Measuring the quality of healthcare systems using composites
Authors: B. Guthrie
Journal: BMJ (2008)

<h3>Abstract</h3> <h3>Background</h3> There are limited data on immune responses to heterologous COVID-19 immunisation schedules, especially following an extended ≥12-week interval between doses. <h3>Methods</h3> 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. <h3>Results</h3> 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&lt;0.001), BNT-ChAd (4776 [4066-5610]; GMR 4.55 [3.56-5.81]; p&lt;0.001) and BNT-BNT (5377 [4596-6289]; GMR 5.66 [4.49-7.15]; p&lt;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&lt;0.001), BNT-ChAd (GMR 4.1 [2.96-5.69]; p&lt;0.001) and BNT-BNT (GMR 6.06 [4.32-8.50]; p&lt;0.001). Previously infected adults had higher S-antibody GMC compared to infection-naïve adults at all time-points and with all vaccine schedules. <h3>Conclusions</h3> 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. <h3>What is already known?</h3> PubMed was searched with the terms “COVID-19 Vaccine” and “heterologous” to identify publications relating to heterologous immunisation schedules with adenoviral-vector and mRNA vaccines from 01 January 2020 until 30 November 2021. Following early reports of vaccine-induced thrombocytosis and thrombocytopenia (VITT) after the first dose of ChAd (ChAdOx1 nCoV-19), several studies reported significantly higher antibody levels, with robust neutralizing activity and cellular immune responses, in adults receiving a heterologous ChAd-mRNA schedule compared to those receiving ChAd-ChAd. Few studies, however, have compared antibody responses after both heterologous schedules (ChAd-mRNA and mRNA-ChAd) with both homologous schedules (ChAd-ChAd and mRNA-mRNA). One UK study (COMCOV) compared all four ChAd and BNT162b2 Pfizer-BioNTech (BNT; mRNA) combinations given four weeks apart and reported very high antibody and T-cell responses four weeks after the second dose for all four schedules. <h3>What are the new findings?</h3> We used the national immunisation register to identify adults who received a heterologous vaccine schedule as part of the national immunisation programme in England and collected blood samples to measure SARS-CoV-2 antibody responses after vaccination. We found that both heterologous schedules (ChAd-BNT and BNT-ChAd) provided superior antibody responses compared to ChAd-ChAd and similar responses to BNT-BNT at 30 days and 12 weeks after second vaccine dose. ChAd-BNT induced higher antibody levels then BNT-ChAd at both timepoints. Antibody responses after vaccination were much higher in previously infected individuals, irrespective of their immunisation schedule. A recent Swedish population-based study reported higher vaccine effectiveness against symptomatic disease with ChAd-BNT than ChAd-ChAd providing real-world confirmation of improved protection with heterologous schedules. <h3>What do the new findings imply?</h3> Our findings add to the growing body of evidence showing high antibody responses following heterologous vaccination schedules with ChAd and BNT, along with robust antibody neutralising activity and cellular responses, especially when compared to ChAd-ChAd. Given that globally COVID-19 vaccine demand far exceeds vaccine supply, these results have important implications for the future deployment of COVID-19 vaccine programmes; particularly where it is logistically and/or operationally difficult to administer two doses of the same vaccine product.