The objective of CROWN CORONATION is the prevention of symptomatic COVID-19 by using combinations of approved and safe repurposed interventions, with complementary mechanisms of action.

CROWN CORONATION is an international, Bayesian platform adaptive, randomized, placebo-controlled trial assessing the effectiveness of candidate interventions in preventing COVID-19 disease in adults.

Randomization will be stratified by age (<50 and ≥50) and site. Participants will be healthcare workers at risk of contracting SARS-CoV-2. Participants will be randomized into one of two arms:

• Education and surveillance plus MR or MMR vaccine
• Education and surveillance plus Placebo

While the initial intervention to be tested on the platform will be the MR or MMR vaccine, other interventions might be added or removed over the course of the trial. The trial will evaluate which of the intervention arms is most effective at decreasing the incidence of symptomatic COVID-19 disease, without unacceptable side effects or safety events.

All participants will require be required to have a mobile phone to participate. This is standard in all the countries in this study. Most, but not all, will also have a smartphone. Participants will complete weekly data logs via SMS texting. Follow-up information will be collected until approximately 5 months after the end of treatment or death. Participants who develop symptomatic COVID-19 during the last month of observation will at a minimum be followed-up until symptom resolution and at a maximum until 6 months after randomization (whichever comes first). Telemedicine approaches to collecting information on participants will be used where possible. The trial will provide adherence support interventions that have been shown in randomized controlled trials to improve adherence to Human Immunodeficiency Virus treatment and adapted for HIV Pre-Exposure Prophylaxis (HIV PrEP) (e.g. two-way SMS with check in for those that report symptoms or adverse events). The database will be hosted on UK-based servers which are expected to be managed by Sealed Envelope Ltd. Local investigators will have access to the part of the CRF to enable recording of outcome data and/or severity of COVID-19 symptoms. Participants will be given a secure login to enable them to complete an initial participant health questionnaire and the regular data logs. It is envisaged that these will be completed at least weekly.

Inclusion criteria

1. Volunteers without clinical evidence of COVID-19 infection aged 18 years and older.
2. Healthcare workers based in a primary, secondary or tertiary healthcare setting with a high risk of developing COVID-19 due to their potential exposure to patients with SARS-CoV-2 infection.
3. Must have a mobile phone and access to the Internet for data collection purposes.
4. Participants who are willing and able to provide informed consent via an electronic consent process.

Exclusion criteria

1. Prior enrollment into other COVID-19 interventional prevention or treatment trials (observational trials not excluded).
2. Self-reported or diagnosed current infection with SARS-CoV-2 or previous COVID-19 diagnosis.
3. Self-reported current acute respiratory infection.
4. Concurrent and/or recent involvement in other research or use of the investigational product, a product considered to be equivalent to the investigational product, or any other product that is likely to interfere with the investigational products in this trial used within three months of study enrolment.
5. Self-reported known allergies to any of the IMPs and excipients of the IMPs and placebo.
6. Self-reported presence or history of the conditions listed in the appendices.
7. Self-reported current use of medication known to interact with any of the medications listed in the appendices.
8. Inability or unwillingness to be followed up for the trial period.

For M-M-R II

• Pregnant women.
• Individuals receiving high dose corticosteroids, other immuno-suppressive drugs, alkylating agents or anti-metabolites.
• Individuals undergoing radiotherapy.
• Any malignant disease either untreated or currently undergoing therapy.
• History of administration of gammaglobulin or blood transfusions within the previous 3 months.
• Participants with an allergy to the MR (MMR) vaccine or its components, including neomycin.
• Idiopathic thrombocytopenic purpura (ITP)
• Untreated tuberculosis
• Prior receipt of any vaccines (licensed or investigational) ≤30 days before enrollment
• Planned receipt of any vaccine other than the study intervention within 30 days before and after the study vaccination (not including the flu vaccination via injection)
• Prior receipt of an investigational or licensed vaccine likely to impact on interpretation of the trial data (e.g. Adenovirus vectored vaccines, any coronavirus vaccines).
• Any confirmed or suspected immunosuppressive or immunodeficient state, including untreated HIV infection with a CD4T count <200 /mL
• Asplenia

Individual participant data that underlie the results reported in the main publication may be shared, after de-identification.

From 3 months after the last patient last visit onward.

Investigators whose proposed use of the data has been approved by a review committee identified for this purpose.

For the MR or MMR vaccine, there will be a placebo vaccine. Attempts will be made to maintain masking for other interventions (e.g. oral tablets) added to the platform by including suitable placebo options.