Good news! My high school buddies liked to tease me from time to time reminding me that my initials TB stand for tuberculosis! 😊
It seems to be extraordinary difficult to develop new vaccines for TB!
"There is currently only one vaccine for tuberculosis — the world’s deadliest infectious disease, killing more than 1 million people annually — and it was approved over 100 years ago."
"A large-scale screen of tuberculosis proteins has revealed several possible antigens that could be developed as a new vaccine for TB, the world’s deadliest infectious disease.
In the new study, a team of MIT biological engineers was able to identify a handful of immunogenic peptides, out of more than 4,000 bacterial proteins, that appear to stimulate a strong response from a type of T cells responsible for orchestrating immune cells’ response to infection.
There is currently only one vaccine for tuberculosis, known as BCG, which is a weakened version of a bacterium that causes TB in cows. This vaccine is widely administered in some parts of the world, but it poorly protects adults against pulmonary TB. ...
identifying TB proteins presented on the surface of infected human cells. When an immune cell such as a phagocyte is infected with Mycobacterium tuberculosis, some of the bacterial proteins get chopped into fragments called peptides, which are then displayed on the surface of the cell by MHC proteins. These MHC-peptide complexes act as a signal that can activate T cells.
MHCs, or major histocompatibility complexes, come in two types known as class I and class II. Class I MHCs activate killer T cells, while class II MHCs stimulate helper T cells. In human cells, there are three genes that can encode MHC-II proteins, and each of these comes in hundreds of variants. This means that any two people can have a very different repertoire of MHC-II molecules, which present different antigens. ...
To try to answer the question, the researchers infected human phagocytes with Mycobacterium tuberculosis. After three days, they extracted MHC-peptide complexes from the cell surfaces, then 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 often in the infected cells. Then, they further tested those peptides by exposing them to T cells donated by people who had previously been infected with TB.
They found that 24 of these peptides did elicit a T cell response in at least some of the samples. None of the proteins from which these peptides came worked for every single donor, but Bryson believes that a vaccine using a combination of these peptides would likely work for most people. ...
To evaluate whether the proteins they identified could make a good vaccine, the researchers created mRNA vaccines encoding two protein sequences — EsxB and EsxG. The researchers designed several versions of the vaccine, which were targeted to different compartments within the cells.
The researchers then delivered this vaccine into human phagocytes, where they found that vaccines that targeted cell lysosomes — organelles that break down molecules — were the most effective. These vaccines induced 1,000 times more MHC presentation of TB peptides than any of the others.
They later found that the presentation was even higher if they added EsxA to the vaccine, because it allows the formation of the heterodimers that can poke through the lysosomal membrane.
The researchers currently have a mix of eight proteins that they believe could offer protection against TB for most people, but they are continuing to test the combination with blood samples from people around the world. ..."
From the editor's summary and abstract:
"Editor’s summary
Despite decades of research, we are still awaiting an effective vaccine to prevent infection with tuberculosis (TB). CD4+ T cells are essential to respond to infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB, and vaccines for TB may need to be targeted toward this population.
Here, Leddy et al. did just that. The authors performed immunopeptidomics to identify candidate peptides expressed by Mtb that, when presented in the context of major histocompatibility complex class II (MHC-II) on phagocytic cells, activated CD4+ T cells in culture. The authors then developed several mRNA immunogens targeting different subcellular regions to show that such localization greatly affects antigen presentation capacity by phagocytic cells in vitro. These data highlight the promise of this CD4+ T cell–focused mRNA vaccine for TB and demonstrate the utility of this immunopeptidomics approach. ...
Abstract
No currently licensed vaccine reliably prevents pulmonary tuberculosis (TB), a leading cause of infectious disease mortality. Developing effective new vaccines requires identifying which Mycobacterium tuberculosis (Mtb) proteins are presented on major histocompatibility complex class II (MHC-II) by infected human phagocytes (target cells) and defining their capacity for recognition by CD4+ T cells. Vaccine designs must elicit T cell responses recognizing the same peptide-MHC complexes presented by infected cells. Although many human CD4+ T cell Mtb epitopes have been described, presentation on MHC-II by infected cells in most cases has not been directly evaluated.
Using mass spectrometry (MS), we demonstrated that Mtb type VII secretion system (T7SS) substrates are enriched in the MHC-II repertoire of Mtb-infected human monocyte-derived phagocytes and that many of these antigens are immunogenic in people with prior evidence of Mtb infection.
We next used MS to guide TB messenger RNA (mRNA) vaccine design, increasing the presentation of target MHC-II epitopes by orders of magnitude by incorporating design features that mirror aspects of antigen presentation dynamics in infected phagocytes.
Our results provide a strategy for TB vaccine design that is guided by bottom-up unbiased discovery. Our approach combines targeted evaluation of antigen presentation in human cells paired with rapid iterative testing of mRNA vaccine designs to optimize antigen presentation before animal studies or human clinical trials."
Immunopeptidomics can inform the design of mRNA vaccines for the delivery of Mycobacterium tuberculosis MHC class II antigens (no public access)
Immunopeptidomics informs discovery and delivery of Mycobacterium tuberculosis MHC-II antigens for vaccine design (preprint, open access)
Fig. 1 Immunopeptidomics identifies potential vaccine targets presented on MHC-II in Mtb-infected human dendritic cells
