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Randomized Controlled Trial
. 2023 Jun;86(6):574-583.
doi: 10.1016/j.jinf.2023.03.027. Epub 2023 Apr 6.

Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study - A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines

Robert H Shaw  1 , Melanie Greenland  2 , Arabella S V Stuart  3 , Parvinder K Aley  2 , Nick J Andrews  4 , J Claire Cameron  5 , Sue Charlton  6 , Elizabeth A Clutterbuck  2 , Andrea M Collins  7 , Tom Darton  8 , Tanya Dinesh  2 , Christopher J A Duncan  9 , Saul N Faust  10 , Daniela M Ferreira  7 , Adam Finn  11 , Anna L Goodman  12 , Christopher A Green  13 , Bassam Hallis  6 , Paul T Heath  14 , Helen Hill  7 , Teresa Lambe  15 , Vincenzo Libri  16 , Patrick J Lillie  17 , Ella Morey  2 , Yama F Mujadidi  2 , Ruth Payne  8 , Emma L Plested  2 , Samuel Provstgaard-Morys  2 , Maheshi N Ramasamy  3 , Mary Ramsay  4 , Robert C Read  10 , Hannah Robinson  2 , Gavin R Screaton  18 , Nisha Singh  2 , David P J Turner  19 , Paul J Turner  20 , Rachel White  2 , Jonathan S Nguyen-Van-Tam  21 , Xinxue Liu  2 , Matthew D Snape  22 ; Com-COV2 Study Group
Affiliations
Randomized Controlled Trial

Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study - A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines

Robert H Shaw et al. J Infect. 2023 Jun.

Abstract

Background: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development.

Methods: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration.

Findings: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies.

Interpretation: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics.

Isrctn: 27841311 EudraCT:2021-001275-16.

Keywords: Adenovirus vector; Antibody; Heterologous; Persistence; SARS-CoV2; T-cell; Vaccine; mRNA lipid nanoparticle.

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Conflict of interest statement

Declaration of interests At the time of this study, MDS acted on behalf of the University of Oxford as an Investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines. He received no personal financial payment for this work. Subsequent to this study MDS is employed by Moderna Biotech UK and holds equity in this company. Moderna Biotech had no role in the study design, analysis of data or interpretation of results. JSN-V-T was seconded to the Department of Health and Social Care (DHSC), England from October 2017 to March 2022; since leaving DHSC he reports a lecture fee from AstraZeneca. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and chair of the WHO European Technical Advisory Group of Experts (ETAGE) on Immunisation. He is an investigator and/or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer, and Sanofi, and of other vaccines from these and other manufacturers, including GlaxoSmithKline, VPI Pharmaceuticals, Takeda, and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. PTH acts on behalf of St. George's University of London as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva. He receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca, and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering the ChAd vaccine and is an occasional consultant to Vaccitech, unrelated to this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in -vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University’s revenue sharing policy. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests. The views expressed in this manuscript are those of its authors and not necessarily those of DHSC, VTF or NIHR.

