Summary
Background
Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating 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).
Methods
Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (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. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311.
Findings
Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation.
Interpretation
Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification.
Funding
UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.
Introduction
Our world in data. Statistics and research coronavirus pandemic (COVID-19). https://doi.org/10/2021 2021. https://ourworldindata.org/coronavirus (accessed Nov 30, 2021).
As of Oct 20, 2021, over 3 billion people globally have received at least one dose of a SARS-COV-2 vaccine, but only 2·8% of people in low-income countries.
Our world in data. Statistics and research coronavirus pandemic (COVID-19). https://doi.org/10/2021 2021. https://ourworldindata.org/coronavirus (accessed Nov 30, 2021).
Although there are now 24 different vaccines approved worldwide, manufacturing issues, raw material shortages, and surges in infection have led to supply chain disruption and delays.
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COVID-19 Vaccine Market Dashboard.
The emergence of new safety concerns with available vaccines led to changes in vaccine deployment policy. In early 2021, multiple countries implemented age restrictions for the ChAdOx1 n-CoV-19 vaccine (AstraZeneca, hereafter referred to as ChAd) after the emergence of vaccine-induced thrombocytopenia and thrombosis, and recent pauses in immunisation of young people with mRNA vaccines due to concerns about myocarditis.
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AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets.
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Use of the AstraZeneca COVID-19 (AZD1222) vaccine: updated JCVI statement.
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Such changes have disrupted roll-out plans, and have the potential to do so in future. Additionally, concerns about waning vaccine immunity, and the potential for existing schedules to protect against new SARS-CoV-2 variants of concern have led to questions on the optimisation of vaccine schedules.
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Evidence before this study
Most high-income countries have now vaccinated their adult populations with a primary course of COVID-19 vaccine, but deployment remains low across lower income regions. Heterologous prime-boost schedules are a measure that could enhance deployment flexibility and improve access to vaccines. Evidence to support the use of mixed schedules is rapidly evolving. We searched PubMed for articles published between database inception and Oct 20, 2021 using the terms “(COVID) AND (heterologous) AND (vaccin*) NOT (BCG)” with no language restrictions. An additional search was done of the medRxiv preprint server. There are few randomised controlled trials examining heterologous schedules, but many observational studies. Heterologous schedules studied included: ChAdOx1 nCoV-19 (ChAd)/BNT162b2 (BNT), BNT/ChAd, ChAd/mRNA-1273, Ad26/Ad5, ChAd/BBV152, Coronavac/ChAd, Coronavac/Convidecia, and Ad26/BNT. Where a homologous comparator was included, reactogenicity appeared increased in heterologous boost, but was tolerated. There were no safety concerns identified in any study. Heterologous schedules were immunogenic, with mRNA boost after ChAd prime inducing higher concentrations of neutralising antibodies when compared with homologous ChAd. mRNA boost after ChAd prime induced a T-cell response above that of homologous comparators. Adenoviral-vectored boost after inactivated prime appears to enhance immunogenicity over that of inactivated prime-boost.
Added value of this study
These data are the first from a randomised controlled trial of COVID-19 vaccines of heterologous mRNA boost and protein-subunit boost. We have shown that reactogenicity at boost is consistently increased in heterologous versus homologous schedules of ChAd and mRNA vaccines, but not increased by NVX-CoV2373 (NVX) boost after ChAd or BNT prime. mRNA-1273 as a heterologous boost after ChAd or BNT prime induces a higher binding and neutralising antibody response than either homologous schedule. Heterologous boost with NVX after ChAd prime was superior to homologous ChAd for induction of humoral and cellular immunity. NVX after BNT prime did not meet non-inferiority criteria for binding antibodies when compared with homologous BNT; however, in a non-randomised comparison, binding antibody concentrations were still well above the geometric mean concentration observed following ChAd/ChAd. Decrements in neutralising antibody responses to beta and delta variants of concern were largely conserved across schedules, whereas T-cell responses were not affected.
