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

Background: Use 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. Methods: Com-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. Findings: Between 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. Interpretation: Despite 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. Funding: UK Vaccine Task Force and National Institute for Health Research

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial

BackgroundPriming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca).MethodsCom-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33).FindingsBetween Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules.InterpretationThese data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Home monitoring of HbA1c in diabetes mellitus: A protocol for systematic review and narrative synthesis on reliability, accuracy, and patient acceptability

AbstractIntroductionWorldwide there are an estimated 463 million people with diabetes. [1] In the UK people with diabetes are offered an annual review including monitoring of Haemoglobin A1c (HbA1c). [2] [3] This can identify people with diabetes who are not meeting their glycaemic targets, enabling early intervention. Those who do not attend these reviews often have higher HbA1c levels and poorer health outcomes. [4] During the Coronavirus disease of 2019 (COVID-19) pandemic, there was a 77% reduction in monitoring of HbA1c in the UK. [5] We hypothesise that people with diabetes could take finger-prick samples at home for the measurement of HbA1c.Method and AnalysisWe will perform a systematic review of current evidence for capillary blood collected at home for the measurement of HbA1c. We will examine the validity, reliability, safety, and patient acceptability of the use of capillary blood compared with the usual standard of care of venous blood. We will explore variables which affect validity of results. Using core terms of ‘Diabetes’, ‘HbA1c’ and ‘Capillary sampling’ we will search MEDLINE, Embase, CINAHL, Web of Science Core Collection, Google Scholar, Open Grey and other grey literature from database inception until 2021. Risk of bias will be assessed using the ‘COSMIN risk of bias tool to assess the quality of studies on reliability and measurement error’. Database searches and data extraction for primary outcomes will be conducted in duplicate. We will produce a narrative synthesis exploring how variables of capillary blood collection impact on validity, as well as exploring the safety and acceptability of patient self-collection.Ethics and DisseminationThis review will be submitted for publication in a peer-reviewed open-access journal. We will present our results at both national and international conferences. As a systematic review with no primary participant data or involvement, ethical approval is not applicable.PROSPERO registration numberCRD42021225606Strengths and limitations of this studyTo our knowledge this is the first systematic review to explore all postal methods of capillary blood collection for the measurement of HbA1c.This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, which offers transparency and enhances reproducibility.Due to anticipated heterogeneity in statistical approaches, summary analyses, sample storage, transportation, extraction, and assay, meta-analysis is unlikely to be appropriate and therefore narrative synthesis will be used.Due to the exclusion criteria, our findings may not be generalisable to a wider population including children, and those with haemoglobinopathies, high erythrocyte turnover or other conditions likely to affect HbA1c result.</jats:sec

Postal methods for monitoring HbA1c in diabetes mellitus: a protocol for systematic review

BackgroundWorldwide there are an estimated 463 million people with diabetes. In the UK people with diabetes are offered annual review, which includes monitoring of haemoglobin A1c (HbA1c). This can identify people with diabetes who are not meeting their glycaemic targets, enabling early intervention. Those who do not attend these reviews often have poorer health outcomes. During the COVID-19 pandemic, there was a 77% reduction in monitoring of HbA1c in the UK.AimIt is hypothesised that people with diabetes could take finger-prick samples at home for measurement of HbA1c. This study will examine the agreement and correlation of capillary HbA1c values compared with a venous reference standard. It will explore reliability and repeatability of capillary HbA1c testing methods, as well as the direction of effect of storage variables. The study will also explore patient acceptability and safety. It will look at capillary blood methods that would be suitable for posting.Design &amp; settingA systematic review will be undertaken.MethodThe core terms of ‘Diabetes’, ‘HbA1c’ and ‘Capillary sampling’ will be used to search MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science Core Collection, Google Scholar, OpenGrey, and other grey literature, from database inception until 2021. Risk of bias will be assessed using the ‘COSMIN Risk of Bias tool to assess the quality of studies on reliability and measurement error’.ConclusionA narrative synthesis will be produced to explore whether there are viable postal alternatives to venous sampling, as well as exploring acceptability and safety of patient self-collection.</jats:sec

Postal methods for monitoring HbA1c in diabetes mellitus: a protocol for systematic review

Background Worldwide there are an estimated 463 million people with diabetes. In the UK people with diabetes are offered annual review, which includes monitoring of haemoglobin A1c (HbA1c). This can identify people with diabetes who are not meeting their glycaemic targets, enabling early intervention. Those who do not attend these reviews often have poorer health outcomes. During the COVID-19 pandemic, there was a 77% reduction in monitoring of HbA1c in the UK.Aim It is hypothesised that people with diabetes could take finger-prick samples at home for measurement of HbA1c. This study will examine the agreement and correlation of capillary HbA1c values compared with a venous reference standard. It will explore reliability and repeatability of capillary HbA1c testing methods, as well as the direction of effect of storage variables. The study will also explore patient acceptability and safety. It will look at capillary blood methods that would be suitable for posting.Design &amp; setting A systematic review will be undertaken.Method The core terms of ‘Diabetes’, ‘HbA1c’ and ‘Capillary sampling’ will be used to search MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science Core Collection, Google Scholar, OpenGrey, and other grey literature, from database inception until 2021. Risk of bias will be assessed using the ‘COSMIN Risk of Bias tool to assess the quality of studies on reliability and measurement error’.Conclusion A narrative synthesis will be produced to explore whether there are viable postal alternatives to venous sampling, as well as exploring acceptability and safety of patient self-collection

Home monitoring of Haemoglobin A1c in diabetes:A systematic review and narrative synthesis on accuracy, reliability, and patient acceptability

AimIn the United Kingdom people with diabetes who do not attend annual review appointments often have higher Haemoglobin A1c (HbA1c) levels.1-3 We aim to determine the acceptability of self-collected posted capillary blood samples, and if they produce accurate and reliable HbA1c results.MethodsWe include adult studies comparing capillary blood to venous blood for measuring HbA1c. We exclude methods not suitable for postage. Electronic databases of MEDLINE, Embase, CINAHL, Web of Science, Google Scholar, and OpenGrey were searched from inception to September 2021, as well as relevant conference abstracts. Two reviewers performed study selection, data extraction, and risk of bias assessment independently. Narrative synthesis was performed.ResultsOur search retrieved 3747 records. Following de-duplication and screening 30 articles were included. The mean difference (MD) and limits of agreement (LoA) between capillary and venous HbA1c were smaller and narrower respectively when micro/capillary tubes (micro/cap) were used for capillary blood storage compared to Dried Blood Spots (capDBS). (micro/cap MD range -0.4 to 1.4 mmol/mol vs capDBS MD range -4.3 to 7.2 mmol/mol, micro/cap LoA width 2.4 to 6mmol/mol vs capDBS LoA width 11.7 to 16.8 mmol/mol). After using self-collection kits, 83-96% of participants reported satisfaction, 87-99% found it easy, and 69-94% reported they would use it again.ConclusionMicrotubes/capillary tubes look promising as a method of self-collecting and posting capillary blood samples for the measurement of HbA1c based on the accuracy and reliability findings presented. DBS samples demonstrated comparatively poorer accuracy. Data on acceptability were limited and further research is needed