BCG and DTPw vaccination induce altered programmes of “trained” innate immunity in mice

Vaccines prevent >2 million deaths annually by eliciting antigen-specific adaptive immunity, however increasing evidence suggests that vaccines also elicit nonspecific effects on morbidity and mortality unrelated to the targeted disease. Live vaccinations (e.g. BCG) are generally associated with beneficial nonspecific effects, while some inactivated vaccines (e.g. DTPw) have controversially been associated with increased all-cause mortality. We hypothesised that BCG and DTPw induce altered programmes of ‘trained innate immunity’ i.e. epigenetic reprogramming which alters innate responses to subsequent stimuli. To investigate this, we immunized 4-week-old mice with BCG or DTPw alone, or with both vaccines in two different schedules (BCG followed two weeks later by DTPw or DTPw followed by BCG). At 12 weeks post-immunisation, we assessed cytokine responses in monocytes and DCs by ICS, following stimulation with bacterial, fungal or viral antigens. BCG immunisation led to significantly increased TNF production by monocytes following stimulation with heat-killed Candida albicans (HKCA), as has been previously reported. In contrast, DTPw immunisation induced significantly increased IL6 production by DCs stimulated with either HKCA or LPS. Interestingly, immunisation with BCG prior to DTPw supressed IL6 production compared to DTPw alone or mock vaccination. Our findings indicate that immunisation of mice with BCG or DTPw induces altered programmes of trained innate immunity altering cytokine responses to subsequent microbial encounters. Furthermore, our data demonstrate that previously administered vaccines may modify the programme of trained innate immunity induced by other subsequently administered vaccines. Our ongoing studies are now investigating the transcriptomic and epigenetic basis for the observed phenotypes.