AUTHOR=Yang Haoyan , Lei Xinkui , Chai Siyu , Zhang Sigen , Su Guimin , Du Lin 

TITLE=A multi-epitope vaccine incorporating adhesin-derived antigens protects against Mycobacterium tuberculosis infection and dissemination

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1707471

DOI=10.3389/fimmu.2025.1707471

ISSN=1664-3224

ABSTRACT=IntroductionAdhesion to host cells is the first and essential step in Mycobacterium tuberculosis (M. tuberculosis) infection. Among adhesion molecules, the PGRS domain of PE_PGRS33 plays a critical role in invasion but is dominated by B cell epitopes and lacks sufficient T cell epitopes, restricting its capacity to induce a balanced immune response.MethodsTo overcome this limitation, we employed an integrative reverse vaccinology pipeline combining computational prediction and experimental validation. Helper and cytotoxic T lymphocyte epitopes were incorporated from multiple M. tuberculosis adhesins as well as other virulence-associated proteins, and adjuvant sequences were systematically evaluated in silico.ResultsAmong three multi-epitope constructs, the Toll-like receptor 2 (TLR2)-agonist and  pan HLA DR-binding epitope (PADRE)-adjuvanted vaccine (TLR2-vaccine) emerged as the most promising candidate. In murine models, TLR2-vaccine induced strong antigen-specific antibody and IFN-γ responses, significantly reduced bacterial loads following H37Ra challenge, and effectively prevented extrapulmonary dissemination.DiscussionThese findings highlight the potential of adhesin-inclusive multi-epitope vaccines to elicit both humoral and cellular immunity and demonstrate how computational vaccinology can accelerate the development of targeted interventions against tuberculosis.