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AbstractObjectiveTo estimate the real world effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S vaccines against confirmed covid-19 symptoms (including the UK variant of concern B.1.1.7), admissions to hospital, and deaths.DesignTest negative case-control study.SettingCommunity testing for covid-19 in England.Participants156 930 adults aged 70 years and older who reported symptoms of covid-19 between 8 December 2020 and 19 February 2021 and were successfully linked to vaccination data in the National Immunisation Management System.InterventionsVaccination with BNT162b2 or ChAdOx1-S.Main outcome measuresPrimary outcomes were polymerase chain reaction confirmed symptomatic SARS-CoV-2 infections, admissions to hospital for covid-19, and deaths with covid-19.ResultsParticipants aged 80 years and older vaccinated with BNT162b2 before 4 January 2021 had a higher odds of testing positive for covid-19 in the first nine days after vaccination (odds ratio up to 1.48, 95% confidence interval 1.23 to 1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore compared with the baseline post-vaccination period. Vaccine effects were noted 10 to 13 days after vaccination, reaching a vaccine effectiveness of 70% (95% confidence interval 59% to 78%), then plateauing. From 14 days after the second dose a vaccination effectiveness of 89% (85% to 93%) was found compared with the increased baseline risk. Participants aged 70 years and older vaccinated from 4 January (when ChAdOx1-S delivery commenced) had a similar underlying risk of covid-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (51% to 69%) from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% (41% to 73%) from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards. On top of the protection against symptomatic disease, a further 43% (33% to 52%) reduced risk of emergency hospital admission and 51% (37% to 62%) reduced risk of death was observed in those who had received one dose of BNT162b2. Participants who had received one dose of ChAdOx1-S had a further 37% (3% to 59%) reduced risk of emergency hospital admission. Follow-up was insufficient to assess the effect of ChAdOx1-S on mortality. Combined with the effect against symptomatic disease, a single dose of either vaccine was about 80% effective at preventing admission to hospital with covid-19 and a single dose of BNT162b2 was 85% effective at preventing death with covid-19.ConclusionVaccination with either one dose of BNT162b2 or ChAdOx1-S was associated with a significant reduction in symptomatic covid-19 in older adults, and with further protection against severe disease. Both vaccines showed similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 was associated with further protection against symptomatic disease. A clear effect of the vaccines against the B.1.1.7 variant was found.

Recent studies suggest an increased risk of reinfection with the SARS-CoV-2 Omicron variant compared with previous variants, potentially due to an increased ability to escape immunity specific to older variants, high antigenic divergence of Omicron from earlier virus variants as well as its altered cell entry pathway. The present study sought to investigate epidemiological evidence for differential SARS-CoV-2 reinfection intervals and incidence rates for the Delta versus Omicron variants within Wales. Reinfections in Wales up to February 2022 were defined using genotyping and whole genome sequencing. The median inter-infection intervals for Delta and Omicron were 226 and 192 days, respectively. An incidence rate ratio of 2.17 for reinfection with Omicron compared to Delta was estimated using a conditional Poisson model, which accounted for several factors including sample collection date, age group, area of residence, vaccination and travel status. These findings are consistent with an increased risk of reinfection with the Omicron variant, and highlight the value of monitoring emerging variants that have the potential for causing further waves of cases.

IntroductionThe emergence of the novel respiratory SARS-CoV-2 and subsequent COVID-19 pandemic have required rapid assimilation of population-level data to understand and control the spread of infection in the general and vulnerable populations. Rapid analyses are needed to inform policy development and target interventions to at-risk groups to prevent serious health outcomes. We aim to provide an accessible research platform to determine demographic, socioeconomic and clinical risk factors for infection, morbidity and mortality of COVID-19, to measure the impact of COVID-19 on healthcare utilisation and long-term health, and to enable the evaluation of natural experiments of policy interventions.Methods and analysisTwo privacy-protecting population-level cohorts have been created and derived from multisourced demographic and healthcare data. The C20 cohort consists of 3.2 million people in Wales on the 1 January 2020 with follow-up until 31 May 2020. The complete cohort dataset will be updated monthly with some individual datasets available daily. The C16 cohort consists of 3 million people in Wales on the 1 January 2016 with follow-up to 31 December 2019. C16 is designed as a counterfactual cohort to provide contextual comparative population data on disease, health service utilisation and mortality. Study outcomes will: (a) characterise the epidemiology of COVID-19, (b) assess socioeconomic and demographic influences on infection and outcomes, (c) measure the impact of COVID-19 on short -term and longer-term population outcomes and (d) undertake studies on the transmission and spatial spread of infection.Ethics and disseminationThe Secure Anonymised Information Linkage-independent Information Governance Review Panel has approved this study. The study findings will be presented to policy groups, public meetings, national and international conferences, and published in peer-reviewed journals.

