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Opposite effects of Vaccinia and modified Vaccinia Ankara on trained immunity

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European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

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.

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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

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Acknowledgements

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

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).

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Authors and Affiliations

  1. Department of Internal Medicine, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525GA, Nijmegen, The Netherlands

    Bastiaan A. Blok, Reinout van Crevel & Mihai G. Netea

  2. Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark

    Bastiaan A. Blok, Kristoffer J. Jensen, Peter Aaby & Christine S. Benn

  3. Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Odense, Denmark

    Bastiaan A. Blok & Christine S. Benn

  4. Department of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark

    Kristoffer J. Jensen

  5. Virus Research and Development Laboratory, Statens Serum Institut, Copenhagen, Denmark

    Anders Fomsgaard

  6. Infectious Disease Research Unit, Clinical Institute, University of Southern Denmark, Odense, Denmark

    Anders Fomsgaard

Authors
  1. Bastiaan A. Blok
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  2. Kristoffer J. Jensen
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  7. Mihai G. Netea
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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.

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Correspondence to Mihai G. Netea.

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Christine S. Benn and Mihai G. Netea shared last authors

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Blok, B.A., Jensen, K.J., Aaby, P. et al. Opposite effects of Vaccinia and modified Vaccinia Ankara on trained immunity. Eur J Clin Microbiol Infect Dis 38, 449–456 (2019). https://doi.org/10.1007/s10096-018-03449-z

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  • DOI: https://doi.org/10.1007/s10096-018-03449-z

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