Background. A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody ...responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults. Methods. We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved. Results. A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans. Conclusions. This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP. Clinical Trials Registration. ISRCTN: 78768849.
Coronavirus disease-19 (COVID-19) causes immune perturbations which may persist long term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at ...3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate, or severe disease and investigated whether it associates with long COVID. At 3 months, patients with severe disease displayed persistent activation of CD4
and CD8
T-cells, based on expression of HLA-DR, CD38, Ki67, and granzyme B, and elevated plasma levels of interleukin-4 (IL-4), IL-7, IL-17, and tumor necrosis factor-alpha (TNF-α) compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation. Patients with severe disease reported a higher number of long COVID symptoms which did not however correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex, and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.
Patients with chronic liver disease have much higher mortality associated with influenza compared to other risk groups (1). Influenza vaccine uptake is much lower in adults with chronic liver disease ...(37.3%) compared to adults aged over 65 (72.4%) or other risk groups (44.9%) (2).
Hospital-based interventions for inpatients have been shown to increase uptake (3).
Vaccination records of patients admitted to a Hepatology ward were reviewed retrospectively to understand what proportion were eligible but did not receive annual influenza vaccine through current services.
Data was collected for inpatients 26th September 2020 to 29th November 2020. GP records were used to check vaccination status within the window 01/09/2020 to 28/02/2021. Patients not registered with a local GP or deceased were excluded. We compared the rates of vaccination between at risk groups.
134 were eligible for influenza vaccination and inclusion. 95 (70.9%) were not immunised at the time of admission. 36 (29.1%) went on to be immunised in the same influenza season, leaving 59 (44.0%) of individuals not receiving a vaccine at all.
Vaccination rates are below the 75% target. Most patients, who were eligible at the time of admission, never received an influenza vaccination. An inpatient influenza vaccination programme could utilise this missed opportunity to increase vaccine uptake.
In early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. ...Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September-November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months.
ComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared.
Set-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 at least daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial.
The statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods.
ISRCTN14391248, registered on 30 March 2021.
In February 2021, the UK Department of Health and Social Care sought evidence on the safety and immunogenicity of COVID-19 and influenza vaccine co-administration to inform the 2021/2022 influenza ...vaccine policy. Co-administration could support vaccine uptake and reduce healthcare appointments. ComFluCOV was a randomised controlled trial designed to provide this evidence. This report outlines the methods used to deliver the trial in 6 months to answer an urgent public health question as part of the COVID-19 pandemic response.
ComFluCOV was commissioned by the Department of Health and Social Care and was managed by the Bristol Trials Centre, a UK-registered clinical trials unit. It was classed as an Urgent Public Health trial which facilitated fast-track regulatory approvals. Trial materials and databases were developed using in-house templates and those used in other COVID-19 vaccine trials. Participants were recruited by advertising, and via a trial website. Electronic trial systems enabled daily review of participant data. Weekly virtual meetings were held with stakeholders and trial sites.
ComFluCOV was delivered within 6 months from inception to reporting, and trial milestones to inform the Department of Health and Social Care policy were met. Set-up was achieved within 1 month. Regulators provided expedited reviews, with feedback ahead of submission. Recruitment took place at 12 sites. Over 380 site staff were trained. Overall, 679 participants were recruited in two months. The final report to the Department of Health and Social Care was submitted in September 2021, following a preliminary safety report in May 2021. Trial results have been published.
The rapid delivery of ComFluCOV was resource intensive. It was made possible in part due to a unique set of circumstances created by the pandemic situation including measures put in place to support urgent public health research and public support for COVID-19 vaccine research. Elements of the trial could be adopted to increase efficiency in 'non-pandemic' situations including working with a clinical trials unit to enable immediate mobilisation of a team of experienced researchers, greater sharing of resources between clinical trials units, use of electronic trial systems and virtual meetings.
ISRCTN14391248, submitted on 17/03/2021. Registered on 30/03/2021.
