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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/JCI196648

Immunotherapy targeting drug-tolerant Mycobacterium tuberculosis persisters accelerates tuberculosis cure in preclinical models

Styliani Karanika,1 Tianyin Wang,1 Addis Yilma,1 Jennie Ruelas Castillo,1 James T. Gordy,2 Hannah Bailey,1 Darla Quijada,1 Kaitlyn Fessler,2 Rokeya Tasneen,1 Elisa M. Rouse Salcido,1 Farah Shamma,1 Harley T. Harris,1 Fengyixin Chen,2 Rowan E. Bates,2 Heemee Ton,2 Jacob Meza,2 Yangchen Li,2 Alannah D. Taylor,2 Jean J. Zheng,2 Jiaqi Zhang,2 Theodoros Karantanos,3 Amanda R. Maxwell,4 Eric L. Nuermberger,1 J. David Peske,5 Richard B. Markham,2 and Petros C. Karakousis1

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Karanika, S. in: PubMed | Google Scholar |

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Chen, F. in: PubMed | Google Scholar

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Li, Y. in: PubMed | Google Scholar

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Zhang, J. in: PubMed | Google Scholar

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

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1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Maxwell, A. in: PubMed | Google Scholar

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Nuermberger, E. in: PubMed | Google Scholar

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Peske, J. in: PubMed | Google Scholar |

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Markham, R. in: PubMed | Google Scholar

1Center for Tuberculosis Research, Division of Infectious Diseases, Departme, Johns Hopkins University School of Medicine, Baltimore, United States of America

2W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America

3Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, United States of America

4Department of Molecular and Comparative Pathobiology, Research Animal Resou, Johns Hopkins University, Baltimore, United States of America

5Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospita, Baltimore, United States of America

Find articles by Karakousis, P. in: PubMed | Google Scholar |

Published February 3, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI196648.
Copyright © 2026, Karanika et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 3, 2026 - Version history
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Abstract

Mycobacterium tuberculosis (Mtb) remains a global health crisis, ranking among the deadliest infectious diseases worldwide. In response to the World Health Organization’s call for therapeutic vaccines to complement antibiotic regimens and reduce tuberculosis (TB) treatment duration, we developed an intranasal DNA vaccine fusing the Mtb stringent response gene relMtb with the gene encoding the dendritic cell-targeting chemokine Mip3a/CCL20. Administered alongside the first-line regimen, this vaccine accelerated stable cure in immunocompetent murine TB models, reducing lung inflammation and eliciting robust and sustained RelMtb-stimulated T-cell responses systemically and locally. The Mip3a/relMtb vaccine enhanced dendritic cell recruitment, activation, and spatial coordination with T cells, suggesting improved innate-adaptive immune synergy. Notably, it augmented the efficacy of a novel drug-resistant TB regimen as well. Critically, the vaccine induced analogous antigen-stimulated T-cell immunity in nonhuman primates, the gold standard for preclinical TB vaccine evaluation, with responses detected in blood and bronchoalveolar lavage mirroring those observed in the murine models. These findings underscore the potential of this strategy to advance therapeutic TB vaccine development targeting Mtb persisters while providing a framework to define correlates of vaccine-mediated protection.

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