BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner.

Valerie A.C.M Koeken,Jona Walk,Rob J.W Arts,L Charlotte J De Bree,Reinout Van Crevel,Vera P Mourits,Heidi Lemmers,Martin Jaeger,Helga Dijkstra,Simone J.C.F.M Moorlag,Mihai G Netea,Leo A.B Joosten,Christine S Benn,Branko Cirovic

doi:10.1172/jci133935

Abstract

BACKGROUNDInduction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODSWe investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTSWhile BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSIONThe capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDINGNetherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation.

Highlights

The traditional view of vaccines is that they protect against a particular infection by induction of long-lasting specific adaptive immune memory
A total of 307 healthy volunteers were included in the 300BCG cohort
We examined if inflammatory protein profiles predicted ex vivo PBMC–derived cytokine production before and after bacillus Calmette-Guérin (BCG) vaccination

Summary

Introduction

The traditional view of vaccines is that they protect against a particular infection by induction of long-lasting specific adaptive immune memory. The discovery of the induction of nonspecific innate immune memory ( termed trained immunity) by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) has led to a paradigm shift in our understanding of our immune system [1, 2]. Lenge, up to 1 year after vaccination [3,4,5,6] The longevity of this effect is explained by BCG-induced reshaping of hematopoietic stem and progenitor cells within the bone marrow compartment, resulting in long-lasting transcriptional changes associated with myeloid cell development and function [3, 4]. Induction of innate immune memory, termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. The overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases

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Results