BCG-induced trained immunity enhances acellular pertussis vaccination responses in an explorative randomized clinical trial
Joshua Gillard,
Bastiaan A. Blok,
Daniel R. Garza,
Prashanna Balaji Venkatasubramanian,
Elles Simonetti,
Marc J. Eleveld,
Guy A. M. Berbers,
Pieter G. M. van Gageldonk,
Irma Joosten,
Ronald de Groot,
L. Charlotte J. de Bree,
Reinout van Crevel,
Marien I. de Jonge,
Martijn A. Huynen,
Mihai G. Netea,
Dimitri A. Diavatopoulos
Affiliations
Joshua Gillard
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Bastiaan A. Blok
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center
Daniel R. Garza
Center for Molecular and Biomolecular Informatics, Radboud University Medical Center
Prashanna Balaji Venkatasubramanian
Center for Molecular and Biomolecular Informatics, Radboud University Medical Center
Elles Simonetti
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Marc J. Eleveld
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Guy A. M. Berbers
Centre for Infectious Disease Control, National Institute of Public Health and the Environment
Pieter G. M. van Gageldonk
Centre for Infectious Disease Control, National Institute of Public Health and the Environment
Irma Joosten
Laboratory for Medical Immunology, Radboud University Medical Center
Ronald de Groot
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
L. Charlotte J. de Bree
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center
Reinout van Crevel
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center
Marien I. de Jonge
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Martijn A. Huynen
Center for Molecular and Biomolecular Informatics, Radboud University Medical Center
Mihai G. Netea
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center
Dimitri A. Diavatopoulos
Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Abstract Acellular pertussis (aP) booster vaccines are central to pertussis immunization programs, although their effectiveness varies. The Bacille Calmette-Guérin (BCG) vaccine is a prototype inducer of trained immunity, which enhances immune responses to subsequent infections or vaccinations. While previous clinical studies have demonstrated that trained immunity can protect against heterologous infections, its effect on aP vaccines in humans is unknown. We conducted a clinical study in order to determine the immunological effects of trained immunity on pertussis vaccination. Healthy female volunteers were randomly assigned to either receive BCG followed by a booster dose of tetanus-diphteria-pertussis inactivated polio vaccine (Tdap-IPV) 3 months later (BCG-trained), BCG + Tdap-IPV concurrently, or Tdap-IPV followed by BCG 3 months later. Primary outcomes were pertussis-specific humoral, T- and B-cell responses and were quantified at baseline of Tdap-IPV vaccination and 2 weeks thereafter. As a secondary outcome in the BCG-trained cohort, ex vivo leukocyte responses were measured in response to unrelated stimuli before and after BCG vaccination. BCG vaccination 3 months prior to, but not concurrent with, Tdap-IPV improves pertussis-specific Th1-cell and humoral responses, and also increases total memory B cell responses. These responses were correlated with enhanced IL-6 and IL-1β production at the baseline of Tdap-IPV vaccination in the BCG-trained cohort. Our study demonstrates that prior BCG vaccination potentiates immune responses to pertussis vaccines and that biomarkers of trained immunity are the most reliable correlates of those responses.