Tuberculosis (TB): Practice Essentials, Background, Pathophysiology

Controlled Kill Switches Improve TB Vaccine Safety

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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.

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Subscribe for FREE 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.

References: 

1. Smith AA, Su H, Wallach J, et al. A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity. Nat Microbiol. 2025;10(2):468-481. Doi: 10.1038/s41564-024-01895-4

2. Wang X, Su H, Wallach JB, et al. Engineered Mycobacterium tuberculosis triple-kill-switch strain provides controlled tuberculosis infection in animal models. Nat Microbiol. 2025;10(2):482-494. Doi: 10.1038/s41564-024-01913-5

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Revolutionizing TB Prevention: Breakthrough In MRNA Vaccine Research

A groundbreaking development in tuberculosis (TB) prevention has emerged from Australian researchers, who have crafted an innovative mRNA vaccine. This new vaccine has shown significant promise, successfully enhancing immunity in pre-clinical trials conducted on mice, setting the stage for further clinical evaluations.

This mRNA-based solution leverages the same technology that proved effective against COVID-19, potentially outperforming the traditional Bacillus Calmette-Guérin (BCG) vaccine, introduced over a century ago. Experts involved suggest that the mRNA vaccine offers not just enhanced efficacy but also the ability to adapt quickly, making it an attractive alternative for global TB control efforts.

The study underlines the vast potential of mRNA technology, already acclaimed for its rapid deployment capabilities against infectious diseases. It suggests that, once validated in larger models and eventual human trials, this could signal a new era in combating TB, particularly in regions hardest hit by the disease.

(With inputs from agencies.)

New MRNA Vaccine To Help Fight Tuberculosis

Mycobacterium tuberculosis (Public Health Image Library, NIAID, Image ID: 18139)

Tuberculosis (TB) is the number one cause of infectious mortality worldwide, despite treatments being widely available. A new vaccine breakthrough may provide the mechanism to reduce the infectivity rate of this ancient bacterial disease. The vaccine is at the pre-clinical trial stage.

The candidate vaccine is part of a successful collaboration between three leading Australian research institutions: Sydney Infectious Diseases Institute at University of Sydney, the Centenary Institute and the Monash Institute of Pharmaceutical Science (MIPS) at Monash University.

Remarkably, the only approved vaccine for TB is the century-old Bacillus Calmette-Guerin (BCG) vaccine. This vaccine contains a weakened form of the Mycobacterium bovis bacteria, which is closely related to the bacteria that cause TB. The vaccine helps the immune system recognize and fight off TB bacteria if exposed in the future. It happens to be the most widely used vaccine on the planet, with more than 4 billion doses delivered. Yet BCG is an imperfect vaccine that wanes in effectiveness as children age into adolescence.

The vaccine is based on mRNA technology, where genetic instructions are used to trigger an immune response in the body, as opposed to using a weakened or deadened version of an infectious agent.

mRNA vaccines are a type of vaccine that use messenger RNA (mRNA) to instruct cells to produce a protein that triggers an immune response. This immune response helps the body recognize and fight off the actual virus or pathogen if it encounters it in the future.

The study demonstrated that a new mRNA vaccine was successful in triggering an immune defence response that helped to reduce TB numbers in infected mice.The researchers also discovered that for mice that had received the BCG vaccine, a booster dose of the new mRNA vaccine significantly improved their long-term protection.

A US man receives a coronavirus vaccine – Copyright AFP/File ENRIQUE CASTRO

Senior author Professor Jamie Triccas, Deputy Director of the Sydney Infectious Diseases Institute, explains further: "Our findings demonstrate that an mRNA vaccine can induce potent, pathogen-specific immune responses that target TB, a disease that has long evaded effective vaccine development. This represents a major advance in TB vaccine research and provides a strong rationale for further clinical development."

The researchers hope that the mRNA vaccine will ultimately be more effective and consistent than the BCG when used in humans. This is because, unlike protein-based or live-attenuated vaccines (those that contain a weakened version of a pathogen), mRNA vaccines allow for rapid adaptation, making them an attractive option for global TB control efforts.

mRNA vaccines offer the ability to be a scalable, cost-effective, and adaptable platform in a form that can be rapidly deployed against infectious diseases.

The research team is looking to advance their vaccine to clinical trials.

The research appears in the journal eBioMedicine, titled "An LNP-mRNA vaccine modulates innate cell trafficking and promotes polyfunctional Th1 CD4+ T cell responses to enhance BCG-induced protective immunity against Mycobacterium tuberculosis."

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