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

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.

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Figure 1: Immunogenicity of RhCMV/TB and i.d. administered BCG vaccines (Study 1).
Figure 2: Outcome of Mtb challenge (Study 1).
Figure 3: Immunogenicity of RhCMV/TB vaccines (Study 2).
Figure 4: Outcome of Mtb challenge (Study 2 and overall).
Figure 5: Transcriptional response to Mtb challenge is reduced in protected RMs.
Figure 6: Pre-challenge transcriptional profiles correlate with post-challenge outcome in RhCMV/TB-vaccinated RMs.

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References

  1. 1

    Cambier, C.J., Falkow, S. & Ramakrishnan, L. Host evasion and exploitation schemes of Mycobacterium tuberculosis. Cell 159, 1497–1509 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Orme, I.M., Robinson, R.T. & Cooper, A.M. The balance between protective and pathogenic immune responses in the TB-infected lung. Nat. Immunol. 16, 57–63 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Shaler, C.R., Horvath, C.N., Jeyanathan, M. & Xing, Z. Within the enemy's camp: contribution of the granuloma to the dissemination, persistence and transmission of Mycobacterium tuberculosis. Front. Immunol. 4, 30 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Pai, M. et al. Tuberculosis. Nat. Rev. Dis. Primers 2, 16076 (2016).

    Article  PubMed  Google Scholar 

  5. 5

    Comas, I. et al. Human T cell epitopes of Mycobacteriumtuberculosis are evolutionarily hyperconserved. Nat. Genet. 42, 498–503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Comas, I. et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacteriumtuberculosis with modern humans. Nat. Genet. 45, 1176–1182 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Dorhoi, A. & Kaufmann, S.H. Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis. Semin. Immunopathol. 38, 153–166 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Hawn, T.R. et al. Tuberculosis vaccines and prevention of infection. Microbiol. Mol. Biol. Rev. 78, 650–671 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Kaufmann, S.H. Future vaccination strategies against tuberculosis: thinking outside the box. Immunity 33, 567–577 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Griffiths, K.L. et al. Targeting dendritic cells to accelerate T cell activation overcomes a bottleneck in tuberculosis vaccine efficacy. Nat. Commun. 7, 13894 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Barclay, W.R. et al. Protection of monkeys against airborne tuberculosis by aerosol vaccination with bacillus Calmette–Guerin. Am. Rev. Respir. Dis. 107, 351–358 (1973).

    CAS  PubMed  Google Scholar 

  12. 12

    Kaushal, D. et al. Mucosal vaccination with attenuated Mycobacteriumtuberculosis induces strong central memory responses and protects against tuberculosis. Nat. Commun. 6, 8533 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Verreck, F.A.W. et al. Variable BCG efficacy in rhesus populations: pulmonary BCG provides protection where standard intradermal vaccination fails. Tuberculosis (Edinb.) 104, 46–57 (2017).

    Article  CAS  Google Scholar 

  14. 14

    Jeyanathan, M. et al. AdHu5Ag85A respiratory mucosal boost immunization enhances protection against pulmonary tuberculosis in BCG-primed nonhuman primates. PLoS One 10, e0135009 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Darrah, P.A. et al. Aerosol vaccination with AERAS-402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high-dose Mycobacteriumtuberculosis challenge. J. Immunol. 193, 1799–1811 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Verreck, F.A. et al. MVA.85A boosting of BCG and an attenuated, phoP-deficient M.tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques. PLoS One 4, e5264 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Tameris, M.D. et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomized, placebo-controlled phase 2b trial. Lancet 381, 1021–1028 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Tameris, M. et al. The candidate TB vaccine, MVA85A, induces highly durable TH1 responses. PLoS One 9, e87340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Jarvis, M.A., Hansen, S.G., Nelson, J.A., Picker, L.J. & Früh, K. in Cytomegaloviruses: From Molecular Pathogenesis to Intervention Vol. 2 (ed. Reddehase, M.J.) 450–462 (Caister Academic Press, 2013).

  20. 20

    Cicin-Sain, L. et al. Cytomegalovirus-specific T cell immunity is maintained in immunosenescent rhesus macaques. J. Immunol. 187, 1722–1732 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Sylwester, A.W. et al. Broadly targeted human-cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Hansen, S.G. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 15, 293–299 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Hansen, S.G. et al. Profound early control of highly pathogenic SIV by an effector memory T cell vaccine. Nature 473, 523–527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Hansen, S.G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Hansen, S.G. et al. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E. Science 351, 714–720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Scanga, C.A. & Flynn, J.L. Modeling tuberculosis in nonhuman primates. Cold Spring Harb. Perspect. Med. 4, a018564 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Sharpe, S. et al. Ultra-low-dose aerosol challenge with Mycobacteriumtuberculosis leads to divergent outcomes in rhesus and cynomolgus macaques. Tuberculosis 96, 1–12 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Gormus, B.J., Blanchard, J.L., Alvarez, X.H. & Didier, P.J. Evidence for a rhesus monkey model of asymptomatic tuberculosis. J. Med. Primatol. 33, 134–145 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Sibley, L. et al. Route of delivery to the airway influences the distribution of pulmonary disease but not the outcome of Mycobacteriumtuberculosis infection in rhesus macaques. Tuberculosis 96, 141–149 (2016).