ObjectivesTo develop a regional model of COVID-19 dynamics for use in estimating the number of infections, deaths and required acute and intensive care (IC) beds using the South West England (SW) as ...an example case.DesignOpen-source age-structured variant of a susceptible-exposed-infectious-recovered compartmental mathematical model. Latin hypercube sampling and maximum likelihood estimation were used to calibrate to cumulative cases and cumulative deaths.SettingSW at a time considered early in the pandemic, where National Health Service authorities required evidence to guide localised planning and support decision-making.ParticipantsPublicly available data on patients with COVID-19.Primary and secondary outcome measuresThe expected numbers of infected cases, deaths due to COVID-19 infection, patient occupancy of acute and IC beds and the reproduction (‘R’) number over time.ResultsSW model projections indicate that, as of 11 May 2020 (when ‘lockdown’ measures were eased), 5793 (95% credible interval (CrI) 2003 to 12 051) individuals were still infectious (0.10% of the total SW population, 95% CrI 0.04% to 0.22%), and a total of 189 048 (95% CrI 141 580 to 277 955) had been infected with the virus (either asymptomatically or symptomatically), but recovered, which is 3.4% (95% CrI 2.5% to 5.0%) of the SW population. The total number of patients in acute and IC beds in the SW on 11 May 2020 was predicted to be 701 (95% CrI 169 to 1543) and 110 (95% CrI 8 to 464), respectively. The R value in SW was predicted to be 2.6 (95% CrI 2.0 to 3.2) prior to any interventions, with social distancing reducing this to 2.3 (95% CrI 1.8 to 2.9) and lockdown/school closures further reducing the R value to 0.6 (95% CrI 0.5 to 0.7).ConclusionsThe developed model has proved a valuable asset for regional healthcare services. The model will be used further in the SW as the pandemic evolves, and—as open-source software—is portable to healthcare systems in other geographies.
The safety of novel therapeutics and vaccines are typically assessed in early phase clinical trials involving “healthy volunteers.” Abnormalities in such individuals can be difficult to interpret and ...may indicate previously unrecognized medical conditions. The frequency of incidental findings (IFs) in healthy volunteers who attend for clinical trial screening is unclear. To assess this, we retrospectively analyzed data for 1838 “healthy volunteers” screened for enrolment in a UK multicenter, phase I/II severe acute respiratory syndrome‐coronavirus 2 (SARS‐COV‐2) vaccine trial. Participants were predominantly White (89.7%, 1640/1828) with a median age of 34 years (interquartile range IQR = 27–44). There were 27.7% of participants (510/1838) who had at least one IF detected. The likelihood of identifying evidence of a potential, new blood‐borne virus infection was low (1 in 238 participants) compared with identification of an elevated alanine transaminase (ALT; 1 in 17 participants). A large proportion of participants described social habits that could impact negatively on their health; 21% consumed alcohol in excess, 10% were current smokers, 11% described recreational drug use, and only 48% had body weight in the ideal range. Our data demonstrate that screening prior to enrollment in early phase clinical trials identifies a range of IFs, which should inform discussion during the consent process. Greater clarity is needed to ensure an appropriate balance is struck between early identification of medical problems and avoidance of exclusion of volunteers due to spurious or physiological abnormalities. Debate should inform the role of the trial physician in highlighting and advising about unhealthy social habits.
It is usual practice after a needle-stick injury for the source patient, with consent, to be tested for blood-borne viruses (BBV) to guide the need for HIV prophylaxis and to organise appropriate ...follow-up of the recipient. If the source patient cannot give consent and therefore is not tested then this uncertainty can heighten the injury-associated anxiety and result in unnecessary prophylaxis for the recipient. General Medical Council (GMC) guidance states that BBV testing for the sole benefit of a healthcare worker is unlawful and may only be performed if it is in the best interests of the patient. The GMC, however, does not clearly define the best interests of the patient in this scenario, so the British Medical Association (BMA) issued guidance in 2016 to fill this gap. This letter sets out to summarise the ethical arguments that underpin the BMA guidance, illustrate how this guidance could be put into practice and raise debate on this issue.
A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ...ChAdOx1 nCoV-19 (AZD1222), against this variant.
Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 − relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.
Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18–55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2–11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6–84·5) for B.1.1.7 and 81·5% (67·9–89·4) for non-B.1.1.7 lineages.
ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2.
UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
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