The disease is called COVID-19 because it was first discovered in 2019, but I’ll just call it COVID. It’s caused by a new virus that can be passed between people touching or passed through the air when an infected person coughs or sneezes, so the hospital staff wear protective clothing. Most people with COVID get better without coming to the hospital, and most who come to the hospital also get better, although they may get worse before they get better. But, a few of those in the hospital die from the illness. The World Health Organisation is organising a trial in many countries in which various potential vaccines are studied, to see whether they are of any use to prevent COVID

Background: This large, international, randomized controlled clinical trial is designed to enable an expeditious, agile and concurrent evaluation of the benefits and risks of multiple candidate preventive vaccines against COVID-19 at international sites with sufficient COVID-19 attack rates. The trial is designed to provide sufficient evidence of safety and vaccine efficacy against COVID-19 to support decision-making about global vaccine deployment, which may include licensure and/or WHO pre-qualification. Final decisions about COVID-19 deployment will be made in each jurisdiction. Simplicity of procedures: Within each country, the investigator invites selected sites and helps them get ethical and regulatory approval and study vaccines, then volunteers’ recruitment can begin. To facilitate collaboration volunteer’s enrolment and randomisation (via a cloud-based GCP-compliant platform) and all other trial procedures are greatly simplified, and no paperwork is required. Once consent has been obtained, electronic entry of anonymised details of a few key characteristics of each volunteer takes only a few minutes. At the end of patient entry, a random vaccine allocation is generated. Eligibility: Adults (age ≥ 16 years), capable of giving personal signed informed consent, healthy participants who are determined by clinical judgment of the investigator to be eligible for inclusion in the study. Participants who are willing and able to comply with all scheduled visits, vaccination plan, laboratory tests (if randomised and consent given, lifestyle considerations, and other study procedures. Consent: The study website https://data.castoredc.com/studies has printable volunteer information in some UN official languages. Once the information has been explained to volunteers, obtaining consent takes only a few minutes. An electronic image of the signature page is kept (or, if national regulations forbid this, a note to file), and the printed information and original consent stays with the volunteer or legal representative. Trial entry; randomization: Once electronic data collection has been completed the volunteer automatically enters the trial and a random allocation of their trial vaccine is generated (by an algorithm that ensures eventual balance in the characteristics just recorded between each study vaccines and its placebos) and displayed. The volunteers will be randomly allocated either to placebo or to one of the study vaccines. Safety: Evaluation of COVID-19 vaccine safety is one of the primary objectives of this trial. All sites will monitor and report serious adverse events (SAEs) at any time after vaccination, by baseline SARS-CoV-2 serostatus where available. Follow-up: Each participant will be contacted weekly for 52 weeks for information as to whether any potentially relevant symptoms have arisen, with laboratory testing triggered if the report suggests COVID-19. Primary objective: The primary objective is to evaluate the effect of each vaccine on the rate of virologically confirmed COVID-19 disease, regardless of severity. Secondary and exploratory objectives. Although the study may lack power for formal statistical inference about vaccine efficacy against severe disease and death due to COVID-19, this secondary endpoint will be calculated and reported for each vaccine. For vaccines that are shown to be effective, their duration of efficacy also will be formally evaluated as a pre-specified secondary endpoint. Additional exploratory endpoints will include VE between the first and second dose, for two-dose vaccine. In addition, VE against specific SARS-CoV-2 variants of concern (as defined by WHO)will be evaluated as a high priority supportive end-point. This will also include a VE analysis in terms of variant-specific mutations and/or dele-tions. Every effort will be made to collect samples for sequencing from cases that occur in the trial. These will be used for various purposes, including assessment of the effects of vaccination on the immune response and on the secondary endpoint of rate of infection with SARS-CoV-2. For candidate vaccines for which both the independent Working Group on Vaccine Prioritization and Trial Steering Committee makes the recommendation on the need for additional safety information before a large number of volunteers is recruited, the following procedures apply. Before proceeding to the recruitment of a larger number of volunteers, the DSMC will review the safety data seven days and thirty days post administration of the last dose. Numbers entered: The trial will rapidly enrol and individually randomize large numbers of adult participants. The trial is endpoint driven, as the main analysis for each vaccine arm versus the concurrent shared placebo/control arm is triggered by occurrence of a total of 150 cases of COVID-19 across these two arms, at which point the results will be reported but blinded follow-up will continue. This fixed number of 150 endpoints is set to provide sufficient power to detect a predefined target level of VE, rejecting the initially specified null hypothesis that VE is < 30%. Adaptive design: A global Data Monitoring Committee will keep the accumulating safety results and major outcome results under regular review. Different candidate vaccines may be available or suitable to enter the trial at different times; for each candidate vaccine, the primary efficacy results are expected within 3-6 months of the vaccine entering the trial. By using a shared placebo/control group and a common Core protocol to evaluate multiple candidate vaccines in the trial, resources allocated to the evaluation of each candidate vaccine are judiciously saved while a high standard of scientific rigor and efficiency is ensured. Add-on studies: Particular countries, or particular groups of sites, may want to collaborate in making further measurements or observations. These could be thought of as Phase 2b trials that are being conducted concurrently with the Phase 3 trial. However, while well-organised additional research studies of additional secondary and supportive endpoints, for which monitoring is valuable but optional at each study site include infection with SARS-CoV-2, trans-mission of SARS-CoV-2, and possible immunological markers as correlates of risk could well be valuable, they are not core requirements in every site. Data security: Patient information will be encrypted and held securely by the WHO. Those analysing it will use only anonymised data, and no identifiable patient details will appear in publications. Publication: This international collaboration is co-ordinated through the World Health Organisation. Major findings will be disseminated by the WHO and published in the names of the collaborators