Immunopeptidomics can inform the design of mRNA vaccines for the delivery of Mycobacterium tuberculosis MHC class II antigens
Year: 2025
Type: article
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.
Source: Science Translational Medicine
Authors: Owen Leddy, Paul Ogongo, Julia Huffaker, Mingyu Gan, Ryan Milligan, Sheikh Mahmud, Heyuan Michael Ni, Yuko Yuki, Kidist Bobosha, Liya Wassie, Mary Carrington, Qingyun Liu, Joel D. Ernst, Forest M. White, Bryan D. Bryson
Institutions: Ragon Institute of MGH, MIT and Harvard, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, University of California, San Francisco, University of North Carolina at Chapel Hill, Frederick National Laboratory for Cancer Research, National Cancer Institute, Armauer Hansen Research Institute, Center for Cancer Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, Harvard University, Harvard University Center for AIDS Research, Frederick National Laboratory for Cancer Research, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, National Institutes of Health, Center for AIDS Research, University of Washington, University of California, San Francisco, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences
Awards: G1203476693, G1234541941, Role of antigen-specific T cell responses in the control of TB, G1575283533, G1722716446, G1897240903, G2132873222, G2150540447, G345173699, G455767199, G4689185066, G6252953675, G7287189751, G7785852513, G8469871428, G8761610486, G9000042795, G9000054876, G9000108037, G9000124043, G9000129761, G9000273435, G9000324900, Quantitative systems biology of glioblastoma cells and their interactions with the neuronal and immunological milieu, G90079629
OpenAlex ID: W4415935429