Implications of all the available evidence
This study adds to the body of evidence that heterologous COVID-19 vaccination is safe, tolerated, and immunogenic. Flexibility of schedules should be considered to improve access to COVID-19 vaccination globally.
Denmark continues its vaccine rollout without the COVID-19 vaccine from AstraZeneca.
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Recommendations on the use of COVID-19 vaccines.
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Vaccins contre la Covid-19 : la HAS maintient la limite d’âge de 55 ans pour Vaxzevria. 12/05/2021.
Since then, a number of studies have shown an acceptable short-term safety profile of ChAd and BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT) heterologous vaccination, although with some transient increased reactogenicity.
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There is accruing evidence that the use of an mRNA boost after adenoviral-vector prime might enhance humoral and cellular responses against SARS-CoV-2, and that this response translates to efficacy against COVID-19.
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The only other available data regarding heterologous schedules comes from preprints that suggest that adenoviral vaccines might be an effective boost for inactivated whole-virion prime.
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Novavax and Serum Institute of India announce submission to World Health Organization for emergency use listing of Novavax’ COVID-19 vaccine.
This vaccine can be transported and stored at standard refrigeration temperatures, making it particularly suitable for deployment in low-resource settings.
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An mRNA vaccine mRNA-1273 (Moderna, hereafter referred to as m1273) has also shown high efficacy in clinical trials, with an acceptable safety profile, although with appreciable reactogenicity after second dose.
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Here, we present findings from the related Com-COV2 study, a non-inferiority randomised controlled trial examining safety, reactogenicity, and immunogenicity of heterologous COVID-19 regimens including m1273 and NVX as boost vaccines for people who received a first dose of ChAd or BNT in the community COVID-19 vaccination programme in the UK, given after the prime at 8–12 weeks.
Methods
Study design
Most participants were enrolled into the general cohort while a subset (n=150, selected on the basis of site capacity and participant availability) were enrolled into an immunology cohort that had mucosal and salivary samples collected, along with two additional blood tests to explore the kinetics of the immune responses.
Participants
Randomisation and masking
Computer generated randomisation lists were prepared by the study statistician. Participants were randomised (1:1:1) to receive a single dose of either the same vaccine as their prime dose (BNT or ChAd homologous schedule), m1273, or NVX (heterologous schedules).
Randomisation was done by random block sizes of three and six. Randomisation was stratified by study site, cohort (immunology or general), and prime vaccine (ChAd/BNT). Clinical research nurses who were not involved in endpoint evaluation did the randomisation using REDCap version 10.6.13 and prepared and administered the vaccine.
Participants were masked to boost vaccine allocation at enrolment. Blinding was maintained by completing pages and by preparing vaccines out of sight of participants, and use of the same syringe type across vaccines, with the drawn volume concealed by applying a masking tape. Following the introduction of COVID-19 vaccine certification in the UK, the study was amended on June 21, 2021, to allow individual participant unblinding where necessary to prevent disadvantage in accessing facilities or travel. This took place after all participants had completed the 28 day postvaccination diary monitoring period. Staff involved in study delivery, including in the assessment of adverse events, were aware of vaccine allocation. Laboratory staff processing the immunology samples remained blinded to vaccine allocation.
Procedures
Participants meeting inclusion and exclusion criteria at the online screening (and additional subsequent telephone screening for some participants) were invited to attend a screening and enrolment visit (day 0). Participants who met final eligibility criteria and provided written informed consent were randomly assigned to a study group and vaccinated at the day 0 visit. Baseline haematological and biochemical blood tests were taken before vaccination at day 0.
Four vaccines were used in this study. ChAd was given as a 0·5 mL intramuscular injection into the upper arm. BNT was given as a 0·3 mL intramuscular injection into the upper arm. m1273 was given as a 0·5 mL intramuscular injection into the upper arm, and NVX as a 0·5 mL intramuscular dose injection into the upper arm.
