Study Objectives

Primary Objectives:

  • To assess vaccine efficacy (VE) of COVID-19 mRNA vaccine to prevent virologically-confirmed symptomatic COVID-19 starting 14 days after dose 2 in adults who are at risk of severe COVID-19.
  • To assess vaccine efficacy (VE) of COVID-19 mRNA vaccine to prevent severe COVID-19 starting 14 days after dose 2 in adults who are at risk of severe COVID-19.
  • To assess safety and tolerability of COVID-19 mRNA vaccine in adults who are at risk of severe COVID-19 

 Secondary Objectives

  • Durability of VE of COVID-19 mRNA vaccine against COVID-19 and against severe COVID-19 through the final study visit (Month 12 post-dose 1) in volunteers with no previous COVID-19.
  • VE of COVID-19 mRNA vaccine against COVID-19 and against severe COVID-19 by neutralization phenotype and Spike sequence features of acquired SARS-CoV-2 viruses (sieve analysis), including VE against the B.1.351/501Y.V2 variant and VE against all other variants combined in volunteers with no previous COVID-19.
  • VE of COVID-19 mRNA vaccine against SARS-CoV-2 infection defined by nucleocapsid protein seroconversion regardless of symptomology in volunteers with no previous COVID-19.
  • VE of COVID-19 mRNA vaccine against asymptomatic SARS-CoV-2 infection defined by nucleocapsid protein seroconversion without prior occurrence of the symptomatic COVID-19 primary endpoint in volunteers with no previous COVID-19.
  • Postvaccination immune response markers as correlates of risk of COVID-19 and as correlates protection against COVID-19.
  • VE of COVID-19 mRNA vaccine against COVID-19 and severe COVID-19 in all participants regardless of baseline SARS-CoV-2 status

Study Design: The study is a multi-center, sequentially monitored for vaccine non-efficacy, individually randomized trial using an immediate versus deferred approach of vaccination. The trial will be double-blind, placebo-controlled in the initial immediate versus deferred vaccination portion of the trial. Regularly planned safety assessments and interim analyses of vaccine non-efficacy and safety will be performed. After the interim analysis for vaccine non-efficacy supports the vaccine being not futile, all enrollees are crossed over in a double-blind fashion. The interim analysis will be performed at 50 primary COVID-19 endpoints that are expected to be accrued in approximately 3.5 months post trial start assuming an approximately 6-week enrolment period; the time would be shorter if enrolment completes sooner. Once the crossover is triggered, all participants are expected to receive their first new immunization within 4 weeks. The plan is for all participants to have received active vaccination by approximately 5 months post trial initiation. All trial participants are followed for 12 months post enrollment to evaluate vaccine efficacy durability. 

Approximately 14,000 participants will be randomized to immediate vaccinations of two doses of COVID-19 mRNA vaccine at Months 0 and 1, or deferred vaccinations at the crossover visit approximately 3.5 months later . A 1:1 allocation ratio is used (7,000 immediate vaccination, 7,000 deferred vaccination).  

Study Population and Size: This study will enroll about 250-500 participants participants who meet one or more of the following criteria: 

  1. Over age 40, who have at least one comorbidity known to be associated with severe COVID-19, 
  2. Women age 18 years or older who are pregnant, and 
  3. HIV-1-infected individuals age 18 years or older

Study Duration: 14 months

Sponsor

  • Division of AIDS (DAIDS)
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • National Institutes of Health (NIH)
  • Department of Health and Human Services (DHHS)
  •  Bethesda, Maryland, USA