RESUMEN
Background Significant hurdles impede the optimal implementation of hematopoietic stem cell transplantation (HSCT) in low-middle income countries (LMICs). Herein, we highlight the challenges faced in LMICs while performing HSCT and report the long-term outcomes of patients with newly diagnosed multiple myeloma (MM) who underwent autologous HSCT (AHSCT) at our center. Besides, we provide a comprehensive review of studies reporting long-term outcomes of AHSCT in MM from the Indian subcontinent. Methodology This study was conducted at the State Cancer Institute, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India. Case records of all patients with MM who received AHSCT from December 2010 to July 2018 were reviewed retrospectively. A non-systematic literature search was performed using PubMed and Google Scholar databases. Data regarding clinicopathological parameters and long-term follow-up were extracted from relevant studies and for patients included in our study. Results At our center, 47 patients (median age 52.0 years) with MM underwent AHSCT. Majority of patients had stage III disease (ISS) and median time to transplant was 11.5 months. The five-year progression free survival (PFS) and overall survival (OS) were 59.1% and 81.2%, respectively. Studies from the Indian subcontinent have observed a five-year OS of ~50% to ~85%. However, a greater variability in the five-year PFS has been reported, ranging from ~20% to ~75%. The median time to transplant has ranged from seven to 17 months (indicating time delays) with median CD34 cell counts of 2.7-6.3×106 cells/kg (lower than developed countries). Conclusions Despite significant resource limitations in LMICs, AHSCT is increasingly been performed in MM with encouraging long-term outcomes.
RESUMEN
BackgroundThe COVID-19 pandemic has affected millions of people globally with major health, social and economic consequences, prompting development of vaccines for use in the general population. However, vaccination uptake is lower in some groups, including in pregnant women, because of concerns regarding vaccine safety. There is evidence of increased risk of adverse pregnancy and neonatal outcomes associated with SARS-CoV-2 infection, but fear of vaccine-associated adverse events on the baby both in short and longer term is one of the main drivers of low uptake for this group. Other vaccines commonly used in pregnancy include influenza and pertussis. These both have reportedly higher uptake compared with COVID-19 vaccination, which may be because they are perceived to be safer. In this study, we will undertake an independent evaluation of the uptake, effectiveness and safety of COVID-19 vaccinations in pregnant women using the QResearch primary care database in England. ObjectivesO_LITo determine COVID-19 vaccine uptake in pregnant women compared to uptake of influenza and pertussis vaccinations. C_LIO_LITo estimate COVID-19 vaccine effectiveness in pregnant women by evaluating the risk of severe COVID-19 outcomes following vaccination. C_LIO_LITo assess the safety of COVID-19 vaccination in pregnancy by evaluating the risks of adverse pregnancy and perinatal outcomes and adverse events of special interest for vaccine safety after COVID-19 vaccination compared with influenza and pertussis vaccinations. C_LI MethodsThis population-based study uses the QResearch(R) database of primary health care records, linked to individual-level data on hospital admissions, mortality, COVID-19 vaccination, SARS-CoV-2 testing data and congenital anomalies. We will include women aged 16 to 49 years with at least one pregnancy during the study period of 30th December 2020 to the latest date available. Babies born during the study period will be identified and linked to the mothers record, where possible. We will describe vaccine uptake in pregnant women by trimester and population subgroups defined by demographics and other characteristics. Cox proportional hazards multivariable regression will be used to identify factors associated with vaccine uptake. The effectiveness of COVID-19 vaccines in pregnant women will be assessed using time varying Royston-Palmar regression analyses to determine unadjusted and adjusted hazard ratios for the occurrence of severe COVID-19 outcomes after each vaccine dose compared with unvaccinated individuals. For the safety analysis, we will we use logistic regression analyses to determine unadjusted and adjusted odds ratios for the occurrence of maternal (e.g. miscarriage, ectopic pregnancy and gestational diabetes) and perinatal outcomes (e.g. stillbirth, small for gestational age and congenital anomalies) by vaccination status compared to unvaccinated individuals. For the adverse events of special interest for vaccine safety (e.g. venous thromboembolism, myocarditis and Guillain Barre syndrome), we will use time varying Royston-Palmar regression analyses to determine unadjusted and adjusted hazard ratios for the occurrence of each outcome by vaccination status to unvaccinated individuals. Ethics and disseminationQResearch is a Research Ethics Approved Research Database with ongoing approval from the East Midlands Multi-Centre Research Ethics Committee (Ref: 18/EM/0400). This study was approved by the QResearch Scientific Committee on 9th June 2022. This research protocol has been developed with support from a patient and public involvement panel, who will continue to provide input throughout the duration of the study. Research findings will be submitted to pre-print servers such as MedRxIv, academic publication and disseminated more broadly through media releases and community groups and conference presentations.
