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.