In a groundbreaking advance that could redefine tuberculosis (TB) vaccine development, researchers at the Massachusetts Institute of Technology have identified promising antigenic targets from Mycobacterium tuberculosis, the bacterium responsible for the world’s deadliest infectious disease. Utilizing cutting-edge immunopeptidomics, the team screened over 4,000 proteins to pinpoint specific peptides capable of provoking robust immune responses. This innovative study heralds a new era in vaccine design, offering hope for more effective TB prevention strategies, especially in adults where existing options falter.
Tuberculosis continues to pose a colossal global health burden, claiming more than a million lives annually despite nearly a century since the introduction of the Bacillus Calmette-Guérin (BCG) vaccine. While BCG, derived from an attenuated bovine TB strain, provides some protection in children, its efficacy against pulmonary TB in adults is markedly limited. Seeking to surmount this challenge, the MIT researchers, led by Bryan Bryson and Forest White, turned to a proteome-wide approach to dissect the complex interplay between M. tuberculosis antigens and human immune recognition.
Central to their methodology was the exploitation of the host’s basic immunological machinery – the major histocompatibility complex class II (MHC-II) molecules. These proteins display peptide fragments derived from intracellular pathogens on the surface of infected cells, serving as beacons for helper T cells that coordinate the broader immune defense. Given human genetic diversity, the vast array of MHC-II variants complicates antigen identification since each variant presents distinct peptides. Thus, the team’s challenge was to sift through thousands of bacterial proteins and uncover those consistently displayed by infected human phagocytes across diverse MHC-II repertoires.
To achieve this, researchers infected primary human phagocytes with live M. tuberculosis and harvested MHC-peptide complexes after a three-day infection period. Using sophisticated mass spectrometry, they identified an ensemble of 27 peptides originating from 13 distinct TB proteins preferentially presented on MHC-II molecules. These findings signify the first direct snapshot of the antigenic landscape governing T cell activation during TB infection at a systems level, bypassing traditional guesswork or reliance on animal models.
The immunogenicity of these peptides was rigorously validated by testing their capacity to activate T cells cultured from blood samples of previously infected individuals. Remarkably, 24 of the 27 peptides elicited measurable T cell responses, though no single antigen uniformly stimulated every donor’s cells. This heterogeneity underscores the complexity of human immune recognition and emphasizes the necessity of polyvalent vaccine formulations combining multiple epitopes to achieve broad population coverage.
Among the most intriguing targets identified belong to the Type VII secretion system (T7SS), a specialized pathway through which M. tuberculosis exports virulence factors to modulate host defenses. The Esx family of proteins, specifically EsxA and EsxB, formed a focal point due to their known role in enabling bacterial escape from phagosomal compartments by forming heterodimeric pores. Their peptides were preferentially presented on both MHC class I and II molecules, suggesting they could provide a dual-pronged stimulus to killer and helper T cells alike.
Capitalizing on these insights, the researchers ventured into the realm of mRNA vaccine technology, inspired by its triumph against COVID-19. They engineered mRNA constructs encoding EsxB and EsxG proteins, delivering them into human phagocytes to assess antigen presentation efficacy. Fascinatingly, mRNA vaccines targeted to lysosomes – intracellular organelles responsible for macromolecule degradation – markedly amplified the display of TB peptides via MHC-II, outperforming other delivery strategies by a thousandfold. Further enhancement was achieved by including EsxA, which facilitates heterodimer formation and lysosomal membrane penetration, thereby optimizing antigen processing and presentation.
This pioneering work proposes a rational blueprint for next-generation TB vaccines incorporating multiple immunodominant proteins identified through immunopeptidomics. The goal is to formulate a cocktail capable of eliciting potent T cell responses across varied human MHC genotypes. While promising, these candidates will undergo extensive validation against blood samples from individuals worldwide to account for genetic and environmental diversity in immune responses. Animal model testing is also underway to establish protective efficacy, with human clinical trials projected in the coming years.
This study represents a monumental leap in vaccine research, melding advanced proteomic technologies with immunological precision to strategically outmaneuver one of humanity’s most persistent infectious foes. By revealing the precise epitopes naturally presented during infection and harnessing mRNA platforms’ versatility, this research opens a conceptual and technical frontier that could finally bridge the century-old gap left by BCG’s shortcomings. The implications extend beyond TB, offering a paradigm for vaccine development against other intracellular pathogens with complex antigenic repertoires.
The funding of this work by the MIT Center for Precision Cancer Research at the Koch Institute, alongside the U.S. National Institutes of Health and Frederick National Laboratory for Cancer Research, underscores a growing convergence of cancer and infectious disease research methodologies. As the scientific community eagerly anticipates further results, this approach epitomizes how integrative biology and novel vaccine modalities can converge to tackle urgent global health challenges with precision and efficacy.
As tuberculosis continues to imperil populations worldwide, particularly in regions burdened by co-infections and drug resistance, the need for innovative preventive measures is critical. This comprehensive immunopeptidomic dissection of the M. tuberculosis proteome, combined with breakthrough mRNA vaccine engineering, exemplifies the type of interdisciplinary innovation requisite to reinvigorate the battle against this ancient scourge. The future landscape of TB vaccination is poised for transformation, promising enhanced protection that could dramatically reduce mortality and morbidity from one of humanity’s deadliest infectious adversaries.
Subject of Research: Mycobacterium tuberculosis antigens and mRNA vaccine development targeting MHC class II presentation for tuberculosis.
Article Title: Immunopeptidomics can inform the design of mRNA vaccines for delivery of Mycobacterium tuberculosis MHC class II antigens.
News Publication Date: 5-Nov-2025.
Web References: http://dx.doi.org/10.1126/scitranslmed.adw9184
Keywords: Tuberculosis, Mycobacterium tuberculosis, Vaccine research, Immunopeptidomics, mRNA vaccine, MHC class II, Type VII secretion system, Esx proteins, T cell immunity, Infectious diseases, Immune epitopes, Phagocytes.
