynn.
The other lead authors of this study include Dirk Schnappinger, Ph.D., and Sabine Ehrt, Ph.D., from Weill Cornell Medicine. Additionally contributing to 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 from Pitt; and Hongwei Su, Ph.D., Joshua Wallach, Yao Liu, Ph.D., Kan Lin, Ph.D., and Valerie Vinette, Ph.D., all from Weill Cornell Medicine.
