Weill Cornell engineers mycobacteria with built-in kill switches to enhance TB vaccine safety.
Researchers at Weill Cornell Medicine have designed two strains of mycobacteria with built-in “kill switches” that can be activated to stop bacterial growth after triggering an immune response. These findings, published on January 10 in Nature Microbiology, address the challenge of engineering bacterial strains that are both effective and safe for use in vaccine development and controlled human infection trials. While tuberculosis (TB) remains under control in many developed regions, it continues to cause over a million deaths annually worldwide.
Addressing tuberculosis through vaccination
Mycobacterium tuberculosis spreads through airborne transmission and can establish persistent lung infections that lead to severe respiratory disease. The widely used Bacillus Calmette-Guérin (BCG) vaccine – composed of a weakened strain of Mycobacterium bovis – provides protection against severe TB in children but has limited effectiveness in preventing pulmonary TB in adults. This has led researchers to explore alternative vaccination strategies.
Mycobacterium tuberculosis
A bacterial species that causes tuberculosis in humans. It spreads through airborne transmission and can establish long-term infections in the lungs, potentially leading to severe respiratory disease.
BCG vaccine
Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine derived from Mycobacterium bovis. It is widely used to protect against severe forms of tuberculosis in children but has limited efficacy in preventing adult pulmonary TB.
Kill switch
A genetic mechanism engineered into bacteria that allows their controlled elimination under specific conditions. In this study, researchers used kill switches to prevent prolonged bacterial persistence following immune activation.
Previous work by collaborators at the University of Pittsburgh and the National Institutes of Health’s Vaccine Research Center demonstrated that delivering a high dose of BCG via intravenous injection, rather than the conventional subcutaneous route, improved protection against TB in adult macaques. However, concerns over safety have hindered the use of high-dose BCG in humans.
Engineering a controlled immune response
“We needed a version of BCG that triggers an immune response, but then you can flip a switch to eliminate the bacteria.” Dr. Dirk Schnappinger.
One of the new studies focuses on making high-dose intravenous BCG safer while maintaining its ability to stimulate immunity. Researchers introduced a genetic system that enables bacterial self-destruction following immune activation. This system relies on lysins – enzymes that viruses use to break down bacterial cells.
By incorporating two lysin genes regulated by an antibiotic-responsive switch, the researchers created a vaccine strain that can be eliminated on demand.
In preclinical tests, macaques received high-dose intravenous BCG while being treated with antibiotics. When antibiotic treatment was stopped, the bacteria self-destructed, releasing antigens that further enhanced immune stimulation. The animals showed strong immune responses and improved protection against M. tuberculosis lung infections.
Despite promising early results, evaluating vaccine efficacy requires large-scale human trials, which can be time-consuming and costly. TB develops slowly and only in a subset of infected individuals, making clinical testing particularly challenging.
Developing safer strains for human trials
The second study, conducted in collaboration with researchers at Harvard T.H. Chan School of Public Health, aims to facilitate controlled human infection studies by creating a highly safe strain of M. tuberculosis. This strain incorporates a “triple kill switch” with three independent molecular mechanisms designed to eliminate the bacteria upon activation.
In experiments using immunocompromised mice, researchers demonstrated that the triple kill switch reliably halted infection, leaving no detectable bacteria. Further testing in animal models is underway to validate its safety and effectiveness before potential use in human trials.
By developing bacterial strains that can be precisely controlled, researchers hope to accelerate TB vaccine development while minimizing risks. Given the global burden of TB, advances in vaccination strategies remain a priority for public health.
