Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis

Rocky Lai; Diana N. Gong; Travis Williams; Abiola F. Ogunsola; Kelly Cavallo; Cecilia S. Lindestam Arlehamn; Sarah Acolatse; Gillian Beamer; Martin T. Ferris; Christopher M. Sassetti; Douglas A. Lauffenburger; Samuel M. Behar

doi:10.1172/JCI167762

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Williams, T. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Cavallo, K. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Lindestam Arlehamn, C. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Beamer, G. in: JCI | PubMed | Google Scholar

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Ferris, M. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Sassetti, C. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Lauffenburger, D. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Wocester, United States of America

²Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America

³Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States of America

⁴Department of Microbiology and Physiological Systems, University of Massachusetts Medical Center, Worcester, United States of America

⁵Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, San Diego, United States of America

⁶Texas Biomedical Research Institute, San Antonio, United States of America

⁷Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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

J Clin Invest. https://doi.org/10.1172/JCI167762.
Copyright © 2023, Lai 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 May 18, 2023 - Version history

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects BCG-induced immunity against Mycobacterium tuberculosis, we studied 24 unique Collaborative Cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG, and then challenged with aerosolized M. tuberculosis. As BCG protects only half of the CC strains tested, we conclude that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to TB. T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after Mtb infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

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Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis

Rocky Lai,¹ Diana N. Gong,² Travis Williams,¹ Abiola F. Ogunsola,¹ Kelly Cavallo,⁴ Cecilia S. Lindestam Arlehamn,⁵ Sarah Acolatse,² Gillian Beamer,⁶ Martin T. Ferris,⁷ Christopher M. Sassetti,¹ Douglas A. Lauffenburger,² and Samuel M. Behar⁴

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Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis

Rocky Lai,1 Diana N. Gong,2 Travis Williams,1 Abiola F. Ogunsola,1 Kelly Cavallo,4 Cecilia S. Lindestam Arlehamn,5 Sarah Acolatse,2 Gillian Beamer,6 Martin T. Ferris,7 Christopher M. Sassetti,1 Douglas A. Lauffenburger,2 and Samuel M. Behar4

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Rocky Lai,¹ Diana N. Gong,² Travis Williams,¹ Abiola F. Ogunsola,¹ Kelly Cavallo,⁴ Cecilia S. Lindestam Arlehamn,⁵ Sarah Acolatse,² Gillian Beamer,⁶ Martin T. Ferris,⁷ Christopher M. Sassetti,¹ Douglas A. Lauffenburger,² and Samuel M. Behar⁴