Opposite effects of Vaccinia and modified Vaccinia Ankara on trained immunity
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.
KeywordsTrained immunity Vaccinia Modified Vaccinia Ankara Heterologous effects
Modified Vaccinia Ankara
Oral polio vaccine
Peripheral blood mononuclear cell
We thank Birgit Knudsen for the technical assistance with the VACV assays.
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.
- 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
- 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.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
- 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.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.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
- 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.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
- 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
- 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.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
- 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.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.Schleupner CJ, Glasgow LA (1978) Peritoneal macrophage activation indicated by enhanced chemiluminescence. Infect Immun 21(3):886–895Google Scholar
- 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.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.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
- 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.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
- 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