Figures

Fig. 1
Fig. 1
Kinetics of immune response over time with all schedules in the seronegative population. (A) Anti-spike IgG titre, (B) T-cell ELISpot count; (C) Live virus neutralisation assay for wild type, Beta, Delta and Omicron variants. D0 refers to time of second dose. Data points are geometric mean concentrations, with whiskers showing the 95% confidence intervals. Day 28 Omicron VOC titres are only available for homologous schedules due to laboratory constraints.
Fig. 2
Fig. 2
Forest plots comparing heterologous and homologous immunological outcomes per timepoint for (A) Anti-spike IG, (B) T-cell ELISpot and (C) Live virus neutralising assay for wild type, Beta, Delta and Omicron variants. GMC (geometric mean concentration) shown per schedule per timepoint with 95% CI (confidence intervals). aGMR (adjusted geometric mean ratio) with 95% CI are displayed using separate mixed effects models for BNT-primed and ChAd-primed groups, adjusting for random effects (site) and fixed effects (schedule, cohort, D0 level, interval between first and second doses, exact number of days between second dose and blood test, BMI, Comorbidity [presence/absence of cardiovascular condition, respiratory condition of diabetes], Sex, Age, Ethnicity) comparing each schedule’s timepoint to the equivalent timepoint in the homologous schedule. Day 28 Omicron VOC titres are only available for homologous schedules due to laboratory constraints and so aGMRs are unavailable at this timepoint. The forestplot for Omicron VOC is not displayed as it suffers more greatly from lower limit censoring. Neutralising activity against Omicron was so low, that large proportions of the samples did not have an NT50 that was above the LLOQ. Values were imputed as half the LLOQ and so the aGMRs have been artefactually brought closer to one. This artefactual bringing closer to one affects lower titres more and therefore affects the D112 timepoint more. Tabulated results for all variants are also available in Supplementary Table 3.
Fig. 2
Fig. 2
Forest plots comparing heterologous and homologous immunological outcomes per timepoint for (A) Anti-spike IG, (B) T-cell ELISpot and (C) Live virus neutralising assay for wild type, Beta, Delta and Omicron variants. GMC (geometric mean concentration) shown per schedule per timepoint with 95% CI (confidence intervals). aGMR (adjusted geometric mean ratio) with 95% CI are displayed using separate mixed effects models for BNT-primed and ChAd-primed groups, adjusting for random effects (site) and fixed effects (schedule, cohort, D0 level, interval between first and second doses, exact number of days between second dose and blood test, BMI, Comorbidity [presence/absence of cardiovascular condition, respiratory condition of diabetes], Sex, Age, Ethnicity) comparing each schedule’s timepoint to the equivalent timepoint in the homologous schedule. Day 28 Omicron VOC titres are only available for homologous schedules due to laboratory constraints and so aGMRs are unavailable at this timepoint. The forestplot for Omicron VOC is not displayed as it suffers more greatly from lower limit censoring. Neutralising activity against Omicron was so low, that large proportions of the samples did not have an NT50 that was above the LLOQ. Values were imputed as half the LLOQ and so the aGMRs have been artefactually brought closer to one. This artefactual bringing closer to one affects lower titres more and therefore affects the D112 timepoint more. Tabulated results for all variants are also available in Supplementary Table 3.
Fig. 3
Fig. 3
Forest plots comparing heterologous and homologous rates of decay of immunological outcomes per time period by aGMR of GMRs for (A) Anti-spike IG, (B) T-cell ELISpot and (C) Live virus neutralising assay for wild type, Beta, Delta and Omicron variants. GMR (geometric mean ratios) with 95% CI are displayed for rows with fold changes, which compare each time period’s fold change for that schedule to the fold change for the same period of the relevant homologous schedule. aGMR (adjusted GMR) with 95% CI are displayed using separate mixed effects models for BNT-primed and ChAd-primed groups, adjusting for random effects (site) and fixed effects (schedule, cohort, D0 level, interval between first and second doses, exact number of days between second dose and blood test, BMI, Comorbidity [presence/absence of cardiovascular condition, respiratory condition of diabetes], Sex, Age, Ethnicity) comparing each schedule’s time period GMR to the equivalent time period GMR in the homologous schedule.
Fig. 3
Fig. 3
Forest plots comparing heterologous and homologous rates of decay of immunological outcomes per time period by aGMR of GMRs for (A) Anti-spike IG, (B) T-cell ELISpot and (C) Live virus neutralising assay for wild type, Beta, Delta and Omicron variants. GMR (geometric mean ratios) with 95% CI are displayed for rows with fold changes, which compare each time period’s fold change for that schedule to the fold change for the same period of the relevant homologous schedule. aGMR (adjusted GMR) with 95% CI are displayed using separate mixed effects models for BNT-primed and ChAd-primed groups, adjusting for random effects (site) and fixed effects (schedule, cohort, D0 level, interval between first and second doses, exact number of days between second dose and blood test, BMI, Comorbidity [presence/absence of cardiovascular condition, respiratory condition of diabetes], Sex, Age, Ethnicity) comparing each schedule’s time period GMR to the equivalent time period GMR in the homologous schedule.
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