Biomarkers of Trained Immunity Following MMR Vaccination

Study Overview
=================
Brief Summary
-----------------
This is a substudy of NCT04333732. The goal of this sub-study is to identify and characterize biomarkers of trained immunity by measuring, in vitro, immune responses to heterologous products, especially viral associated products, in the MMR vaccinated compared placebo groups. All participants are randomly assigned to MMR or placebo injection at baseline, followed by SARS-CoV-2 specific vaccination. Blood is drawn around 60 to 90 days after the last SARS-CoV-2 specific vaccine injection.

Detailed Description
-----------------
A sub-study of the CROWN CORONATION Trial (COVID-19 Research Outcomes Worldwide Network for CORONAvirus prevenTION; NCT04333732). The goal of this sub-study is to identify and characterize biomarkers of trained immunity by measuring, in vitro, immune responses to heterologous products, especially virally associated products, in those exposed to MMR vaccine injection compared to those exposed to 0.9% sodium chloride ('normal saline') placebo injection. A secondary objective is comparison of SARS-CoV-2 neutralization assays between MMR and placebo comparison groups around 60 to 90 days after the last SARS-CoV-2 specific vaccine injection. All participants are randomly assigned to MMR or placebo injection at baseline, followed by SARS-CoV-2 specific vaccination. Blood is drawn around 60 to 90 days after the last SARS-CoV-2 specific vaccine injection. Peripheral blood mononuclear cells (PMBC) will be isolated from samples and stimulated with heterologous products (for example; Roswell Park Memorial Institute medium [RPMI; negative control], MMR [the vaccine itself as specific stimulus], severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2; heat inactivated], influenza virus [heat inactivated], toll-like receptor 3 ligand [TLR3 ligand; poly I:C], toll-like receptor 7/8 ligand [TLR7/8 ligand; R848], toll-like receptor 4 ligand [TLR4 ligand; lipopolysaccharide (LPS)]). Supernatants will be assayed by multiplex luminex protein assay at 24 hr (for example; type I interferons [IFN], interleukin [IL]-1β , IL-6, tumor necrosis factor [TNF]-α) and after 5 days (for example; IFN-γ, IL-17, IL-22, IL-10). This process of testing stimulus-response will be conducted on both the baseline and day 30 samples, collected from both the MMR and Placebo groups. Neutralization assay will be conducted on all samples using wild-type SARS-CoV-2. Measles IgG titres will be measured on all samples. Measles IgG titres will be used for sensitivity analysis.

Official Title
-----------------
Determining Biomarkers of Trained Immunity in a Randomized Controlled Trial of the Measles, Mumps, and Rubella Vaccine - a Sub-study of the CROWN CORONATION Trial

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Diagnostic Test: Heterologous stimuli
* Diagnostic Test: Neutralization assay


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion/ Exclusion Criteria: Prospective participant must already be enrolled into the CROWN CORONATION trial at the sub-study location. Refer to NCT04333732 for list of inclusion / exclusion criteria for the study population.

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

Sexes Eligible for Study
-----------------
All

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

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

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants in the CROWN CORONATION trial<br>The CROWN CORONATION trial will randomly allocate adult participants to a single intramuscular injection of MMR vaccine or Placebo (0.9% saline). All participants in this sub-study receive SARS-CoV-2 specific vaccine subsequent to the MMR or Placebo injection. | Diagnostic Test: Heterologous stimuli<br>* In vitro exposure of peripheral blood mononuclear cells to heterologous stimuli<br>* Other names: For example; RPMI medium, MMR, SARS-CoV-2, Influenza, TLR3 ligand, TLR7/8 ligand, TLR4 ligand;Diagnostic Test: Neutralization assay<br>* In vitro measurement of neutralizing antibody activity to wild-type SARS-CoV-2<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cytokine (or chemokine) production in response to heterologous stimuli | Cytokines such as TNF-α, IL-1β and IL-6 produced by human monocytes, and IFN-γ produced by natural killer (NK)-cells, are markers of trained immunity and these (and other cytokines and chemokines) will be measured in supernatants of stimulated PBMCs from a cohort of participants in the CROWN CORONATION trial. All cytokines and chemokines are measured in picograms/milliliter. | Around 60 to 90 days after last SARS-CoV-2 specific vaccine injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutralization assay | Neutralizing antibody activity to wild-type SARS-CoV-2 | Around 60 to 90 days after last SARS-CoV-2 specific vaccine injection | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID 19, Trained Immunity, Infectious Diseases