Bastiaan A Blok1,2,3, L Charlotte J de Bree1,2,3, Dimitri A Diavatopoulos4, Jeroen D Langereis4, Leo A B Joosten1, Peter Aaby2, Reinout van Crevel1, Christine S Benn2,3, Mihai G Netea1. 1. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen. 3. Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital. 4. 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, The Netherlands.
Abstract
BACKGROUND: Certain vaccines, such as Bacille Calmette-Guérin (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. METHODS: We randomized 75 healthy, female, adult volunteers to receive eitherBCG, 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIALS REGISTRATION: NCT02771782.
RCT Entities:
BACKGROUND: Certain vaccines, such as Bacille Calmette-Guérin (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. METHODS: 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. RESULTS: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. CONCLUSIONS: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. CLINICAL TRIALS REGISTRATION: NCT02771782.
Authors: Valerie Acm Koeken; L Charlotte J de Bree; Vera P Mourits; Simone Jcfm Moorlag; Jona Walk; Branko Cirovic; Rob Jw Arts; Martin Jaeger; Helga Dijkstra; Heidi Lemmers; Leo Ab Joosten; Christine S Benn; Reinout van Crevel; Mihai G Netea Journal: J Clin Invest Date: 2020-10-01 Impact factor: 14.808
Authors: Esther Broset; Jacobo Pardo-Seco; Alex I Kanno; Nacho Aguilo; Ana Isabel Dacosta; Irene Rivero-Calle; Jesus Gonzalo-Asensio; Camille Locht; Luciana C C Leite; Carlos Martin; Federico Martinón-Torres Journal: EBioMedicine Date: 2021-03-09 Impact factor: 8.143
Authors: Paola Brandi; Laura Conejero; Francisco J Cueto; Sarai Martínez-Cano; Gillian Dunphy; Manuel J Gómez; Carlos Relaño; Paula Saz-Leal; Michel Enamorado; Ana Quintas; Ana Dopazo; Joaquín Amores-Iniesta; Carlos Del Fresno; Estanislao Nistal-Villán; Carlos Ardavín; Antonio Nieto; Miguel Casanovas; José Luis Subiza; David Sancho Journal: Cell Rep Date: 2022-01-04 Impact factor: 9.995
Authors: Jonathan J Mandolo; Marc Y R Henrion; Chimwemwe Mhango; End Chinyama; Richard Wachepa; Oscar Kanjerwa; Chikondi Malamba-Banda; Isaac T Shawa; Daniel Hungerford; Arox W Kamng'ona; Miren Iturriza-Gomara; Nigel A Cunliffe; Khuzwayo C Jere Journal: Viruses Date: 2021-12-13 Impact factor: 5.048
Authors: Mihai G Netea; Jorge Domínguez-Andrés; Luis B Barreiro; Triantafyllos Chavakis; Maziar Divangahi; Elaine Fuchs; Leo A B Joosten; Jos W M van der Meer; Musa M Mhlanga; Willem J M Mulder; Niels P Riksen; Andreas Schlitzer; Joachim L Schultze; Christine Stabell Benn; Joseph C Sun; Ramnik J Xavier; Eicke Latz Journal: Nat Rev Immunol Date: 2020-03-04 Impact factor: 53.106