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


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.


Trained immunity Vaccinia Modified Vaccinia Ankara Heterologous effects 



Bacillus Calmette-Guérin


Lactate dehydrogenase






Modified Vaccinia Ankara


Oral polio vaccine


Peripheral blood mononuclear cell


Phosphate-buffered saline


Vaccinia virus



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.


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.


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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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