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Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

2021; Elsevier BV; Volume: 398; Issue: 10303 Linguagem: Inglês

10.1016/s0140-6736(21)01694-9

1474-547X

Xinxue Liu, R. H. Shaw, Arabella Stuart, Melanie Greenland, Parvinder K. Aley, Nick Andrews, J. Claire Cameron, Sue Charlton, Elizabeth Clutterbuck, Andrea M. Collins, Tanya Dinesh, Anna England, Saul N. Faust, Daniela M. Ferreira, Adam Finn, Christopher Green, Bassam Hallis, Paul T. Heath, Helen Hill, Teresa Lambe, Rajeka Lazarus, Vincenzo Libri, Fei Long, Yama F Mujadidi, Emma L Plested, Samuel Provstgaard-Morys, Maheshi Ramasamy, Mary Ramsay, Robert C. Read, Hannah Robinson, Nisha Singh, David P. J. Turner, Paul Turner, L L Walker, Rachel White, Jonathan S Nguyen-Van-Tam, Matthew D. Snape, Alasdair Munro, Jazz Bartholomew, Laura Presland, Sarah Horswill, Sarah Warren, Sophie Varkonyi-Clifford, Stephen Saich, Kirsty Adams, Marivic Ricamara, Nicola Turner, Nicole Y Yee Ting, Sarah Whittley, Tommy Rampling, Amisha Desai, Claire Brown, Ehsaan Qureshi, Karishma Gokani, Kush Naker, Johanna Kellett Wright, Rachel Williams, Tawassal Riaz, Florentina Penciu, Claudio Di Maso, Elizabeth Howe, Iason Vichos, Mujtaba Ghulam Farooq, Rabiullah Noristani, Xin Li Yao, Neil J. Oldfield, Daniel Hammersley, Sue Belton, Simon Royal, Alberto San Francisco Ramos, Cecilia Hultin, Eva Galiza, Farah Shiham, Carla Solórzano, Hannah Sainsbury, Kelly Davies, Pauline Ambrose, Lisa Hitchins, Natalie Baker, Stephanie Leung, Ross Fothergill, Kerry Godwin, Karen R. Buttigieg, Imam H. Shaik, Phill Brown, Chanice Knight, Paminder Lall, Lauren Allen,

Vaccine Coverage and Hesitancy

BackgroundUse of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.MethodsCom-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. 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) were 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 non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 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.FindingsBetween Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.InterpretationDespite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.FundingUK Vaccine Task Force and National Institute for Health Research.