Abstract

BACKGROUND: There are limited data on immune responses to heterologous COVID-19 immunisation schedules, especially following an extended ≥12-week interval between doses. METHODS: SARS-CoV-2 infection-naïve and previously-infected adults receiving ChAd-BNT (ChAdOx1 nCoV-19, AstraZeneca followed by BNT162b2, Pfizer-BioNTech) or BNT-ChAd as part of the UK national immunisation programme provided blood samples at 30 days and 12 weeks after their second dose. Geometric mean concentrations (GMC) of anti-SARS-CoV-2 spike (S-antibody) and nucleoprotein (N-antibody) IgG antibodies and geometric mean ratios (GMR) were compared with a contemporaneous cohort receiving homologous ChAd-ChAd or BNT-BNT. RESULTS: During March-October 2021, 75,827 individuals were identified as having received heterologous vaccination, 9,489 invited to participate, 1,836 responded (19.3%) and 656 were eligible. In previously-uninfected adults, S-antibody GMC at 30 days post-second dose were lowest for ChAd-ChAd (862 [95% CI, 694 - 1069]) and significantly higher for ChAd-BNT (6233 [5522-7035]; GMR 6.29; [5.04-7.85]; p<0.001), BNT-ChAd (4776 [4066-5610]; GMR 4.55 [3.56-5.81]; p<0.001) and BNT-BNT (5377 [4596-6289]; GMR 5.66 [4.49-7.15]; p<0.001). By 12 weeks after dose two, S-antibody GMC had declined in all groups and remained significantly lower for ChAd-ChAd compared to ChAd-BNT (GMR 5.12 [3.79-6.92]; p<0.001), BNT-ChAd (GMR 4.1 [2.96-5.69]; p<0.001) and BNT-BNT (GMR 6.06 [4.32-8.50]; p<0.001). Previously infected adults had higher S-antibody GMC compared to infection-naïve adults at all time-points and with all vaccine schedules. CONCLUSIONS: These real-world findings demonstrate heterologous schedules with adenoviral-vector and mRNA vaccines are highly immunogenic and may be recommended after a serious adverse reaction to one vaccine product, or to increase programmatic flexibility where vaccine supplies are constrained.