BCG-induced Epigenetic Modifications in the NEXT Generation

Study Overview
=================
Brief Summary
-----------------
Non-specific protective effects resulting from the BCG vaccine appear to be paternally inheritable. Since the BCG vaccine is known to induce trained immunity, epigenetics might explain the fathers' contribution to the immune profile of their offspring. Epigenetic inheritance in mice has recently been demonstrated, but is not established in humans yet. By studying the DNA methylation profile of sperm cells after BCG vaccination, we aim to gain insight into the possibility of epigenetic inheritance in human males.

Official Title
-----------------
BCG-induced Epigenetic Modifications in the NEXT Generation

Conditions
-----------------
Trained Immunity, BCG Vaccine, Epigenetics

Intervention / Treatment
-----------------
* Biological: BCG-Vaccine SSI [Statens Serum Institut]) Danish strain 1331
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy Male Age 18-25 years (at the moment of trial start) Exclusion Criteria: Any systemic disease or conditin, or the use of systemic medication (with the exception of non-threatening alelrgies, e.g. hay fever) Smoking or drug use Prior BCG vaccination Other vaccination four weeks prior to trial start or four weeks after the first study visit (no vaccine in the same arm as the BCG vaccine for three months) Acute illness two weeks prior to trial start Known allergy or history of anaphylaxis/other serious adverse reaction to any vaccine Participation in another drug trial Legally incapacitated or unwilling to provide informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 25 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCG vaccine<br>BCG-Vaccine SSI [Statens Serum Institut]) Danish strain 1331 0.1ml (=0.0075mg) One-time vaccination intradermally | Biological: BCG-Vaccine SSI [Statens Serum Institut]) Danish strain 1331<br>* Nothing to add<br>|
| Placebo Comparator: Placebo vaccine<br>0.9% NaCl placebo 0.1ml One-time vaccination intradermally | Biological: Placebo<br>* Nothing to add<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DNA methylation profile of sperm cells (first comparison; CHANGE) | Differentially methylated regions (DMRs) | Comparing T3 to baseline | 
| DNA methylation profile of sperm cells (second comparison; CHANGE) | Differentially methylated regions (DMRs) | Comparing T4 to baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological profile of PBMCs, before and after BCG vaccination (comparison; CHANGE) | Cytokine production assays (e.g. TNFa, IL6, IL1b) | Comparing T1-T4 to baseline | 
| CHANGE of the epigenetic profile of innate immune cells | Differentially methylated regions (DMRs), ATAC sequencing, RNA sequencing | Comparing T1-T4 to baseline |