Methods:

The investigators conducted Com-COV, a participant-blinded, randomized, noninferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged ≥50 years with no or well-controlled comorbidities and no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by laboratory confirmation were eligible and were recruited at eight sites across the United Kingdom. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n = 100) was enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval.

The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered noninferior to the approved homologous schedules if the lower limit of the one-sided 97.5% confidence interval (CI) of the geometric mean ratio of these comparisons was >0.63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.