Stuart ASV, Shaw RH, Liu X, et al. - In comparison to homologous schedules of COVID-19 vaccines, heterologous second dosing with m1273 (mRNA-1273), but not NVX (NVX-CoV2373), elevated transient systemic reactogenicity in this study. Multiple vaccines were inferred to be suitable to complete primary immunization after priming with BNT (BNT162b2) or ChAd (ChAdOx1 nCoV-19), facilitating rapid vaccine deployment worldwide and supporting recognition of such schedules for vaccine certification.

• The importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment has paved the way for this study.

• Mixed priming schedules including an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax) were tested in this single-blind, randomised, non-inferiority trial (Com-COV2).

• A total of 1072 adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT were randomized (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX.

• Among ChAd-primed participants, geometric mean concentration (GMC) 28 days following a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL) and ChAd/NVX (5597 ELU/mL) was found to be non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL) with a GMR of 10·2 for ChAd/m1273 and 2·8 for ChAd/NVX, vs ChAd/ChAd.

• In BNT-primed ones, BNT/m1273 (GMC 22 978 ELU/mL) was non-inferior but not BNT/NVX (8874 ELU/mL), vs BNT/BNT (16 929 ELU/mL) with a GMR of 1·3 for BNT/m1273 and 0·5 for BNT/NVX, vs BNT/BNT; however, NVX still resulted in an 18-fold increment in GMC 28 days post-vaccination.

• Overall 15 serious adverse events occurred, none considered linked with immunization.