Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes. (c) 2021 Elsevier Ltd. All rights reserved.

Automated summary

In addition to targeted immunity, vaccines can have nonspecific effects on mortality and morbidity. Live vaccines like BCG have been associated with reduced infant mortality, while some inactivated vaccines like DTPw have controversially been linked to increased mortality, particularly in high-mortality settings. The nonspecific effects of BCG are thought to be attributed to the induction of trained immunity, whereas the trained immunity induced by non-live vaccines like DTPw is poorly understood. A recent study in mice showed that DTPw vaccination induced a unique program of trained immunity compared to BCG vaccination, altering immune cell responses and chromatin accessibility. The order of administration of BCG and DTPw vaccines also influenced subsequent trained immune responses. Further studies are needed to investigate the potential consequences of DTPw-induced trained immunity in different contexts and explore if other non-live vaccines induce similar changes.