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Opposite effects of Vaccinia and modified Vaccinia Ankara on trained immunity

  • Bastiaan A. Blok
  • Kristoffer J. Jensen
  • Peter Aaby
  • Anders Fomsgaard
  • Reinout van Crevel
  • Christine S. Benn
  • Mihai G. NeteaEmail author
Original Article

Abstract

Vaccines such as Vaccinia or BCG have non-specific effects conferring protection against other diseases than their target infection, which are likely partly mediated through induction of innate immune memory (trained immunity). MVA85A, a recombinant strain of modified Vaccinia Ankara (MVA), has been suggested as an alternative vaccine against tuberculosis, but its capacity to induce positive or negative non-specific immune effects has not been studied. This study assesses whether Vaccinia and MVA are able to induce trained innate immunity in monocytes. Human primary monocytes were primed in an in vitro model with Vaccinia or MVA for 1 day, after which the stimulus was washed off and the cells were rechallenged with unrelated microbial ligands after 1 week. Heterologous cytokine responses were assessed and the capacity of MVA to induce epigenetic changes at the level of cytokine genes was investigated using chromatin immunoprecipitation and pharmacological inhibitors. Monocytes trained with Vaccinia showed significantly increased IL-6 and TNF-α production to stimulation with non-related stimuli, compared to non-trained monocytes. In contrast, monocytes primed with MVA showed significant decreased heterologous IL-6 and TNF-α responses, an effect which was abrogated by the addition of a histone methyltransferase inhibitor. No effects on H3K4me3 were observed after priming with MVA. It can be thus concluded that Vaccinia induces trained immunity in vitro, whereas MVA induces innate immune tolerance. This suggests the induction of trained immunity as an immunological mechanism involved in the non-specific effects of Vaccinia vaccination and points to a possible explanation for the lack of effect of MVA85A against tuberculosis.

Keywords

Trained immunity Vaccinia Modified Vaccinia Ankara Heterologous effects 

Abbreviations

BCG

Bacillus Calmette-Guérin

LDH

Lactate dehydrogenase

LPS

Lipopolysaccharide

MTA

5′-Deoxy-5′methylthioadenosine

MVA

Modified Vaccinia Ankara

OPV

Oral polio vaccine

PBMC

Peripheral blood mononuclear cell

PBS

Phosphate-buffered saline

VACV

Vaccinia virus

Notes

Acknowledgements

We thank Birgit Knudsen for the technical assistance with the VACV assays.

Author contributions

CSB, MGN, RvC, PA, and BAB conceived the study. BAB and KJJ performed the in vitro experiments and analyzed the data. MGN and AF supervised the in vitro experiments. BAB wrote the first draft of the article. All authors contributed to and approved the final version of the manuscript.