RESUMEN
BackgroundThe COVID-19 pandemic and associated national lockdowns created unprecedented disruption to healthcare, with reduced access to services and planned clinical encounters postponed or cancelled. It was widely anticipated that failure to obtain timely treatment would cause progression of illness and increased hospital admissions. Additional concerns were that social and spatial inequalities would widen given the disproportionate impacts of COVID-19 directly. The aim of our study is to determine whether this was observable in England. MethodsWith the approval of NHS England we utilised individual-level electronic health records from OpenSAFELY, which covered [~]40% of general practices in England (mean monthly population size 23.5 million people). We estimated crude and directly age-standardised rates for potentially preventable unplanned hospital admissions: ambulatory care sensitive conditions and urgent emergency sensitive conditions. We considered how trends in these outcomes varied by three measures of social and spatial inequality: neighbourhood socioeconomic deprivation, ethnicity, and geographical region. FindingsThere were large declines in avoidable hospitalisations during the first national lockdown, which then reversed post-lockdown albeit never reaching pre-pandemic levels. While trends were consistent by each measure of inequality, absolute levels of inequalities narrowed throughout 2020 (especially during the first national lockdown) and remained lower than pre-pandemic trends. While the scale of inequalities remained similar into 2021 for deprivation and ethnicity, we found evidence of widening absolute and relative inequalities by geographic region in 2021 and 2022. InterpretationThe anticipation that healthcare disruption from the COVID-19 pandemic and lockdowns would result in more (avoidable) hospitalisations and widening social inequalities was wrong. However, the recent growing gap between geographic regions suggests that the effects of the pandemic has reinforced spatial inequalities.
RESUMEN
BackgroundSehat Sahulat Programme (SSP) is a Social Health Protection (SHP) initiative by the Government of Khyber Pakhtunkhwa (GoKP), covering inpatient services for 100% of the provinces population. In this paper, we describe SSPs role in GoKPs COVID-19 response and draw inferences for similar programmes in Pakistan. Methodology and methodsWe conceptualised SSP as an instrumental case study and collected three complementary data sources. First, we studied GoKPs official documents to understand SSPs benefits package. Then we undertook in-depth interviews and collected non-participant observations at the SSP policy and implementation levels. We recruited participants through direct (verbal and email) and indirect (invitation posters) methods. Use of maximum variation sampling enabled us to understand contrasting views from various stakeholders on SSPs policy dimensions (i.e., coverage and financing), tensions between the policy directions (i.e., whether or not to cover COVID-19) and how policy decisions were made and implemented. We collected data from March 2021 to December 2021. Thematic analysis was conducted with the help of Nvivo12. FindingsThroughout 2020, SSP did not cover COVID-19 treatment. The insurer and GoKP officials considered the pandemic a standard exclusion to insurance coverage. One SSP official said: "COVID-19 is not covered and not relevant to us". GoKP had stopped non-emergency services at all hospitals. When routine services restarted, the insurer did not cover COVID-19 screening tests, which were mandatory prior to hospital admission. In 2021, GoKP engaged 10 private SSP hospitals for COVID-19 treatment. The SSP Reserve Fund, rather than insurance pooled money, was used. The Reserve Fund was originally meant to cover high-cost organ transplants. In 2021, SSP had 1,002 COVID-19-related admissions, which represented 0.2% of all hospital admissions (N=544,841). An advocacy group representative called the COVID-19 care under SSP "too little too late". In contrast, SSP officials suggested their insurance database and funds flow mechanism could help GoKP in future health emergencies. ConclusionThe commercially focused interpretation of SHP arrangements led to a protection gap in the context of COVID-19. SSP and similar programmes in other provinces of Pakistan should emphasise the notion of protection and not let commercial interests lead to protection gaps.