Participants were instructed to notify trial teams if they received a positive SARS-CoV-2 test in the community. They were then invited for a study visit to allow for clinical assessment, collection of blood samples, and a nasopharyngeal swab, and were asked to complete a COVID-19 symptom diary for 7 days.
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The conversion factors to international standard units can be found in the appendix (pp 3–4). Sera from day 0 were analysed at Porton Down, Public Health England, by ECLIA (Cobas platform, Roche Diagnostics) to determine anti-SARS-CoV-2 nucleocapsid IgG status (reported as negative if below a cutoff index of 1·0). The samples from the immunology cohort (n=25) were also tested at Porton Down, UK Health Security Agency to measure the normalised 80% neutralising antibody titre (NT80) for live SARS-CoV-2 virus (lineage Victoria/01/2020) by microneutralisation assays.
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For participants from five of nine selected sites, IFN-γ secreting T cells specific to whole spike protein epitopes, designed based on the Wuhan-Hu-1 sequence (YP_009724390.1), were detected using a modified T-SPOT-Discovery test done at Oxford Immunotec (Abingdon, UK) within 32 h of venepuncture, using the addition of T-Cell Xtend reagent to extend peripheral blood mononuclear cell (PBMC) survival. Participants at the other four sites did not have these taken as their sites were too far from the processing laboratory to enable sample integrity. T-cell frequencies were reported as spot forming cells (SFC) per 250 000 PBMCs with a lower limit of detection of one in 250 000 PBMCs. Intracellular cytokine staining was done on cryopreserved PBMCs, stimulated for 16 h with SARS-CoV-2 antigens (based on the Wuhan-Hu-1 sequence). Cells were stained with viability dye and fluorochrome-conjugated antibodies to CD3, CD4, and CD8 and further stained with fluorochrome-conjugated antibodies specific to IFN-γ, TNF-α, IL-2, IL-4, IL-5, and IL-13. Data are presented as percentage of CD4 or CD8 T cells expressing specific cytokines.
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Outcomes
The primary outcome was non-inferiority of serum SARS-CoV-2 anti-spike IgG concentration 28 days after heterologous boost in comparison with homologous boost (the geometric mean ratio [GMR]) in participants who were seronegative for SARS CoV-2 nucleocapsid IgG at enrolment.
Statistical analysis
Guidelines on clinical evaluation of vaccines: regulatory expectations.
We also presented geometric means, adjusted GMRs, and corresponding two-sided 95% CIs in the mITT population. A heterologous arm was considered superior to its homologous arm if the lower limit of the two-sided 95% CI lies above one, and the homologous boost arm was superior if the upper limit of the two-sided 95% CI lies below one. The analyses for secondary immunological outcome were also carried out among the mITT population. For all immunological outcomes, censored data reported as below the lower limit of detection or lower limit of quantification were imputed with a value equal to half of the threshold before transformation. Correlations between different immunological outcomes were evaluated by Pearson correlation coefficients. Participants who received at least one dose of the study vaccines were included in the safety analysis. The proportion of participants with at least one safety event was reported by vaccine schedule.
The sample size calculation assumed a non-inferiority margin of a 0·63 fold difference between the geometric mean concentration (GMC) in the heterologous and homologous boost arms, a SD of 0·456 on log10 scale, and a true difference in GMC on log10 scale of zero. The study needed to recruit 175 participants in each arm to achieve 90% power at a one-sided 1·25% significance level, after adjusting for an attrition rate of 25% due to baseline SARS-CoV-2 seropositivity or loss to follow-up. Statistical analyses were done using R version 4.1.1 and SAS version 9.4.
Role of the funding source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
Figure 1Trial profile
BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVX-CoV2373 vaccine, Novavax.
Table 1Baseline characteristics by study arm
Data are n (%), mean (SD), or median (range). BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax.
