Non-specific effects of vaccines: Current evidence and potential implications

Bree, L. Charlotte J. de; Koeken, Valerie A C M; Joosten, Leo A. B.; Aaby, Péter; Benn, Christine Stabell; Crevel, Reinout van; Netea, Mihai G.

doi:10.1016/j.smim.2018.06.002

Cited by 197 publications

(183 citation statements)

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“…During the last half century, the immune system has been divided into the innate and adaptive immune systems. In contrast to what was thought to be a unique feature of the adaptive immune system, it has recently been discovered the innate immune system is also capable of building an immunologic memory by adapting to previous exposure to vaccines, pathogens, or microbial components, a process that has been termed “trained immunity.”…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to what was thought to be a unique feature of the adaptive immune system, it has recently been discovered the innate immune system is also capable of building an immunologic memory by adapting to previous exposure to vaccines, pathogens, or microbial components, a process that has been termed "trained immunity." [1][2][3][4] Bacillus Calmette-Guérin (BCG), the live attenuated vaccine developed against tuberculosis, induces trained immunity. After BCG vaccination, monocytes respond with an increased cytokine production upon ex vivo stimulation with unrelated pathogens and TLR agonists, effects dependent on epigenetic and metabolic reprogramming of innate immune cells.…”

Section: Introductionmentioning

confidence: 99%

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The impact of sex hormones on BCG-induced trained immunity

Bree

Janssen

Aaby

et al. 2018

Journal of Leukocyte Biology

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The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) is a well-known immune modulator that induces nonspecific protective effects against heterologous infections through induction of innate immune memory, also termed "trained immunity." In randomized trials in low weight newborns, BCG vaccination reduced neonatal mortality due to decreased incidence of sepsis and respiratory infections. In many studies, sex-differential nonspecific effects of vaccines have been observed, but the mechanisms behind these differential effects are unknown. We investigated whether the important sex hormones estrogen and dihydrotestosterone (DHT) influence BCG-induced trained immunity in human primary monocytes. Although addition of estradiol and DHT to BCG inhibited the production of proinflammatory cytokines after direct stimulation of human monocytes, they did not influence the induction of trained immunity by BCG. In addition, estradiol or DHT did not induce training or tolerance in monocytes themselves. We conclude that these important sex hormones are unlikely to explain the sex-differential effects after BCG vaccination. Future studies should focus on the investigation of alternative mechanisms as an explanation for sex-differential nonspecific effects of BCG vaccination.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The impact of sex hormones on BCG-induced trained immunity

Bree

Janssen

Aaby

et al. 2018

Journal of Leukocyte Biology

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“…Protection against infection induced by BCG vaccination could be mediated through education of the innate immune system to mount a more effective immune response against related and unrelated infections. Indeed, BCG has been shown to reduce all-cause mortality and risk of unrelated infections, as recently reviewed [20], and also shown in the recent BCG revaccination study [21]. The underlying biological mechanism for these effects is likely to involve 'trained immunity', an evolutionarily conserved phenomenon that has been demonstrated in plants, invertebrates and animals [22].…”

Section: Bcg-induced Trained Immunitymentioning

confidence: 93%

Trained innate immunity and resistance to Mycobacterium tuberculosis infection

Koeken

Verrall

Netea

et al. 2019

Clinical Microbiology and Infection

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a b s t r a c tBackground: Some individuals, even when heavily exposed to an infectious tuberculosis patient, develop neither active nor latent tuberculosis infection (LTBI). This 'early clearance' of Mycobacterium tuberculosis is associated with a history of bacillus CalmetteeGu erin (BCG) vaccination. As BCG vaccination can boost innate immune responses through a process termed 'trained immunity', we hypothesize that BCGinduced trained innate immunity contributes to early clearance of M. tuberculosis. Objectives: We describe the epidemiological evidence and biological concepts of early clearance and trained immunity, and the possible relation between these two processes through BCG vaccination. Sources: Relevant data from published reports up to November 2018 were examined in the conduct of this review. Content: Several observational studies and one recent randomized trial support the concept that boosting innate immunity contributes to protection against M. tuberculosis infection, with BCG vaccination providing approximately 50% protection. The molecular mechanisms mediating early clearance remain largely unknown, but we propose that trained immunity, characterized by epigenetic and metabolic reprogramming of innate immune cells such as monocytes or macrophages, is at least partially responsible for eliminating the mycobacteria and inducing early clearance. Implications: Future studies should examine if BCG revaccination increases early clearance of M. tuberculosis through induction of trained immunity. Epigenetic or metabolic modulation may further boost BCG-induced trained innate immunity to promote tuberculosis prevention. New tuberculosis vaccine candidates should also be examined for their capacity to improve protection against M. tuberculosis infection and induce trained immunity. V.A.C.M. Koeken, Clin Microbiol Infect 2019;25:1468

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“…Further immunological and clinical studies are needed to decipher vaccine-induced H.I.-mediated mechanisms and impact on morbidity and mortality contributing to health promotion. Associated potentiators such as booster vaccinations and maternal priming need to be examined carefully in different socioeconomic settings and with a sex-differential analysis (85).…”

Section: Future Research Prioritiesmentioning

confidence: 99%