MIT study finds targets for a new tuberculosis vaccine

A large-scale screen of tuberculosis proteins has revealed potential antigens that could be developed as a new vaccine for TB, the world’s deadliest infectious disease.

In a new study, a team of MIT biological engineers identified a handful of immunogenic peptides from over 4,000 bacterial proteins. These peptides appear to stimulate a strong response from a type of T cells that orchestrates the immune response to infection.

Currently, the only tuberculosis vaccine is BCG, a weakened version of a bacterium that causes TB in cows. While widely administered in some areas, it poorly protects adults against pulmonary TB. Tuberculosis claims over 1 million lives globally each year.

“There’s still a huge TB burden globally that we’d like to make an impact on,” says Bryan Bryson, an associate professor of biological engineering at MIT and a member of the Ragon Institute of Mass General Brigham, MIT, and Harvard. “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.”

Identifying Vaccine Targets

Since the BCG vaccine was developed more than a century ago, no other TB vaccines have been approved. Mycobacterium tuberculosis produces over 4,000 proteins, making it challenging to identify those that might elicit a strong immune response for use in a vaccine.

Bryson and his students aimed to narrow the field of candidates by identifying TB proteins presented on the surface of infected human cells. When a phagocyte is infected, some bacterial proteins are broken into peptides and displayed by MHC proteins, activating T cells.

MHCs, or major histocompatibility complexes, come in two types: class I and class II. Class I MHCs activate killer T cells, while class II MHCs stimulate helper T cells. Human cells have three genes encoding MHC-II proteins, each with hundreds of variants. This leads to different repertoires of MHC-II molecules, presenting different antigens.

“Instead of looking at all of those 4,000 TB proteins, we wanted to ask which of those proteins from TB actually end up being displayed to the rest of the immune system via MHC,” Bryson says. “If we could just answer that question, then we could design vaccines to match that.”

To investigate, researchers infected human phagocytes with Mycobacterium tuberculosis. After three days, they extracted MHC-peptide complexes from the cell surfaces and identified the peptides using mass spectrometry.

Focusing on peptides bound to MHC-II, the researchers found 27 TB peptides, from 13 proteins, that appeared most frequently in the infected cells. They tested these peptides by exposing them to T cells from people previously infected with TB.

They found that 24 of these peptides elicited a T cell response in some samples. While no single protein worked for every donor, Bryson believes a vaccine using a combination of these peptides would likely be effective for most people.

“In a perfect world, if you were trying to design a vaccine, you would pick one protein and that protein would be presented across every donor. It should work for every person,” Bryson says. “However, using our measurements, we’ve not yet found a TB protein that covers every donor we’ve analyzed thus far.”

Enter mRNA Vaccines

Among the vaccine candidates identified are several peptides from type 7 secretion systems (T7SSs). Some of these peptides also appeared in an earlier study from Bryson’s lab on MHC-1.

“Type 7 secretion system substrates are a very small sliver of the overall TB proteome, but when you look at MHC class I or MHC class II, it seems as though the cells are preferentially presenting these,” Bryson says.

Two key proteins, EsxA and EsxB, are secreted by bacteria to help them escape from phagocyte membranes. They cannot break through the membrane on their own, but when joined to form a heterodimer, they can create holes, allowing other T7SS proteins to escape.

To assess the potential of the identified proteins as a vaccine, the researchers created mRNA vaccines encoding two protein sequences – EsxB and EsxG. They designed several versions of the vaccine targeting different cell compartments.

The researchers delivered the vaccine into human phagocytes, finding the most effective vaccines targeted cell lysosomes, organelles that break down molecules. These vaccines induced 1,000 times more MHC presentation of TB peptides than others.

Presentation was even higher when EsxA was added to the vaccine, promoting the formation of heterodimers that can penetrate the lysosomal membrane.

The researchers currently have a mix of eight proteins that they believe could offer protection against TB for most people. They are continuing to test the combination using blood samples from individuals worldwide. Further studies are planned to explore the vaccine's protective effects in animal models. Human trials are likely several years away.

The research was funded by the MIT Center for Precision Cancer Research at the Koch Institute, the National Institutes of Health, the National Institute of Environmental Health Sciences, and the Frederick National Laboratory for Cancer Research.