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.
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We thank C. Kahl, S. Hagen, J. Bae, I. Pelletier, Y. Guo, E.M. Borst, L.S. Uebelhoer and J. Womack for technical assistance, C. Scanga and J. Flynn for guidance on the RM model of TB (including sharing of NHP protocols and provision of Mtb challenge stocks), P. Barry (University of California, Davis) and T. Shenk (Princeton University) for the 68-1 and 68-1.2 BACs, respectively, J. Flynn (University of Pittsburgh) for Mtb Erdman, W. Hanekom, L. Stuart and D. Barber for helpful discussions, D. Casimiro for manuscript review, J. Strussenberg for management of the BSL3 facility, L. Boshears for administrative assistance and A. Townsend for figure preparation. This work was supported by AERAS, the Bill and Melinda Gates Foundation (grant no. OPP1087783; A.A. and D.E.Z.) and the US National Institutes of Health (NIH; grant no. U19 AI106761 (A.A.), P51 OD011092 (ONPRC); U42 OD010426 (ONPRC)).
OHSU, L.J.P., S.G.H., D.M. and K.F. have a significant financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology. The potential individual and institutional conflicts of interest have been reviewed and managed by OHSU. T.G.E. has served as a clinical consultant to Vir Biotechnology and also has a significant financial interest in that company.
Supplementary Figures 1–10 (PDF 1296 kb)
1482 Genes comparably regulated in TB patients and unvaccinated RM from Study 1 and Study 2 after Mtb challenge (XLSX 254 kb)
Pathway enrichments for genes comparably regulated in TB patients and unvaccinated RM from Study 1 and Study 2 after Mtb challenge (XLSX 15 kb)
214 genes with post-challenge expression patterns in vaccinated and unvaccinated RM that are highly significantly associated with scaled combined outcome measure (XLSX 56 kb)
Pathway enrichments for genes with post-challenge expression patterns that are highly significantly associated with scaled combined outcome measure (XLSX 11 kb)
258 genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure (XLSX 77 kb)
Lists of genes exhibiting plausible associations with specific leukocyte populations for RhCMV/TB-vaccinated RM on the day of challenge (XLSX 262 kb)
Cell population enrichments for genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure (XLSX 10 kb)
Pathway enrichments for genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure (XLSX 9 kb)
Wilcoxon rank sum test statistics comparing expression levels of protection signature genes in the RhCMV/TB and BCG+RhCMV/TB groups from Study 1 (XLSX 12 kb)
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Hansen, S., Zak, D., Xu, G. et al. Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nat Med 24, 130–143 (2018). https://doi.org/10.1038/nm.4473
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