Funding

The study was supported by the Danish National Research Foundation through a grant to CVIVA (DNRF108). MGN was supported by the ERC Consolidator Grant (#310372) and a Spinoza Grant of the Netherlands Organization for Scientific Research (NWO).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Flanagan KL, van Crevel R, Curtis N, Shann F, Levy O (2013) Heterologous (‘non-specific’) and sex-differential effects of vaccines: epidemiology, clinical trials and emerging immunological mechanisms. Clin Infect Dis 57(2):283–289CrossRefGoogle Scholar
  2. 2.
    Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM et al (2011) Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 204(2):245–252 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21673035. [cited 2012 Nov 21]CrossRefGoogle Scholar
  3. 3.
    Martins CL, Benn CS, Andersen A, Balé C, Schaltz-Buchholzer F, Do VA et al (2014) A randomized trial of a standard dose of Edmonston-Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions. J Infect Dis 209(11):1731–1738CrossRefGoogle Scholar
  4. 4.
    Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG et al (2016) Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol 16(6):392–400 Available from: http://www.nature.com/nri/journal/vaop/ncurrent/full/nri.2016.43.html?WT.mc_id=FBK_NatureReviews CrossRefGoogle Scholar
  5. 5.
    Aaby P, Martins CL, Garly M-L, Bale C, Andersen A, Rodrigues A et al (2010) Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 341(nov30 2):c6495–c6495 Available from: http://www.bmj.com/cgi/doi/10.1136/bmj.c6495. [cited 2012 Nov 24]CrossRefGoogle Scholar
  6. 6.
    Lund N, Andersen A, Hansen ASK, Jepsen FS, Barbosa A, Biering-Sørensen S et al (2015) The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin Infect Dis 61(10):1504–1511CrossRefGoogle Scholar
  7. 7.
    Jensen ML, Dave S, Schim van der Loeff M, da Costa C, Vincent T, Leligdowicz A et al (2006) Vaccinia scars associated with improved survival among adults in rural Guinea-Bissau. PLoS One 1(1):e101 Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1762358&tool=pmcentrez&rendertype=abstract. [cited 2014 Jun 16]CrossRefGoogle Scholar
  8. 8.
    Aaby P, Gustafson P, Roth A, Rodrigues A, Fernandes M, Sodemann M et al (2006) Vaccinia scars associated with better survival for adults. An observational study from Guinea-Bissau. Vaccine 24(29–30):5718–5725 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16720061. [cited 2014 Jun 16]CrossRefGoogle Scholar
  9. 9.
    Rieckmann A, Villumsen M, Sørup S, Haugaard LK, Ravn H, Roth A et al (2016) Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010. Int J Epidemiol 94:1–11Google Scholar
  10. 10.
    Lankes HA, Fought AJ, Evens AM, Weisenburger DD, Chiu BC-H (2009) Vaccination history and risk of non-Hodgkin lymphoma: a population-based, case-control study. Cancer Causes Control 20(5):517–523 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19011978. [cited 2016 Jun 24]CrossRefGoogle Scholar
  11. 11.
    Pfahlberg A, Kölmel KF, Grange JM, Mastrangelo G, Krone B, Botev IN et al (2002) Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study. J Invest Dermatol 119(3):570–575 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12230497. [cited 2016 Aug 19]CrossRefGoogle Scholar
  12. 12.
    Kleinnijenhuis J, Quintin J, Preijers F, AB JL, Ifrim DC, Saeed S et al (2012) Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 109(43):17537–17542 Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3491454&tool=pmcentrez&rendertype=abstract. [cited 2012 Nov 21]CrossRefGoogle Scholar
  13. 13.
    Blok BA, Arts RJW, van Crevel R, Benn CS, Netea MG (2015) Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol 98(3):347–356 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26150551 CrossRefGoogle Scholar
  14. 14.
    McCurdy LH, Larkin BD, Martin JE, Graham BS (2004) Modified Vaccinia Ankara: potential as an alternative smallpox vaccine. Clin Infect Dis 38(12):1749–1753 Available from: http://cid.oxfordjournals.org/lookup/doi/10.1086/421266. [cited 2016 Jun 24]CrossRefGoogle Scholar
  15. 15.
    Mayr A (2003) Smallpox vaccination and bioterrorism with pox viruses. Comp Immunol Microbiol Infect Dis 26(5):423–430CrossRefGoogle Scholar
  16. 16.
    Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S et al (2013) Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381(9871):1021–1028.  https://doi.org/10.1016/S0140-6736(13)60177-4 [cited 2014 May 27]CrossRefGoogle Scholar
  17. 17.
    Ndiaye BP, Thienemann F, Ota M, Landry BS, Camara M, Dièye S et al (2015) Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 3(3):190–200 Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260015000375. [cited 2016 Jun 24]CrossRefGoogle Scholar
  18. 18.
    Repnik U, Knezevic M, Jeras M (2003) Simple and cost-effective isolation of monocytes from buffy coats. J Immunol Methods 278(1–2):283–292CrossRefGoogle Scholar
  19. 19.
    Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C et al (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12(2):223–232CrossRefGoogle Scholar
