Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine

Scott G. Hansen, Daniel E. Zak, Guangwu Xu, Julia C. Ford, Emily E. Marshall, Daniel Malouli, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Emily Ainslie, Kurt T. Randall, Andrea N. Selseth, Parker Rundstrom, Lauren Herlache, Matthew S. Lewis, Haesun Park, Shannon L. Planer, John M. Turner, Miranda Fischer, Christina ArmstrongRobert C. Zweig, Joseph Valvo, Jackie M. Braun, Smitha Shankar, Lenette Lu, Andrew W. Sylwester, Alfred W. Legasse, Martin Messerle, Michael A. Jarvis, Lynn M. Amon, Alan Aderem, Galit Alter, Dominick J. Laddy, Michele Stone, Aurelio Bonavia, Thomas G. Evans, Michael K. Axthelm, Klaus Früh, Paul T. Edlefsen, Louis J. Picker

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Despite widespread use of the bacille Calmette-Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB) - which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4 + and CD8 + memory T cell responses - can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at ∼1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.

Original languageEnglish (US)
Pages (from-to)130-143
Number of pages14
JournalNature medicine
Volume24
Issue number2
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hansen, S. G., Zak, D. E., Xu, G., Ford, J. C., Marshall, E. E., Malouli, D., Gilbride, R. M., Hughes, C. M., Ventura, A. B., Ainslie, E., Randall, K. T., Selseth, A. N., Rundstrom, P., Herlache, L., Lewis, M. S., Park, H., Planer, S. L., Turner, J. M., Fischer, M., ... Picker, L. J. (2018). Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nature medicine, 24(2), 130-143. https://doi.org/10.1038/nm.4473