    Article  PubMed  Google Scholar 

  30. 30

    Mothé, B.R. et al. The TB-specific CD4+ T cell immune repertoire in both cynomolgus and rhesus macaques largely overlap with humans. Tuberculosis (Edinb.) 95, 722–735 (2015).

    Article  CAS  Google Scholar 

  31. 31

    Langermans, J.A. et al. Divergent effect of bacillus Calmette–Guérin (BCG) vaccination on Mycobacteriumtuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc. Natl. Acad. Sci. USA 98, 11497–11502 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Hsu, T. et al. The primary mechanism of attenuation of bacillus Calmette–Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc. Natl. Acad. Sci. USA 100, 12420–12425 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Hansen, S.G. et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science 340, 1237874 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Zak, D.E. et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 387, 2312–2322 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Cliff, J.M., Kaufmann, S.H., McShane, H., van Helden, P. & O'Garra, A. The human immune response to tuberculosis and its treatment: a view from the blood. Immunol. Rev. 264, 88–102 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Berry, M.P. et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973–977 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Kaforou, M. et al. Detection of tuberculosis in HIV-infected and uninfected African adults using whole-blood RNA expression signatures: a case–control study. PLoS Med. 10, e1001538 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    De Libero, G., Singhal, A., Lepore, M. & Mori, L. Nonclassical T cells and their antigens in tuberculosis. Cold Spring Harb. Perspect. Med. 4, a018473 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Rayner, E.L. et al. Early lesions following aerosol infection of rhesus macaques (Macacamulatta) with Mycobacteriumtuberculosis strain H37RV. J. Comp. Pathol. 149, 475–485 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Steinert, E.M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Thome, J.J. & Farber, D.L. Emerging concepts in tissue-resident T cells: lessons from humans. Trends Immunol. 36, 428–435 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Dallenga, T. & Schaible, U.E. Neutrophils in tuberculosis—first line of defense or booster of disease and targets for host-directed therapy? Pathog. Dis. 74, ftw012 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Mishra, B.B. et al. Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat. Microbiol. 2, 17072 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Ong, C.W. et al. Neutrophil-derived MMP-8 drives AMPK-dependent matrix destruction in human pulmonary tuberculosis. PLoS Pathog. 11, e1004917 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Mattila, J.T., Maiello, P., Sun, T., Via, L.E. & Flynn, J.L. Granzyme B–expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis–infected cynomolgus macaques. Cell. Microbiol. 17, 1085–1097 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Lyadova, I.V. Neutrophils in tuberculosis: heterogeneity shapes the way? Mediators Inflamm. 2017, 8619307 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Martineau, A.R. et al. Neutrophil-mediated innate immune resistance to mycobacteria. J. Clin. Invest. 117, 1988–1994 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Warren, E., Teskey, G. & Venketaraman, V. Effector mechanisms of neutrophils within the innate immune system in response to Mycobacteriumtuberculosis infection. J. Clin. Med. 6, E16 (2017).

    Article  CAS  Google Scholar 

  49. 49

    Seiler, P. et al. Early granuloma formation after aerosol Mycobacteriumtuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines. Eur. J. Immunol. 33, 2676–2686 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Jeyanathan, M. et al. Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes, independent of T cell immunity. Mucosal Immunol. 6, 612–625 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Beverley, P.C. et al. A novel murine cytomegalovirus vaccine vector protects against Mycobacteriumtuberculosis. J. Immunol. 193, 2306–2316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Knight, G.M. et al. Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries. Proc. Natl. Acad. Sci. USA 111, 15520–15525 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Obermoser, G. et al. Systems-scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines. Immunity 38, 831–844 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Fabregat, A. et al. The Reactome pathway Knowledgebase. Nucleic Acids Res. 44 (D1), D481–D487 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Clemmensen, S.N. et al. Olfactomedin 4 defines a subset of human neutrophils. J. Leukoc. Biol. 91, 495–500 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Ambrose, L.R., Morel, A.S. & Warrens, A.N. Neutrophils express CD52 and exhibit complement-mediated lysis in the presence of alemtuzumab. Blood 114, 3052–3055 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    National Research Council. Guide for the Care and Use of Laboratory Animals 8th edn. (The National Academies Press, 2011).

