Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, remains a leading global health threat, infecting millions and causing over a million deaths annually. Despite advancements in medicine, the current vaccine, Bacillus Calmette-Guérin (BCG), has been in use for over a century but offers limited protection, particularly for adults against pulmonary TB. However, new research at Weill Cornell Medicine has led to a groundbreaking approach to designing more effective tuberculosis vaccines using genetically engineered mycobacteria with built-in “kill switches.” These bacteria, designed to self-destruct after eliciting an immune response, promise to address some of the limitations of current TB vaccines and pave the way for safer, more effective vaccination strategies.
The Challenge of Tuberculosis and Current Vaccination Limitations
Mycobacterium tuberculosis spreads through the air and can cause chronic infections in the lungs, leading to severe respiratory diseases and complications. The BCG vaccine, derived from the closely related Mycobacterium bovis, has been used to prevent TB for decades. It is especially effective in protecting children from severe forms of TB, such as TB meningitis. However, BCG has limited efficacy in protecting adults from pulmonary tuberculosis, a condition that accounts for the majority of TB-related deaths. As a result, BCG is still widely used only in high-incidence countries.
The lack of an effective vaccine for adults has kept TB a persistent global health problem. Though TB is under control in many developed countries, its high mortality rate worldwide remains a major health concern, especially in low- and middle-income nations. This has prompted a renewed effort among researchers to design more effective vaccines and therapies to combat TB, ultimately aiming to eliminate the disease and its devastating consequences.
The Innovative Approach: Self-Destructing Bacteria for Safer Vaccines
A team of researchers at Weill Cornell Medicine, led by Dr. Dirk Schnappinger, professor of microbiology and immunology, has developed a promising new approach to improving TB vaccines. They designed strains of mycobacteria with a built-in “kill switch,” which can be activated after the bacteria elicit an immune response, ensuring that the bacteria self-destruct in a controlled manner. This innovative strategy aims to overcome the safety and efficacy challenges of existing vaccines by providing a way to activate the self-destruction mechanism once the bacteria have triggered the desired immune response.
In preclinical studies, the researchers engineered Mycobacterium bovis (the bacterium used in BCG) to contain lysins, enzymes that can break down the bacterial cell walls. These lysins, typically encoded by viruses that infect bacteria, are employed as molecular “kill switches.” When triggered by specific regulatory genes, these lysins cause the engineered bacteria to self-destruct after performing their job of stimulating the immune system.
The Role of Lysins and Kill Switches in Vaccine Design
The researchers tested around 20 different strategies before finding that lysins could effectively serve as kill switches for the bacteria. By placing the lysin genes under the control of antibiotic-sensitive gene regulators, the team was able to design a system where the bacteria could be “turned on” by introducing antibiotics, prompting them to stimulate an immune response. Once the immune system was activated, the researchers could “flip the switch” by removing the antibiotics, causing the bacteria to self-destruct.
This novel approach of using lysins as kill switches provides a safer alternative to the traditional BCG vaccine, which does not have the self-destruction mechanism and can potentially cause adverse reactions in certain populations. By designing the bacteria to die after they trigger the immune system, the researchers are effectively preventing the risk of prolonged infection or other unintended consequences in vaccinated individuals.
Preclinical Results: Testing on Macaque Monkeys
In their experiments, the researchers administered high doses of the engineered BCG vaccine intravenously to macaque monkeys. The high-dose intravenous injection is a technique that has shown promise in improving the vaccine’s ability to protect against pulmonary tuberculosis in animal models. However, this method also presents potential safety concerns, as large doses of live bacteria could pose risks to the monkeys’ health.
By using the kill-switch technology, the researchers ensured that once the immune response had been triggered, the engineered bacteria would self-destruct, minimizing the risk of adverse effects. The results were promising: the engineered BCG vaccine produced a robust immune response in the monkeys, and the self-destruct mechanism was successfully activated, leading to the destruction of the bacteria without any signs of lingering infection. This suggests that the new vaccine could provide strong protection against TB without the safety concerns associated with traditional vaccines.
Overcoming the Challenges of Clinical Trials
While the preclinical results are promising, translating this research into a viable vaccine for humans remains a significant challenge. Testing new vaccines, especially one involving live bacteria, requires extensive clinical trials to ensure their safety and efficacy. Tuberculosis does not develop quickly, and only a small fraction of people who are infected develop full-blown TB, making it difficult to assess the effectiveness of a vaccine in clinical trials.
Moreover, conducting large-scale clinical trials for new vaccines is a costly and time-consuming process. Given the enormous resources required to test new TB vaccines, researchers are exploring ways to streamline the process and accelerate development. One strategy is to design bacteria strains that can be used in controlled human infection studies, allowing researchers to test vaccines more quickly and safely in a clinical setting.
A Collaborative Effort: Working Towards Safe and Effective TB Vaccines
In collaboration with researchers from the University of Pittsburgh, the National Institutes of Health’s Vaccine Research Center, and Harvard T.H. Chan School of Public Health, the team at Weill Cornell Medicine has taken steps to address the challenge of conducting safe and controlled human infection trials. The researchers engineered a new strain of Mycobacterium tuberculosis with a triple kill switch, using three independent molecular mechanisms to destroy the bacteria after they have elicited an immune response.
In animal models, including severely immunocompromised mice, the triple kill switch was successfully activated, ensuring that the bacteria were eliminated without causing harm. This development has the potential to make clinical trials for TB vaccines much safer and more feasible, as it would allow researchers to test the vaccines in a controlled environment without the risk of uncontrolled infections.
The Path Forward: Testing and Clinical Trials
While the results so far have been promising, further testing in mice and non-human primates is necessary to confirm the reliability and safety of the new strains with kill switches. Researchers are planning additional trials to refine the system and test its effectiveness in human challenge trials, which involve infecting healthy volunteers with controlled doses of Mycobacterium tuberculosis to assess the efficacy of new vaccines.
The team at Weill Cornell Medicine is aware of the potential risks involved in testing live bacteria, especially with a pathogen as dangerous as Mycobacterium tuberculosis. Ensuring the highest safety standards and rigorously testing these new vaccine candidates will be critical as they move towards human trials.
The Future of TB Vaccines: A Step Towards Eradicating Tuberculosis
The development of self-destructing bacteria with kill switches represents a significant step forward in the fight against tuberculosis. If successful, these engineered vaccines could offer a safer and more effective alternative to BCG, providing better protection against pulmonary tuberculosis, especially in adults. By addressing the safety concerns of live bacterial vaccines and accelerating the vaccine development process, researchers hope to create a vaccine that can ultimately help eliminate TB as a global health threat.
With continued research and collaboration, the possibility of a more effective TB vaccine within reach is more promising than ever. As the world grapples with the ongoing threat of tuberculosis, innovative approaches like the one developed by Weill Cornell Medicine may be key to overcoming the challenges that have long hindered the development of a truly effective TB vaccine.
