How to make the TB vaccine more effective

Date:
March 11, 2022
Source:
Texas Biomedical Research Institute
Summary:
Briefly blocking a key molecule when administering the only approved
vaccine for tuberculosis vastly improves long-term protection
against the devastating disease in mice, researchers report.



FULL STORY ========================================================================== Briefly blocking a key molecule when administering the only approved
vaccine for tuberculosis vastly improves long-term protection against the devastating disease in mice, researchers from Texas Biomedical Research Institute report this week in the Journal of Immunology. The finding,
if it continues to hold true in nonhuman 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 1 million a year. The Bacillus Calmette-Gue'rin (BCG) vaccine
is widely used to inoculate children against TB, but its effectiveness
wanes over time.

Researchers around the world are hunting for more effective vaccines
and treatments.

"We are very excited that we can reverse BCG's waning effectiveness by combining it with a host-directed therapy into one dose, which makes it
very practical for the clinic," says Joanne Turner, PhD, Texas Biomed's Executive Vice President, Research, and senior paper author.

Decades of research Turner emphasized the finding builds on more than
20 years of research.

Throughout her career, she has been investigating the role of a molecule, interleukin-10 (IL-10) on TB. IL-10 typically helps dampen excessive inflammation during infection, but through numerous studies, Turner
and her colleagues have found IL-10 does more harm than good in TB, definitively showing it drives TB infection.

In previous studies, Turner and her colleagues blocked IL-10 at different
times during infection -- late into infection, the first three weeks
during infection -- and have knocked out IL-10 completely. All signs
pointed to improved TB control and longer survival. In the current study,
the team looked at what happens if they temporarily block IL-10 before infection occurs, at the same time as giving the BCG vaccine.



========================================================================== Host-directed therapy + vaccine The researchers combined the BCG
vaccine with an antibody that blocks IL-10 activity for about one
week. Since the antibody targets the host, not the pathogen, that makes
it a "host-directed therapy." They gave the mixture to mice in one shot,
waited six weeks to ensure the IL-10 blocker was no longer present and the
BCG protection had been generated, and then exposed the mice to TB. Those
mice controlled TB infection for nearly a year, which is significant for
mice with normal lifespans of about two years. In contrast, mice given
only the BCG vaccine lost control of TB infection within two months and
had significant inflammation and damage in the lungs. Notably, the mice
given the vaccine/IL-10 blocker had higher levels of various long-term
memory immune cells, which are critical for ongoing TB control.

"This shows that the early development of an immune response is key for controlling TB infection in the long run, and that IL-10 inhibits the development of that long-term immunity," Turner says. "But by briefly
blocking IL-10 at the same time as giving the vaccine, it allows the
vaccine and immune system to do their jobs, creating those long-lasting
memory immune cells." Collaborators at Texas Biomed plan to investigate
if the combination is safe and effective in nonhuman primates. If those
results are also promising then the combination could move into human
clinical trials. The team is optimistic, especially since the BCG
vaccine is already in widespread use and the IL-10 blocker is being
tested against other diseases.

Models matter Experimentally, IL-10 had been somewhat dismissed as playing
a significant role in TB, even though it was detected in humans with
TB. But that conclusion was made in the most common strain of research
mouse, which is fairly resistant to TB and don't produce much IL-10.

Turner began investigating a different mouse strain, called CBA/J,
which is much more susceptible to TB. Working with these mice, she and colleagues began to piece together IL-10's role and what happens when
it is blocked. To definitively show a molecule's function, researchers
often knock out the gene that codes for the molecule. Turner bred the
CBA/J IL-10 knock-out mice, which required several years of effort,
and since 2011 the mice have been instrumental in proving IL-10 drives
TB. These mice can even form human-like granulomas, which are cellular aggregates that form around the bacteria to prevent it from spreading.

"We only saw that because we were working in a different mouse strain
than the standard laboratory mouse strain," Turner says. "It is gratifying
that those knock-out mice we developed are available for other researchers
to work with.

Diversity in animal models is important to understand the commonalities
across species that help us better understand human diseases."

========================================================================== Story Source: Materials provided by
Texas_Biomedical_Research_Institute. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Varun Dwivedi, Shalini Gautam, Colwyn A. Headley, Tucker
Piergallini,
Jordi B. Torrelles, Joanne Turner. IL-10 Receptor Blockade Delivered
Simultaneously with Bacillus Calmette-Gue'rin Vaccination Sustains
Long- Term Protection against Mycobacterium tuberculosis Infection
in Mice. The Journal of Immunology, 2022; 208 (6): 1406 DOI:
10.4049/jimmunol.2100900 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220311141432.htm

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