Table 2Summary of immunogenicity between heterologous and homologous prime-boost schedules at 28 days post boost
In the per-protocol analysis, data are n/N, GMC (95% CI), and GMR (98·75% CI); in the modified intention-to-treat analysis, data are n/N, GMC (95% CI), and GMR (95% CI). BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT50=50% focus reduction neutralising antibody titre. GMC=geometric mean concentration. GMR=geometric mean ratio. m1273=mRNA–1273 vaccine, Moderna. NT80=80% neutralising antibody titre. NVX=NVXCoV2373 vaccine, Novavax. NT50=50% neutralising antibody titre. SFC=spot-forming cells. PBMC=peripheral blood mononuclear cell.
Figure 2Correlation in the modified intention-to-treat population
(A) SARS-CoV-2 anti-spike IgG and cellular response by IFN-γ ELISpot (the subset with cellular data only, n=582), (B) SARS-CoV-2 anti-spike IgG and live virus neutralising antibodies (the subset with live virus neutralising antibodies data only, n=289), (C) live virus neutralising antibodies and cellular response by IFN-γ ELISpot at 28 days after boost (the subset with live virus neutralising antibodies data only, n=289), (D) live virus neutralising antibodies tested at University of Oxford and those tested at Porton Down, UK Health Security Agency (the immunology cohort, n=123). Ellipses show the 95% CI for different vaccine schedules assuming multivariate normal distributions. Pearson correlation coefficients (95% CI) are presented for each vaccine schedule. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT50=50% focus reduction neutralising antibody titre. m1273=mRNA-1273 vaccine, Moderna. NT80=80% neutralising antibody titre. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot forming cells.
Figure 3Kinetics of immunogenicity by vaccine schedule
Cellular response data were available in around 60% of sites, the other study sites did not collect plasma samples due to logistical challenges; data presented at day 7 and day 14 were from the immunology cohort only. Data presented from day 0 and day 28 are for all participants in the modified intention-to-treat-population. Boxplots represent the median and 25th and 75th percentiles; the whiskers extend up to the largest value, not greater than 1·5 times the IQR beyond the box. (A) Anti-spike IgG and (B) T-cell response. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. m1273=mRNA−1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot-forming cells.
Table 3Summary of immunogenicity against variants of concern between heterologous and homologous prime-boost schedules at 28 days after boost
Data shown are geometric mean (95% CI), unless otherwise specified. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. ELU=ELISA laboratory units. FRNT50=50% focus reduction neutralising antibody titre. GMC=geometric mean concentration. GMR=geometric mean ratio. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax. PBMCs=peripheral blood mononuclear cells. SFC=spot-forming cells.
Figure 4Severity of solicited local and systemic reactions in days 0–7 following boost vaccination by study arm as self-reported in participant electronic diaries
Data are (A) local at vaccination site and (B) systemic. The severity presented is the participant’s highest severity across 7 days after vaccination for each solicited adverse event. Fever was defined as mild if 38·0°C to <38·5°C, moderate if 38·5°C to <39°C, and severe if ≥39·0°C. Feverish was self-reported feeling of feverishness. For systemic symptoms, grading was classified as mild if easily tolerated with no limitation on normal activity; moderate if some limitation of daily activity; severe if unable to perform normal daily activity. BNT=BNT162b2 vaccine, Pfizer–BioNTech. ChAd=ChAdOx1 nCoV-19 vaccine, AstraZeneca. m1273=mRNA-1273 vaccine, Moderna. NVX=NVXCoV2373 vaccine, Novavax.
Discussion
COVID-19 vaccine surveillance report: 14 October 2021 (week 41).
Additionally, the T-cell response across all groups was greatest with ChAd/NVX, which might prove important in terms of durability of protection and protection against new SARS-CoV-2 variants.
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These data align with real-world evidence of robust effectiveness of mixed schedules against disease.
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Together, these findings support use of the mixed schedules studied here in rapid and flexible global deployment of COVID-19 vaccines. Accordingly, these schedules should be widely recognised for travel and certification.
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It is interesting to note that in the groups receiving an NVX boost, there is a modest increase in antibody titres after day 7; although the samples’ size are small, this finding warrants further investigation.
