Training of Innate Immunity by Vaccination With γ-irradiated BCG

1. INTRODUCTION AND RATIONALE

The live attenuated Bacillus Calmette-Guerin (BCG) vaccine protects against extrapulmonary infection with Mycobacterium tuberculosis and against leprosy [1, 2]. It has been shown that vaccination with BCG also leads to non-specific protective effects: early administration of BCG vaccination could lead to reduced child mortality, mainly as a result of reduced neonatal sepsis, respiratory infection, and fever. [3-5] Furthermore, BCG has also been used in patients with bladder cancer, to induce an improved reaction of the immune system, which prevents tumor progression and dead. [6] Recently, it was shown that BCG vaccination can induce epigenetic changes in human monocytes, which result in higher pro-inflammatory cytokines response upon restimulation with non-related pathogens in vitro. [7] The observed effects are proposed to be due to modulation of the human innate immune system, in a process called 'trained immunity'. Upon stimulation with a pathogen, the innate immune system becomes primed and is able to react faster and more efficient to a secondary (and non-related) stimulus. [7, 8]

Considering these beneficial effects of BCG on innate host defense, it is reasonable to hypothesize that it would be helpful to generate a 'trained immunity status' in hosts defective in T- and B-cell immunity, as they are more vulnerable to infections. However, because of their immune compromised status, these patients cannot be vaccinated with live attenuated vaccines (e.g. BCG). [9] Vaccination with y-irradiated BCG would be possible, but it is not known whether the γ-irradiated vaccine has the same protective non-specific effects on innate host defense. In recent in-vitro experiments, the investigators have demonstrated that y-irradiated BCG can train monocytes in vitro (not published). Therefore, the aim of this study is to determine whether γ-irradiated BCG is able to train the human innate immune system of healthy volunteers in-vivo, just as shown before with the live attenuated BCG vaccine [7]. 2. OBJECTIVES

Primary Objective: To determine whether γ-irradiated BCG can train the innate immune system in vivo, by comparing cytokine production upon ex-vivo restimulation with pathogens before, 2 weeks and 3 months after vaccination with y-irradiated BCG. 3. STUDY DESIGN

An explorative intervention study with a duration of three months will be performed. 15 Healthy volunteers will be recruited to receive a vaccination with γ-irradiated BCG. After informed consent, 40ml of blood will be drawn before vaccination and at 2 weeks and 3 months post-vaccination. 4. STUDY POPULATION 4.1 Population Healthy volunteers, 18 - 55 yr old. 4.2 Inclusion criteria The subjects must be healthy adults, aged 18 - 55 years old. 4.3 Exclusion criteria Subjects are excluded when they are from tuberculosis endemic countries, if they have been in contact with tuberculosis patients or if they already have been vaccinated with BCG. The subjects are excluded from the study if they suffer for any disease, including intercurrent infections. Subjects are not allowed to use any medication except oral anticonceptive agents.