BCG-induced trained immunity enhances acellular pertussis vaccination responses in an explorative randomized clinical trial

Joshua Gillard,Ronald De Groot,Bastiaan A Blok,Marc J Eleveld,Elles Simonetti,Marien I De Jonge,Martijn A Huynen,Daniel R Garza,Pieter G M Van Gageldonk,Reinout Van Crevel,Prashanna Balaji Venkatasubramanian,L Charlotte J De Bree,Guy A M Berbers,Mihai G Netea,Irma Joosten,Dimitri A Diavatopoulos

doi:10.1038/s41541-022-00438-4

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.

Highlights

Pertussis is a highly transmissible acute respiratory disease caused by the bacterium Bordetella pertussis and has re-emerged a serious public health issue despite high vaccine coverage[1]
Antibody concentrations remained higher than baseline up to a year post-vaccination (Y1), with the exception of TET, which had waned in the BCGtrained and Bacille Calmette-Guérin (BCG) + Tdap cohorts (Supplementary Fig. 2a)
We show that trained immunity that is induced by BCG vaccination 3 months prior to, but not concurrent with, a booster dose of Tdap-inactivated poliovirus (IPV), augments pertussis IgG responses and modulates pertussis-specific cellular responses

Summary

Introduction

Pertussis is a highly transmissible acute respiratory disease caused by the bacterium Bordetella pertussis and has re-emerged a serious public health issue despite high vaccine coverage[1]. The disease was controlled in industrialized countries through vaccination with whole-cell pertussis vaccines (wPs) that were implemented in the 1940s-1950s. These vaccines were highly effective and induced long-term protection. AP vaccines are widely used to boost immunity in pre-school children, adolescents, and adults. High reactogenicity and safety concerns led to their replacement in the 1990s–2000s by acellular pertussis vaccines (aPs). Despite these measures and their improved safety profile, multiple studies have shown that aPinduced immunity remains suboptimal[2] and wanes over time[3]. The growing need for new and improved vaccination strategies has led to the exploration of new adjuvants that target innate immunity and enhance specific immunity to aPs7–9

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