Two independent research teams have made significant advances in tuberculosis vaccine development, identifying novel antigens and utilizing mRNA technology to create next-generation vaccine candidates that could address the limitations of the century-old BCG vaccine.
MIT Team Identifies Key TB Vaccine Targets Through Comprehensive Screening
Researchers at MIT conducted a large-scale screen of more than 4,000 tuberculosis proteins to identify potential vaccine antigens. The team, led by Bryan Bryson, associate professor of biological engineering at MIT, and Forest White, professor of biological engineering, focused on proteins presented on the surface of infected human cells through MHC complexes.
"There's still a huge TB burden globally that we'd like to make an impact on. What we've tried to do in this initial TB vaccine is focus on antigens that we saw frequently in our screen and also appear to stimulate a response in T cells from people with prior TB infection," said Bryson.
The researchers infected human phagocytes with Mycobacterium tuberculosis and extracted MHC-peptide complexes from cell surfaces after three days. Using mass spectrometry, they identified 27 TB peptides from 13 proteins that appeared most frequently in infected cells. When tested against T cells from people previously infected with TB, 24 of these peptides elicited immune responses in at least some samples.
Type 7 Secretion System Proteins Show Promise
Among the most promising candidates were peptides from type 7 secretion systems (T7SSs), including EsxA and EsxB proteins. These proteins help bacteria escape from cellular membranes by forming heterodimers that can poke holes in phagocyte membranes.
The MIT team created mRNA vaccines encoding EsxB and EsxG proteins, testing various cellular targeting approaches. Vaccines targeting cell lysosomes proved most effective, inducing 1,000 times more MHC presentation of TB peptides than other versions. Adding EsxA further enhanced presentation by enabling heterodimer formation.
BIDMC Develops Trivalent mRNA Vaccine for Clinical Testing
Separately, researchers at Beth Israel Deaconess Medical Center (BIDMC) developed a trivalent mRNA vaccine combining three TB antigens identified through systematic screening of immune responses in TB-exposed humans.
"We systematically evaluated multiple potential TB vaccine antigens to develop a novel TB vaccine candidate," said Dan H. Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at BIDMC. "We used the mRNA platform that is flexible, scalable, and can combine multiple antigens into one shot."
The BIDMC team's screening pipeline tested which antigens elicited responses from human immune cells and ranked them by strength. Their trivalent vaccine concept showed superior performance compared to BCG in animal models, reducing infection rates, bacterial spread, and bacterial levels in lungs.
"The three antigens we chose have not previously been evaluated in clinical trials. Our trivalent mRNA vaccine concept improved upon the century-old BCG shot in animal models—it reduced infection rates, reduced bacterial spread, and lowered bacterial levels in the lungs," said lead author Samuel J. Vidal, MD, PhD.
Addressing Critical Global Health Need
Both research efforts address the urgent need for improved TB vaccines. Tuberculosis kills more than 1 million people annually worldwide, making it the leading cause of death from infectious disease. The current BCG vaccine, developed over 100 years ago, poorly protects adults against pulmonary TB despite being widely administered in some regions.
"Choosing which antigens to target is a significant challenge in TB vaccine development," noted Vidal. The complexity stems from Mycobacterium tuberculosis producing more than 4,000 proteins, creating a daunting challenge for vaccine designers.
Clinical Development Plans
The BIDMC trivalent vaccine is planned to move into Phase 1 clinical trials to test safety and effectiveness in humans. The MIT team continues testing their combination of eight proteins with blood samples from people worldwide and plans additional animal studies before human trials, which are likely several years away.
"Taken together, our findings open the door to a new vaccine candidate for TB," said Barouch. "We're excited to be moving this novel TB vaccine candidate toward clinical trials."
Both teams leveraged mRNA vaccine technology, the same platform that enabled rapid COVID-19 vaccine development, offering flexibility and scalability for combining multiple antigens in single formulations. The research represents a significant step forward in TB vaccine development after decades without new approved vaccines for this devastating disease.
