Researchers at Weill Cornell Medicine have developed two engineered strains of mycobacteria with “kill switches” that can be activated to stop bacterial activity after eliciting an immune response. This breakthrough aims to enhance tuberculosis (TB) vaccination efforts and overcome safety challenges in designing bacteria for controlled human infection trials or improved vaccines. Despite TB being under control in many developed nations, it remains a significant global health concern, causing over a million deaths annually.
“BCG protects children from tuberculosis meningitis, but it doesn’t effectively protect adults from pulmonary tuberculosis, which is why it’s only used in high-incidence countries,” stated Dr. Dirk Schnappinger, professor of microbiology and immunology at Weill Cornell Medicine and a senior author on both of the new studies.
Mycobacterium tuberculosis, the bacterium responsible for TB, spreads easily through the air and can cause severe respiratory disease by establishing chronic lung infections. The widely used Bacille Calmette-Guérin (BCG) vaccine, developed from Mycobacterium bovis, has been available for over a century but offers limited protection. Previous research at the University of Pittsburgh and the National Institutes of Health’s Vaccine Research Center demonstrated that administering high doses of BCG intravenously provided better protection against lung infections in macaque monkeys than the standard subcutaneous method.
In one of the new papers, the team aimed to make this high-dose intravenous injection safer, without destroying the vaccine’s ability to stimulate a strong immune response. “We needed a version of BCG that triggers an immune response, but then you can flip a switch to eliminate the bacteria,” stated Dr. Schnappinger.
Building on this research, scientists engineered a new BCG strain with a kill switch. They administered high doses of this modified vaccine intravenously to antibiotic-treated macaques. When the antibiotic treatment was stopped, the kill switch activated, halting the infection. Additionally, the self-destructing bacteria released antigens that further enhanced the animals’ immune responses. This resulted in strong immunity, offering protection against subsequent lung infections with M. tuberculosis.
After testing about 20 different strategies, the investigators found that lysins, enzymes encoded by viruses that can infect BCG, cause the bacteria to self-destruct. Using a clever bit of molecular engineering, they placed two different lysin genes under the control of gene regulators that respond to an antibiotic. By adding or taking away the antibiotic, they could then flip the kill switch. “The lysins were known, but I don’t think they have been utilized as kill switches previously,” stated Dr. Sabine Ehrt, professor of microbiology and immunology at Weill Cornell Medicine and a senior author on the papers.
“Despite the promising preclinical results, evaluating if the vaccination actually works takes a long time and many people to test it. Tuberculosis doesn’t develop quickly and only in a small fraction of the people who are infected,” Dr. Schnappinger explained. Such enormous, lengthy clinical trials can cost hundreds of millions of dollars, a major barrier to new vaccines. The urgent need for an effective TB vaccine has prompted researchers to find innovative ways to accelerate vaccine development.
In collaboration with Harvard T.H. Chan School of Public Health, researchers developed an even safer strain of M. tuberculosis equipped with a triple kill switch. This system relies on three independent molecular mechanisms to eliminate the bacteria. Even in severely immunocompromised mice, the switch effectively stopped the infection, leaving no detectable bacteria. This development could pave the way for controlled human infection studies, ensuring safety while advancing TB vaccine research.
Now, they are setting up additional tests in mice and non-human primates to confirm the system’s reliability with the goal of using the new strain in human challenge trials of new vaccines. “We are starting with one of the most successful human pathogens ever, so we are very aware of the safety concerns, and that challenge has to be met at the highest levels,” stated Dr. Schnappinger.
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