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The ChAd/m1273 schedule also produced a substantial cellular response, whereas both heterologous and homologous mRNA schedules (BNT/m1273 and BNT/BNT) showed lower responses. Strikingly, the BNT/NVX schedule produced a response below that of all other schedules studied, suggesting important differences in the ability of adenoviral-vectored and mRNA vaccines to prime T cells for subsequent stimulation by protein antigens.
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Additionally, there was evidence of increased reactogenicity for the heterologous over the homologous mRNA schedule (BNT/m1273 vs BNT/BNT). This effect could be due to the mixing of different mRNA vaccines, or m1273 being more reactogenic than BNT, potentially consistent with higher mRNA dosage; however, it is not possible to differentiate these possible causes in our study. By contrast, there was no evidence of increased reactogenicity for the NVX containing schedules. Importantly, within the limits of the sample size of this study, none of the schedules raised any safety concerns.
Our world in data. Statistics and research coronavirus pandemic (COVID-19). https://doi.org/10/2021 2021. https://ourworldindata.org/coronavirus (accessed Nov 30, 2021).
Of the mixed schedules studied, perhaps the most relevant to these countries is the ChAd/NVX, given that neither of these vaccines require ultra-low temperature storage and the low cost of ChAd. NVX has recently been the subject of a WHO Emergency Use Licence and should become available under the COVAX scheme.
Gavi signs agreement with Novavax to secure doses on behalf of COVAX Facility.
Furthermore data for mixed schedules across platforms could help to inform the use of third-dose boosters, in addition with data from CoV-BOOST (ISRCTN12348322)
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and the recent work by Atmar and colleagues
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supporting use of mRNA vaccines for adenoviral-primed individuals. Such schedules could also allow avoidance of a second mRNA vaccine dose in adolescents, given concerns regarding myocarditis, and this hypothesis is being further studied in Com-COV3.
ISRCTN12348322. Comparing COVID-19 vaccine schedule combinations in adolescents (Com-COV3).
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JCVI statement on COVID-19 vaccination of children aged 12 to 15 years.
COVID-19 vaccine equity and booster doses.
Any increased reactogenicity with heterologous regimes might be amplified in younger groups, as reported in studies of homologous vaccine schedules.
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COVID-19 vaccine equity and booster doses.
As participants were recruited after community prime, this dose was not randomised, meaning that some caution is required when comparing ChAd versus BNT community-primed groups, especially as there were higher rates of comorbidity in the BNT-primed groups. Additionally, the proportion of participants primed with ChAd versus BNT differed according to site, creating the potential for different amounts of exposure to SARS-CoV-2 between the groups. This fact is especially important when comparing the number of breakthrough infections observed between ChAd-primed and BNT-primed groups. Due to logistical and pragmatic constraints, we were not able to incorporate a full comparative schedule for all vaccines, and thus cannot provide evidence for the use of mixed mRNA schedules in both permutations, nor the effect of prime with a protein-based vaccine followed by ChAd or mRNA.
This research confirms previous evidence of mixed adenoviral and mRNA schedules as being safe, tolerable, and immunogenic alternatives to homologous schedules when given at an 8–12 weeks interval. It also provides new evidence on the response to mixed mRNA vaccinations in a randomised trial, and novel data for the incorporation of protein-based COVID-19 vaccines into heterologous schedules. These results provide reassurance that there are multiple appropriate options to complete primary immunisation in individuals primed with BNT or ChAd, which will facilitate rapid vaccine deployment globally.
MDS and JSN-V-T conceived the trial and MDS is the chief investigator. MDS, ASVS, RHS, and XL contributed to the protocol and design of the study. ASVS, ELP, RHS, and RW led the implementation of the study. XL and MG did the statistical analysis and have verified the underlying data. ASVS, RHS, MG, XL, and MDS drafted the report. All other authors contributed to the implementation and data collection. All authors reviewed and approved the final report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Declaration of interests
MDS acts 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. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. 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 on Immunisation. He is an investigator 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 or provides 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. 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 ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG benefits 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.