  58. 58

    Capuano, S.V. III et al. Experimental Mycobacteriumtuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect. Immun. 71, 5831–5844 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Rumboldt, Z., Huda, W. & All, J.W. Review of portable CT with assessment of a dedicated head CT scanner. AJNR Am. J. Neuroradiol. 30, 1630–1636 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Rubin, G.D. Lung nodule and cancer detection in computed tomography screening. J. Thorac. Imaging 30, 130–138 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Luciw, P.A. et al. Stereological analysis of bacterial load and lung lesions in nonhuman primates (rhesus macaques) experimentally infected with Mycobacterium tuberculosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 301, L731–L738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Zvi, A., Ariel, N., Fulkerson, J., Sadoff, J.C. & Shafferman, A. Whole-genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses. BMC Med. Genomics 1, 18 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Zeileis, A. Object-oriented computation of sandwich estimators. J. Stat. Softw. 16, 1–16 (2006).

    Article  Google Scholar 

  64. 64

    Zeileis, A. Econometric computing with HC and HAC covariance matrix estimators. J. Stat. Softw. 11, 1–17 (2004).

    Article  Google Scholar 

  65. 65

    R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2015).

  66. 66

    Holm, S. A simple sequentially rejective multiple-test procedure. Scand. J. Stat. 6, 65–70 (1979).

    Google Scholar 

  67. 67

    Agresti, A. & Coull, B.A. Approximate is better than “exact” for interval estimation of binomial proportions. Am. Stat. 52, 119–126 (1998).

    Google Scholar 

  68. 68

    Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Zimin, A.V. et al. A new rhesus macaque assembly and annotation for next-generation sequencing analyses. Biol. Direct 9, 20 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Anders, S., Pyl, P.T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    Article  CAS  Google Scholar 

  71. 71

    Robinson, M.D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11, R25 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Robinson, M.D., McCarthy, D.J. & Smyth, G.K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Ritchie, M.E. et al. limma powers differential expression analyses for RNA sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Zeileis, A. & Hothorn, T. Diagnostic checking in regression relationships. R News 2, 7–10 (2002).

    Google Scholar 

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Acknowledgements

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)).

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Contributions

S.G.H. planned animal experiments and supervised all immunological and virological studies and data analysis; G.X. and J.C.F. processed monkey samples and tissues and performed immunological and bacteriological analyses, assisted by R.M.G., C.M.H., A.B.V., E.A., K.T.R., A.N.S., P.R., L.H., H.P. and M.S.L.; A.W.S. performed assay development and supervised flow cytometry; K.F., D.M., E.E.M., M.M. and M.A.J. designed, constructed and/or validated the RhCMV/TB vectors used in the study; A.W.L. supervised all animal procedures, including CT scanning, assisted by S.L.P., J.M.T., M.F., C.A., and R.C.Z.; M.K.A. planned and provided overall supervision of monkey protocols, interpreted CT scans, performed all necropsies and interpreted both gross pathology and histopathology; D.J.L. designed experimental approaches and reviewed data; M.S., A.B. and T.G.E. contributed to data interpretation and/or study design; L.L. performed the antibody assays under the supervision of G.A.; J.V., J.M.B. and S.S. processed samples and data for transcriptomic analysis; D.E.Z. planned, executed and interpreted the transcriptomics analysis, assisted by L.M.A., S.S., and A.A.; P.T.E. planned and performed all statistical analyses; L.J.P. conceived the RhCMV vector strategy, planned and supervised all experiments and data analysis, and wrote the manuscript, assisted by S.G.H., P.T.E., D.E.Z. and M.K.A.

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Correspondence to Louis J Picker.

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Competing interests

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.

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Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 1296 kb)

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Supplementary Table 1

1482 Genes comparably regulated in TB patients and unvaccinated RM from Study 1 and Study 2 after Mtb challenge (XLSX 254 kb)

Supplementary Table 2

Pathway enrichments for genes comparably regulated in TB patients and unvaccinated RM from Study 1 and Study 2 after Mtb challenge (XLSX 15 kb)

Supplementary Table 3

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)

Supplementary Table 4

Pathway enrichments for genes with post-challenge expression patterns that are highly significantly associated with scaled combined outcome measure (XLSX 11 kb)

Supplementary Table 5

258 genes with pre-challenge expression patterns in RhCMV-vaccinated RM that are significantly associated with scaled combined outcome measure (XLSX 77 kb)

Supplementary Table 6

Lists of genes exhibiting plausible associations with specific leukocyte populations for RhCMV/TB-vaccinated RM on the day of challenge (XLSX 262 kb)

Supplementary Table 7

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)

Supplementary Table 8

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)

Supplementary Table 9

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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