{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:09:35Z","timestamp":1790514575771,"version":"4.1.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T00:00:00Z","timestamp":1553731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","award":["310372"],"award-info":[{"award-number":["310372"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Netherlands Organization for Scientific Research"},{"DOI":"10.13039\/501100001732","name":"Danish National Research Foundation","doi-asserted-by":"publisher","award":["DNRF108"],"award-info":[{"award-number":["DNRF108"]}],"id":[{"id":"10.13039\/501100001732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Certain vaccines, such as Bacille Calmette-Gu\u00e9rin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Tdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Tdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical Trials Registration<\/jats:title>\n                  <jats:p>NCT02771782.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciz246","type":"journal-article","created":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T12:12:03Z","timestamp":1553256723000},"page":"455-463","source":"Crossref","is-referenced-by-count":43,"title":["Interacting, Nonspecific, Immunological Effects of Bacille Calmette-Gu\u00e9rin and Tetanus-diphtheria-pertussis Inactivated Polio Vaccinations: An Explorative, Randomized Trial"],"prefix":"10.1093","volume":"70","author":[{"given":"Bastiaan A","family":"Blok","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen,","place":["The Netherlands"]},{"name":"Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut , Copenhagen"},{"name":"Odense Patient Data Explorative Network, University of Southern Denmark\/Odense University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L Charlotte J","family":"de Bree","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen,","place":["The Netherlands"]},{"name":"Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut , Copenhagen"},{"name":"Odense Patient Data Explorative Network, University of Southern Denmark\/Odense University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri A","family":"Diavatopoulos","sequence":"additional","affiliation":[{"name":"Section Pediatric Infectious Diseases and Radboud Center for Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre , Nijmegen,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen D","family":"Langereis","sequence":"additional","affiliation":[{"name":"Section Pediatric Infectious Diseases and Radboud Center for Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre , Nijmegen,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo A B","family":"Joosten","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Aaby","sequence":"additional","affiliation":[{"name":"Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut , Copenhagen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine S","family":"Benn","sequence":"additional","affiliation":[{"name":"Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut , Copenhagen"},{"name":"Odense Patient Data Explorative Network, University of Southern Denmark\/Odense University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai G","family":"Netea","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,28]]},"reference":[{"key":"2024111411410057100_CIT0001","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nri.2016.43","article-title":"Harnessing the beneficial heterologous effects of vaccination","volume":"16","author":"Goodridge","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"2024111411410057100_CIT0002","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.it.2013.04.004","article-title":"A small jab - 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