The path to a better tuberculosis vaccine runs through Montana

The path to a better tuberculosis vaccine runs through Montana

A team of Montana researchers is playing a key role in developing a more effective vaccine against tuberculosis, an infectious disease that has killed more people than any other.

The BCG (Bacille Calmette-Guérin) vaccine, developed in 1921, remains the only tuberculosis vaccine. While effectiveness in young children is 40 to 80%, effectiveness in adolescents and adults is very low, leading to a global push to develop a more effective vaccine.

A trial is currently underway at the University of Montana's Center for Translational Medicine. The center specializes in the improvement and development of vaccines by adding so-called novel adjuvants. An adjuvant is a substance contained in the vaccine, such as fat molecules or aluminum salts, that enhances the immune response. Novel adjuvants are those that have not yet been used in humans. Scientists find that adjuvants provide stronger, more precise and more lasting immunity than would be the case with antigens that produce antibodies alone.

Triggering specific immune system responses and deepening and broadening the response with adjuvants is known as precision vaccination. “It’s not a one-size-fits-all solution,” said Ofer Levy, a professor of pediatrics at Harvard University and director of the Precision Vaccines Program at Boston Children’s Hospital. “A vaccine might work differently in a newborn than in an older adult and a middle-aged person.”

The ultimate precision vaccine, Levy said, would be lifelong protection against disease with one shot. “A one-time protection against influenza or a one-time protection against Covid, that would be the holy grail,” Levy said.

Jay Evans, director of the University of Montana center and scientific and strategic director and co-founder of Inimmune, a private biotechnology company in Missoula, said his team has been working on a tuberculosis vaccine for 15 years. The private-public partnership is developing vaccines and trying to improve existing vaccines, and he said there are still five years until the tuberculosis vaccine is widely available.

It has not gone unnoticed at the Center that this cutting-edge vaccine research and production is located in a state that has enacted one of the most extreme anti-vaccination laws in the country during the 2021 pandemic. The law prohibits companies and governments from discriminating against people who are not vaccinated against Covid-19 or other diseases and effectively prohibits both public and private employers from requiring employees to be vaccinated against Covid-19 or other diseases. A federal judge later ruled that the law could not be enforced in health care facilities such as hospitals and doctor's offices.

In mid-March, the Bill & Melinda Gates Medical Research Institute announced that it had begun the third and final phase of clinical trials for the new vaccine in seven countries. The trials are expected to last around five years. Research and production is carried out in several locations, including a manufacturing facility in Hamilton owned by GSK, a giant pharmaceutical company.

Known as the forgotten pandemic, tuberculosis kills up to 1.6 million people each year, mostly in impoverished areas of Asia and Africa, despite being both preventable and treatable. The United States has seen an increase in tuberculosis cases over the past decade, particularly due to the influx of migrants, and the number of cases increased by 16% from 2022 to 2023. Contracting a tuberculosis infection is 20 times more likely than people without HIV.

“TB is a complex pathogen that has been affecting humans for centuries,” said Alemnew Dagnew, who leads the new vaccine program for the Gates Medical Research Institute. "Because it has been in humans for many years, it has evolved and has a mechanism to evade the immune system. And the immunology of tuberculosis is not yet fully understood."

The University of Montana Center for Translational Medicine and Inimmune collectively employ 80 people who specialize in researching a range of adjuvants to understand the specifics of immune responses to various substances. “You have to tailor it, like tools in a toolbox, to the pathogen you're vaccinating against,” Evans said. “We have a whole library of adjuvant molecules and formulations.”

Vaccines are made more precise primarily through the use of adjuvants. There are three basic types of natural excipients: aluminum salts; squalene, which is made from shark liver; and some types of saponins, which are fat molecules. It is not fully understood how they stimulate the immune system. The Missoula center has also developed and patented a synthetic adjuvant, UM-1098, that triggers a specific type of immune response and is added to new vaccines.

One of the most promising molecules used to boost the immune system's response to vaccines is a saponin molecule from the bark of the Quillay tree, which is harvested in Chile from trees at least ten years old. Such molecules have been used by Novavax in its Covid vaccine and by GSK in its widely used shingles vaccine Shingrix. These molecules are also a key component in the new tuberculosis vaccine, the so-called M72 vaccine.

But there is room for improvement.

“The vaccine is 50% effective, which doesn't sound like much, but basically there's no effective vaccine right now, so 50% is better than what's out there,” Evans said. “We want to take what we have learned from this vaccine development with additional adjuvants to make it even better and increase it by 50% to 80% or more.”

In contrast, measles vaccines are 95% effective.

According to Medscape, around 15 vaccine candidates are being developed to replace the BCG vaccine, three of which are in Phase 3 clinical trials.

One approach the Evans Center is researching to improve the effectiveness of the new vaccine is to take a piece of the bacterium that causes tuberculosis, synthesize it and combine it with the adjuvant QS-21, made from the Quillay tree. “It stimulates the immune system in a way specific to tuberculosis, triggering an immune response that is even closer to what we get with natural infections,” Evans said.

The University of Montana center is researching the treatment of various problems not generally considered treatable with vaccines. For example, they are entering the first phase of clinical trials for an allergy vaccine and the first phase of trials for a cancer vaccine. And later this year, clinical trials will begin for vaccines that block the effects of opioids like heroin and fentanyl. The University of Montana received the largest grant in its history, $33 million, for anti-opioid vaccine research. It creates an antibody that binds to the drug in the bloodstream, preventing it from reaching the brain and causing the high.

For now, however, the eyes of health experts around the world are on trials of the new tuberculosis vaccines, which, if successful, could help save countless lives in the world's poorest areas.

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