| Institution: | 1. Precision Medicine Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia;2. University of Applied Sciences Leiden, Zernikedreef 11, 2333 CK Leiden, the Netherlands;3. Department of Peadiatrics, University of British Columbia, 2775 Laurel Street, 10th Floor, Room 10117, Vancouver, BC V5Z 1M9, Canada;4. Department of Experimental Medicine, University of British Columbia, 2775 Laurel Street, 10th Floor, Room 10117, Vancouver, BC V5Z 1M9, Canada;5. Telethon Kids Institute, 100 Roberts Road, Subiaco, Western Australia 6008, Australia;6. Vaccinology and Immunology Research Trials Unit, Women''s and Children''s Hospital, North Adelaide, SA 5006, Australia;7. Child and Adolescent Health, Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5006, Australia;8. College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia;1. Toronto General Hospital Research Institute, University Health Network, Toronto, Canada and Department of Immunology, University of Toronto, Toronto, Canada;2. Bandim Health Project, Department of Clinical Research, Odense University Hospital, University of Southern Denmark, Denmark;3. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA |
| Abstract: | 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. |