  20. 20.
    Yang H, Cain CA, Woan MC, Tompkins WA (1982) Evaluation of hamster natural cytotoxic cells and vaccinia-induced cytotoxic cells for Thy-1.2 homologue by using a mouse monoclonal alpha-Thy-1.2 antibody. J Immunol (Baltimore, Md 1950) 129(5):2239–2243Google Scholar
  21. 21.
    Carpenter EA, Ruby J, Ramshaw IA (1994) IFN-y, TNF, and IL-6 production by vaccinia virus immune spleen cells. An In Vitro Study J Immunol 152:2652–2659Google Scholar
  22. 22.
    Schleupner CJ, Glasgow LA (1978) Peritoneal macrophage activation indicated by enhanced chemiluminescence. Infect Immun 21(3):886–895Google Scholar
  23. 23.
    Deng L, Dai P, Ding W, Granstein RD, Shuman S (2006) Vaccinia virus infection attenuates innate immune responses and antigen presentation by epidermal dendritic cells. J Virol 80(20):9977–9987CrossRefGoogle Scholar
  24. 24.
    Nohmi K, Tokuhara D, Tachibana D, Saito M, Sakashita Y, Nakano A et al (2015) Zymosan induces immune responses comparable with those of adults in monocytes, dendritic cells, and monocyte-derived dendritic cells from cord blood. J Pediatr 167(1):155–162.e2.  https://doi.org/10.1016/j.jpeds.2015.03.035 CrossRefGoogle Scholar
  25. 25.
    Bekkering S, Blok BA, Joosten LA, Riksen NP, van Crevel R, Netea MG (2016) In vitro experimental model of trained innate immunity in human primary monocytes. Clin Vaccine Immunol. 23(12):926–933Google Scholar
  26. 26.
    Scherer CA, Magness CL, Steiger KV, Poitinger ND, Caputo CM, Miner DG et al (2007) Distinct gene expression profiles in peripheral blood mononuclear cells from patients infected with vaccinia virus, yellow fever 17D virus, or upper respiratory infections. Vaccine 25(35):6458–6473CrossRefGoogle Scholar
  27. 27.
    Price PJR, Torres-Domínguez LE, Brandmüller C, Sutter G, Lehmann MH (2013) Modified vaccinia virus Ankara: innate immune activation and induction of cellular signalling. Vaccine 31(39):4231–4234.  https://doi.org/10.1016/j.vaccine.2013.03.017 [cited 2014 Jun 16]CrossRefGoogle Scholar
  28. 28.
    Yáñez A, Hassanzadeh-Kiabi N, Ng MY, Megías J, Subramanian A, Liu GY et al (2013) Detection of a TLR2 agonist by hematopoietic stem and progenitor cells impacts the function of the macrophages they produce. Eur J Immunol 43(8):2114–2125CrossRefGoogle Scholar
  29. 29.
    Verrall AJ, Netea MG, Alisjahbana B, Hill PC, van Crevel R (2014) Early clearance of Mycobacterium tuberculosis: a new frontier in prevention. Immunology 141(4):506–513 Available from: http://doi.wiley.com/10.1111/imm.12223. [cited 2016 Jun 27]CrossRefGoogle Scholar
  30. 30.
    Netea MG, van Crevel R (2014) BCG-induced protection: effects on innate immune memory. Semin Immunol 26(6):512–517 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25444548. [cited 2016 Jun 24]CrossRefGoogle Scholar
  31. 31.
    Oie KL, Pickup DJ (2001) Cowpox virus and other members of the orthopoxvirus genus interfere with the regulation of NF-κB activation. Virology 288(1):175–187 Available from: http://linkinghub.elsevier.com/retrieve/pii/S0042682201910906. [cited 2016 Jun 17]CrossRefGoogle Scholar
  32. 32.
    Bohuslav J, Kravchenko VV, Parry GC, Erlich JH, Gerondakis S, Mackman N et al (1998) Regulation of an essential innate immune response by the p50 subunit of NF-kappaB. J Clin Invest 102(9):1645–1652 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9802878. [cited 2016 Jun 17]CrossRefGoogle Scholar
  33. 33.
    Kasteenbauer S, Ziegler-Heitbrock HW (1999) NF-kappaB1 (p50) is upregulated in lipopolysaccharide tolerance and can block tumor necrosis factor gene expression. Infect Immun 67(4):1553–1559 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10084986. [cited 2016 Jun 17]Google Scholar
  34. 34.
    Greten FR, Arkan MC, Bollrath J, Hsu L-C, Goode J, Miething C et al (2007) NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta. Cell 130(5):918–931 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17803913. [cited 2016 Jun 17]CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Bastiaan A. Blok
    • 1
    • 2
    • 3
  • Kristoffer J. Jensen
    • 2
    • 4
  • Peter Aaby
    • 2
  • Anders Fomsgaard
    • 5
    • 6
  • Reinout van Crevel
    • 1
  • Christine S. Benn
    • 2
    • 3
  • Mihai G. Netea
    • 1
    Email author
  1. 1.Department of Internal MedicineRadboud University Medical CentreNijmegenThe Netherlands
  2. 2.Research Center for Vitamins and Vaccines, Bandim Health ProjectStatens Serum InstitutCopenhagenDenmark
  3. 3.Odense Patient Data Explorative NetworkUniversity of Southern Denmark/Odense University HospitalOdenseDenmark
  4. 4.Department of Immunology and Vaccinology, National Veterinary InstituteTechnical University of DenmarkFrederiksbergDenmark
  5. 5.Virus Research and Development LaboratoryStatens Serum InstitutCopenhagenDenmark
  6. 6.Infectious Disease Research Unit, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark

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