Breakthroughs in Tuberculosis Vaccines: Moving Beyond BCG

Tuberculosis (TB) remains one of the most persistent global health challenges. Despite decades of effort, it continues to be the leading cause of death from a single infectious disease. According to the World Health Organization (WHO), more than 10 million people developed active TB disease in 2024, resulting in 1.2 million deaths. Whereas the world has relied on a single licensed vaccine for over a century, a recent wave of research is aiming to shorten treatment times and prevent disease relapse.

The Limitation of the Current Standard: The BCG Vaccine

For over a hundred years, the Bacillus Calmette-Guérin (BCG) vaccine has been the primary tool in the fight against TB. Administered as a skin injection at birth in endemic areas, BCG uses a weakened form of Mycobacterium bovis to stimulate immunity.

While the BCG vaccine is 70-80% effective at preventing severe forms of the disease, such as TB meningitis, it is significantly less effective at preventing the pulmonary form of TB that affects the lungs. BCG does not provide lifelong protection, creating an urgent need for more effective vaccines that can reduce infection spread and prevent progression to active disease, as noted by Professor Helen McShane of Oxford’s Jenner Institute.

Targeting “Persisters”: The Johns Hopkins DNA Vaccine

A significant hurdle in treating TB is the existence of drug-tolerant bacterial “persisters.” These bacteria can survive prolonged antibiotic therapy, often leading to disease relapse after treatment ends. To combat this, researchers at Johns Hopkins Medicine and the Johns Hopkins Bloomberg School of Public Health have developed a therapeutic intranasal DNA vaccine.

How the DNA Vaccine Works

Unlike traditional vaccines, this nose-delivered DNA vaccine fuses two genes to direct the immune system specifically toward these drug-tolerant persisters. In a study published in the Journal of Clinical Investigation, lead author Styliani Karanika, M.D., reported that when administered alongside first-line TB drug therapy in mice, the vaccine:

• Helped clear disease bacteria faster.
• Reduced inflammation in the lungs.
• Prevented relapse after the treatment period concluded.

Innovative Delivery and Specialized Research at Oxford

The Jenner Institute at the University of Oxford is exploring whether the route of administration can improve the efficacy of the existing BCG vaccine. Since TB is naturally contracted by inhaling droplets into the lungs, researchers are testing whether delivering BCG via inhalation is more effective than the traditional skin injection.

Focus on High-Risk Populations

Oxford’s research also addresses specific vulnerabilities, particularly in patients with Type 2 Diabetes. Evidence suggests that people with Type 2 Diabetes are more susceptible to TB, potentially because the BCG vaccine does not stimulate as strong an immune response in this group. A current study is recruiting volunteers with and without Type 2 Diabetes to evaluate how different administration methods—skin injection versus inhalation—affect the immune response over a six-month period.

The Global Pipeline: Phase 3 Clinical Trials

The push for a more effective vaccine has reached a critical milestone with the Bill & Melinda Gates Medical Research Institute initiating a Phase 3 clinical trial of a tuberculosis vaccine candidate. Phase 3 trials are essential for confirming safety and effectiveness in large populations before a vaccine can be approved for widespread use.

Frequently Asked Questions

What are TB “persisters”?

Persisters are drug-tolerant bacteria that can survive standard antibiotic treatments. Because they remain dormant or resistant, they can cause the disease to return even after a patient has completed their medication course.

Why is an inhaled vaccine being tested?

Because TB enters the body through the lungs, researchers believe that delivering the vaccine via inhalation may better stimulate the immune system in the specific area where the infection occurs.

Is the DNA vaccine a replacement for antibiotics?

No. The Johns Hopkins DNA vaccine is designed as a therapeutic vaccine, meaning it is intended to be used alongside first-line drug therapy to improve outcomes and prevent relapse, not to replace antibiotics.

The Path Forward

The transition from a single, century-old vaccine to a diversified strategy—including therapeutic DNA vaccines, inhaled boosters, and new Phase 3 candidates—marks a pivotal shift in tuberculosis research. By targeting drug-tolerant bacteria and optimizing delivery methods, the medical community is moving closer to reducing the global burden of this infectious disease.