Biomarkers of Trained Immunity Following MMR Vaccination

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Diagnostic test: Heterologous stimuli; Diagnostic test: Neutralization assay

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.

• Study Type: Observational
• Enrollment (Actual): 96

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The CROWN CORONATION trial enrolls adults at risk of developing COVID-19 due to their work in the healthcare environment. To be eligible, prospective participants for the CROWN CORONATION trial must not have a contra-indication to receiving the live attenuated Measles, Mumps and Rubella vaccine (MMR) and must not be exposed to agents that may complicate the interpretation of findings regarding the hypothesized protective effect of MMR for the prevention of COVID-19. The sub-study will consecutively approach all participants enrolled in the CROWN CORONATION trial to elicit enrolment in the sub-study cohort.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Participants in the CROWN CORONATION trial; 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; In vitro exposure of peripheral blood mononuclear cells to heterologous stimuli; Other Names: For example; RPMI medium, MMR, SARS-CoV-2, Influenza, TLR3 ligand, TLR7/8 ligand, TLR4 ligand; Diagnostic test: Neutralization assay; In vitro measurement of neutralizing antibody activity to wild-type SARS-CoV-2

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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Michael S Avidan, MD, Washington Univeristy School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2020
• Primary Completion (Actual): June 28, 2021
• Study Completion (Actual): June 28, 2021

Study Registration Dates

• First Submitted: November 20, 2020
• First Submitted That Met QC Criteria: November 20, 2020
• First Posted (Actual): November 27, 2020

Study Record Updates

• Last Update Posted (Actual): November 26, 2021
• Last Update Submitted That Met QC Criteria: November 24, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: COVID 19; Infectious Diseases; Trained Immunity
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 202011081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The project team will make the de-identified data available to the public within 1 year after publication using a public repository. Prior to that time, data will be deposited in the Washington University Open Scholarship repository. Any request for data not deposited in the repository must be directed to the Principal Investigator
• IPD Sharing Time Frame: 1 Year
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No