Briefly blocking a key molecule during the administration of the only approved tuberculosis vaccine significantly improves long-term protection against the devastating disease in mice, researchers at the Texas Biomedical Research Institute report this week in the Journal of Immunology. The discovery, if it continues to hold true in non-human primates and clinical trials, has the potential to save millions of lives.
Tuberculosis (TB) infects more than 10 million people a year, killing more than a million people a year. The Bacillus Calmette-Guérin (BCG) vaccine is widely used to vaccinate children against tuberculosis, but its effectiveness decreases over time. Researchers around the world are searching for more effective vaccines and treatments.
“We are very pleased to be able to reverse the diminishing efficacy of BCG by combining it with host-directed therapy in a single dose, which makes it very practical for the clinic,” said Joanne Turner, PhD, Vice-Chancellor. Executive Chair, Research, and Senior Author of Articles.
decades of research
Turner pointed out that the finding builds on more than 20 years of research. Throughout her career, she has studied the role of a molecule, interleukin-10 (IL-10) on tuberculosis. IL-10 typically helps quell excessive inflammation during infection, but through numerous studies, Turner and colleagues found that IL-10 does more harm than good in tuberculosis, definitively showing that it is the source of tuberculosis infection.
In previous studies, Turner and colleagues blocked IL-10 at different times during infection – late in infection, the first three weeks of infection – and eliminated IL-10 completely. All signs pointed to better TB control and longer survival. In the current study, the team looked at what happens if they temporarily block IL-10 before the infection occurs, at the same time as the administration of the BCG vaccine.
Host-directed therapy + vaccine
The researchers combined the BCG vaccine with an antibody that blocks IL-10 activity for about a week. Since the antibody targets the host, not the pathogen, this makes it a “host-directed therapy”. They gave the mixture to the mice all at once, waited six weeks to make sure the IL-10 blocker was no longer present and the BCG protection had been generated, then exposed the mice to tuberculosis. . These mice controlled TB infection for nearly a year, which is significant for mice with a normal lifespan of about two years. In contrast, mice given only the BCG vaccine lost control of TB infection within two months and showed significant lung inflammation and damage. Notably, mice given the vaccine/IL-10 inhibitor had higher levels of various long-term memory immune cells, which are essential for the ongoing control of tuberculosis.
“This shows that the early development of an immune response is essential for controlling TB infection in the long term, and that IL-10 inhibits the development of this long-term immunity,” Turner said. “But by briefly blocking IL-10 at the same time as the vaccine is given, it allows the vaccine and the immune system to do their job, creating these long-lasting memory immune cells.”
The Texas Biomed collaborators plan to study whether the combination is safe and effective in non-human primates. If these results are also promising, the combination could move on to human clinical trials. The team is optimistic, especially since the BCG vaccine is already widely used and the IL-10 blocker is being tested against other diseases.
Experimentally, IL-10 has been somewhat dismissed as playing an important role in tuberculosis, even though it has been detected in humans with tuberculosis. But this conclusion was made in the most common strain of research mice, which is quite resistant to tuberculosis and does not produce much IL-10.
Turner began studying another strain of mice, called CBA/J, which is much more susceptible to tuberculosis. By working with these mice, she and her colleagues began to piece together the role of IL-10 and what happens when it is blocked. To definitively show a molecule’s function, researchers often eliminate the gene that codes for the molecule. Turner bred the CBA/J IL-10 knockout mice, which took several years of effort, and since 2011 the mice have been instrumental in proving that IL-10 causes tuberculosis. These mice can even form human-like granulomas, which are cell clumps that form around the bacteria to prevent it from spreading.
“We only saw this because we were working on a different strain of mice than the standard lab mouse strain,” says Turner. “It is gratifying that these knockout mice that we have developed are available for other researchers to work with. The diversity of animal models is important for understanding commonalities between species that help us better understand human disease. .”