There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0–28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04–2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21–6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01–1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99–13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04–1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14–8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15–1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15–1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22–2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection.

In the context of the WHO’s measles and rubella elimination targets and European Immunization Agenda 2030, this large cross-sectional study aimed to identify inequalities in measles vaccination coverage in Wales, UK. The vaccination status of individuals aged 2 to 25 years of age, alive and resident in Wales as of 31 August 2021, was ascertained through linkage of the National Community Child Health Database and primary care data. A series of predictor variables were derived from five national datasets and all analysis was carried out in the Secure Anonymised Information Linkage Databank at Swansea University. In these 648,895 individuals, coverage of the first dose of measles-containing vaccine (due at 12–13 months of age) was 97.1%, and coverage of the second dose (due at 3 years and 4 months) in 4 to 25-year-olds was 93.8%. In multivariable analysis, excluding 0.7% with known refusal, the strongest association with being unvaccinated was birth order (families with six or more children) and being born outside of the UK. Living in a deprived area, being eligible for free school meals, a lower level of maternal education, and having a recorded language other than English or Welsh were also associated with lower coverage. Some of these factors may also be associated with refusal. This knowledge can be used to target future interventions and prioritise areas for catch up in a time of limited resource.

Universal immunization substantially reduces morbidity and mortality from vaccine-preventable diseases. In recent years, routine immunization coverage has varied considerably among countries across the WHO European Region, and among different populations and districts within countries. It has even declined in some countries. Sub-optimal immunization coverage contributes to accumulations of susceptible individuals and can lead to outbreaks of vaccine-preventable diseases. The European Immunization Agenda 2030 (EIA2030) seeks to build better health in the WHO European Region by ensuring equity in immunization and supporting immunization stakeholders in devising local solutions to local challenges. The factors that influence routine immunization uptake are context specific and multifactorial; addressing immunization inequities will require overcoming or removing barriers to vaccination for underserved individuals or populations. Local level immunization stakeholders must first identify the underlying causes of inequities, and based on this information, tailor resources, or service provision to the local context, as per the organization and characteristics of the health care system in their countries. To do this, in addition to using the tools already available to broadly identify immunization inequities at the national and regional levels, they will need new pragmatic guidance and tools to address the identified local challenges. It is time to develop the necessary guidance and tools and support immunization stakeholders at all levels, especially those at the subnational or local health centre levels, to make the vision of EIA2030 a reality.

•First study to examine equality in coverage of COVID-19 vaccination across Wales.•Overall vaccination coverage for COVID-19 vaccination is high.•Vaccination coverage is lower in more deprived areas and among ethnic minority groups.•First vaccine study to use census linkage providing high data coverage on ethnic group.•Closing the vaccination equity gap before further waves of infection should be a priority. The COVID-19 pandemic has highlighted existing health inequalities for ethnic minority groups and those living in more socioeconomically deprived areas in the UK. With higher levels of severe outcomes in these groups, equitable vaccination coverage should be prioritised. The aim of this study was to identify inequalities in coverage of COVID-19 vaccination in Wales, UK and to highlight areas which may benefit from routine enhanced surveillance and targeted interventions. Records within the Wales Immunisation System (WIS) population register were linked to the Welsh Demographic Service Dataset (WDSD) and central list of shielding patients, held within the Secure Anonymised Information Linkage (SAIL) Databank. Ethnic group was derived from the 2011 census and over 20 administrative electronic health record (EHR) data sources. Uptake of first dose of any COVID-19 vaccine was analysed over time, with the odds of being vaccinated as at 25th April 2021 by sex, health board of residence, rural/urban classification, deprivation quintile and ethnic group presented. Using logistic regression models, analyses were adjusted for age group, care home resident status, health and social care worker status and shielding status. This study included 1,256,412 individuals aged 50 years and over. Vaccine coverage increased steadily from 8th December 2020 until mid-April 2021. Overall uptake of first dose of COVID-19 vaccine in this group was 92.1%. After adjustment the odds of being vaccinated were lower for individuals who were male, resident in the most deprived areas, resident in an urban area and an ethnic group other than White. The largest inequality was seen between ethnic groups, with the odds of being vaccinated 0.22 (95 %CI 0.21–0.24) if in any Black ethnic group compared to any White ethnic group. Ongoing monitoring of inequity in uptake of vaccinations is required, with better targeted interventions and engagement with deprived and ethnic communities to improve vaccination uptake.

