Painstaking experiments have revealed the cellular signatures that signify a tuberculosis infection, providing a series of targets for new vaccines that could finally subdue one of the world’s leading killers.
In the study, published in Science Translational Medicine on Nov. 5, researchers identified proteins expressed on the surface of cells infected with TB and used mRNA to coax uninfected human cells to produce the bacterial compounds, a key first step toward new vaccines.
“It’s one of the most impactful things I feel like I’ve done in my career,” Bryan Bryson, Ph.D., a bioengineer at the Massachusetts Institute of Technology who led the study, told Fierce Biotech in an interview.
“The antigens that he's identifying should be high on the list of targets for inclusion in the next generation of vaccines,” Samuel Behar, M.D., Ph.D., a tuberculosis researcher at the UMass Chan Medical School who was not part of Bryson’s study, told Fierce. “This is fantastic work.”
TB, caused by the bacterium Mycobacterium tuberculosis, kills about 4,000 people globally every single day, Bryson said. Despite the disease’s long entanglement with human history, there is just one vaccine to prevent it: the Bacillus Calmette Guérin (BCG) vaccine, which was first given in 1921 and uses a weakened form of a related bacteria that infects cattle. Though BCG prevents severe forms of TB in children, it isn’t effective in all populations, and the shot doesn’t work well in adults.
Many past attempts to develop new TB preventives have started from mouse studies, Bryson said, a common approach in the vaccine field.
“That, for many cases, has been a sufficiently powerful approach,” he said. “But it hasn't been good enough for TB.”
Bryson decided to tackle the TB problem from a different starting point, conducting experiments that he likened to “swimming underwater” and said others described as “absolutely insane.” He wanted to directly measure the proteins found on the surface of human cells infected with TB.
Doing so wasn’t easy. TB is a biosafety level 3 pathogen, meaning working with it requires strict safety measures to avoid infection and a possible outbreak. And the bacteria are difficult and slow to grow in the lab, Bryson said.
“It is more complicated than most other types of work,” Behar said. “Particularly what he’s doing.”
When a cell is infected with M. tuberculosis, it mounts a defense, chopping up the bacterium’s proteins and presenting them on its surface as a kind of alarm to signal to the immune system that there’s trouble afoot. Bryson’s team infected a variety of human cells with TB and then harvested the receptors from their surfaces, called human leukocyte antigen (HLA) complexes, that present proteins to passing T cells.
By analyzing the HLA complexes from these cells with mass spectrometry, the team found that many infected cells were presenting proteins used by the bacteria to acquire nutrients, Bryson said, part of a system called the type VII secretion system.
“These are a very small, privileged class of proteins that are secreted by a very specialized secretion system in the bacteria,” Bryson explained. “Many of the proteins being presented to the immune system are actually proteins that are not present in the BCG vaccine.”
Identifying the dozen or so TB antigens sitting on an infected cell’s surface alongside tens of thousands of other proteins has been a holy grail for some time, Behar said. Both he and Bryson compared it to finding a needle in a haystack, which Behar said was aided by significant advances in mass spectrometry within the last decade or so.
When Bryson initially submitted these results to scientific journals for publication, however, peer reviewers wanted more translational work. But conducting a clinical trial of a vaccine targeting these newfound proteins was prohibitively expensive. Then, the COVID-19 pandemic struck, and with it came the Nobel Prize-winning advent of mRNA vaccines.
Instead of a vaccine that uses a weakened version of the bacteria or whole bacterial proteins, mRNA vaccines instead deliver instructions that human cells can use to build the pathogenic proteins themselves, which the immune system can then respond to. Bryson’s team tested a suite of mRNA constructs with blood from donors and found that cells were able to use the mRNA to build the type VII secretion system proteins.
“We think that this is a pretty compelling strategy for a number of reasons,” Bryson said. “It helps you get to an answer around what are your most probable candidates, in a pretty scalable and interesting way that lets us be really close to human translation.”
Because not everyone’s HLA complexes present the same TB proteins, Bryson is now focused on fully capturing the diversity of bacterial remnants expressed by infected cells, so a future vaccine can be as broadly effective as possible. He’s also working on protein-based vaccines to see how they compare to the mRNA approach, but some of the bacterial compounds have proven tricky to pin down.
“I have personally been trying to work on one protein in our vaccine for the last six months,” Bryson said. “Some of these proteins are a nightmare to purify.”
Behar agreed that fully capturing the range of TB proteins expressed by the diverse set of HLA molecules found in humans is a critical next step.
“It's just going to require doing this kind of analysis over and over,” he said.
Bryson’s ultimate goal is to find a partner to bring a new TB vaccine into clinical trials to finally put a stop to one of humanity’s most persistent foes.
“I'm still quite optimistic that in my lifetime, we are actually going to have a TB vaccine that works,” he said. “And I believe that the insights we're making here will make it into that final vaccine.”