Issue Title: Advances in Pharmacophores and 3-D Screening This paper describes the extension of our earlier multiobjective method for generating plausible pharmacophore hypotheses to incorporate partial matches. Diverse sets of molecules rarely adopt exactly the same binding mode, and so allowing the identification of partial matches allows our program to be applied to larger and more diverse datasets. The method explores the conformational space of a series of ligands simultaneously with their alignment using a multiobjective genetic algorithm (MOGA). The principles of Pareto ranking are used to evolve a diverse set of pharmacophore hypotheses that are optimised on conformational energy of the ligands, the goodness of the overlay and the volume of the overlay. A partial match is defined as a pharmacophoric feature that is present in at least two, but not all, of the ligands in the set. The number of ligands that map to a given pharmacophore point is taken into account when evaluating an overlay. The method is applied to a number of test cases extracted from the Protein Data Bank (PDB) where the true overlay is known.[PUBLICATION ABSTRACT]

•Small differences in vaccine uptake in the most and least deprived areas.•Significant inequalities in timeliness, widening for doses two and three.•Consideration is needed on interventions that will help improve timeliness.•Need for routine monitoring of timeliness and what influences delayed vaccination. Infants aged under one year are at the highest risk of severe complications or death from pertussis infection. Prompt vaccination with a three dose course at two, three and four months of age decreases the amount of time they are vulnerable following waning of maternal antibodies. In Wales, uptake of all three doses of the primary course of pertussis containing vaccine is high. However, timeliness and equity at a population level have not been previously reported. This analysis included 163,733 children born from 1st January 2013 to 31st December 2017. In this cohort 87.9% received the first dose of a pertussis containing vaccine by 12 weeks of age, 87.1% had received all three doses by 24 weeks of age, and 96.3% received three doses by 52 weeks of age. Differences in uptake between those living in the most deprived and least deprived quintiles of Lower Super Output Area (LSOA) were smaller than differences in timeliness, but statistically significant. In 2017 the difference in timely uptake between those living in the most and least deprived quintiles was 4%, 5% and 7% for doses one, two and three respectively. There was a difference of 10% in the proportion of infants receiving all three primary vaccinations on time between the most and least deprived quintile of LSOAs. Consideration is needed on interventions that will help improve timeliness such as enhanced follow up of defaulters, electronic communication between primary care data systems, enhanced health visitor intervention and opportunistic vaccination in those who fail to attend scheduled vaccination appointments. There is also the need for routine monitoring of timeliness and further research into what influences delayed vaccination.

The Live Attenuated Influenza Vaccine (LAIV) protects two-year-old children against influenza and serious illness, however uptake across Wales is sub-optimal and below Welsh Government targets. Awareness of the vaccine and its effectiveness, convenience of appointments/clinics and lack of central appointment provision may influence uptake. We piloted provision of set appointment dates and times to investigate impact on uptake of LAIV amongst two-year-olds and identify potential operational issues in a pragmatic selection of general practices. Parents/guardians of two-year-olds in pilot practices (n=9) were sent a personalised letter using the UK Government Notify System, a scheduled vaccination appointment and an evidence-based Frequently Asked Questions sheet. Children in non-pilot practices (n=37) received a general letter and FAQ sheet, without a scheduled appointment. Intervention practices were selected based on low LAIV uptake amongst two-year-olds in the two previous influenza seasons. A mixed-methods, uncontrolled, evaluation of the pilot included analysis of vaccination practice-level uptake data and qualitative data from baseline and follow-up stakeholder surveys. Further patient-level analysis of the intervention to determine individual effects and impact on deprivation-based health inequalities is planned. Compared to the previous year, pilot practices saw a median increase in LAIV uptake amongst two-year-olds of 30·4% (IQR 11·7% to 33·6%), whilst non-pilot practices saw a median decrease of 4·7% (IQR 16·0% to 2·2%). Uptake increased for 100% (9/9) of the pilot practices, but for only 35% (13/37) of non-pilot practices, compared to the previous year. Qualitative feedback noted advantages including saved administration time and improved planning, but also disadvantages including wasted clinical time from non-attenders. The findings indicate that issuing appointment dates and times should be considered as part of a range of measures to improve LAIV uptake in two-year-olds amongst low performing practices. However, the pragmatic, unblinded nature of the study design and the within practice annual comparisons are limitations, and mean results should be interpreted with caution. Further controlled evaluation, including assessment of lost time due to DNAs and feasibility of scaling, is needed. There was no additional funding provided to undertake this study. Staff time was contributed by Cwm Taf Morgannwg University Health Board and Public Health Wales.