RESUMEN
BackgroundThe imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described. MethodsWe conducted a population-based longitudinal study in 2,312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and moderate/severe asthma exacerbations were collected via monthly on-line questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders. ResultsRelaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and moderate/severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted odds ratio 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31). ConclusionsRelaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of moderate/severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant. FundingBarts Charity, UKRI
RESUMEN
ObjectivesTo (a) derive and validate risk prediction algorithms (QCovid4) to estimate risk of COVID-19 mortality and hospitalisation in UK adults with a SARS-CoV-2 positive test during the Omicron pandemic wave in England and (b) evaluate performance with earlier versions of algorithms developed in previous pandemic waves and the high-risk cohort identified by NHS Digital in England. DesignPopulation-based cohort study using the QResearch database linked to national data on COVID-19 vaccination, high risk patients prioritised for COVID-19 therapeutics, SARS-CoV-2 results, hospitalisation, cancer registry, systemic anticancer treatment, radiotherapy and the national death registry. Settings and study period1.3 million adults in the derivation cohort and 0.15 million adults in the validation cohort aged 18-100 years with a SARS-CoV-2 positive test between 11th December 2021 and 31st March 2022 with follow up to 30th June 2022. Main outcome measuresOur primary outcome was COVID-19 death. The secondary outcome of interest was COVID-19 hospital admission. Models fitted in the derivation cohort to derive risk equations using a range of predictor variables. Performance evaluated in a separate validation cohort. ResultsOf 1,297,984 people with a SARS-CoV-2 positive test in the derivation cohort, 18,756 (1.45%) had a COVID-19 related hospital admission and 3,878 (0.3%) had a COVID-19 death during follow-up. Of the 145,404 people in the validation cohort, there were 2,124 (1.46%) COVID-19 admissions and 461 (0.3%) COVID-19 deaths. The COVID-19 mortality rate in men increased with age and deprivation. In the QCovid4 model in men hazard ratios were highest for those with the following conditions (for 95% CI see Figure 1): kidney transplant (6.1-fold increase); Downs syndrome (4.9-fold); radiotherapy (3.1-fold); type 1 diabetes (3.4-fold); chemotherapy grade A (3.8-fold), grade B (5.8-fold); grade C (10.9-fold); solid organ transplant ever (2.4-fold); dementia (1.62-fold); Parkinsons disease (2.2-fold); liver cirrhosis (2.5-fold). Other conditions associated with increased COVID-19 mortality included learning disability, chronic kidney disease (stages 4 and 5), blood cancer, respiratory cancer, immunosuppressants, oral steroids, COPD, coronary heart disease, stroke, atrial fibrillation, heart failure, thromboembolism, rheumatoid/SLE, schizophrenia/bipolar disease sickle cell/HIV/SCID; type 2 diabetes. Results were similar in the model in women. O_FIG O_LINKSMALLFIG WIDTH=100 HEIGHT=200 SRC="FIGDIR/small/22278733v1_fig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@4e93b7org.highwire.dtl.DTLVardef@c3e600org.highwire.dtl.DTLVardef@1311bd4org.highwire.dtl.DTLVardef@11a3246_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1C_FLOATNO QCOVID4 (mortality): Adjusted hazard ratios for COVID-19 death in men mutually adjusted and also adjusted for fractional polynomial terms for age and BMI C_FIG COVID-19 mortality risk was lower among those who had received COVID-19 vaccination compared with unvaccinated individuals with evidence of a dose response relationship. The reduced mortality rates associated with prior SARS-CoV-2 infection were similar in men (adjusted hazard ratio (HR) 0.51 (95% CI 0.40, 0.64)) and women (adjusted HR 0.55 (95%CI 0.45, 0.67)). The QCOVID4 algorithm explained 76.6% (95%CI 74.4 to 78.8) of the variation in time to COVID-19 death (R2) in women. The D statistic was 3.70 (95%CI 3.48 to 3.93) and the Harrells C statistic was 0.965 (95%CI 0.951 to 0.978). The corresponding results for COVID-19 death in men were similar with R2 76.0% (95% 73.9 to 78.2); D statistic 3.65 (95%CI 3.43 to 3.86) and C statistic of 0.970 (95%CI 0.962 to 0.979). QCOVID4 discrimination for mortality was slightly higher than that for QCOVID1 and QCOVID2, but calibration was much improved. ConclusionThe QCovid4 risk algorithm modelled from data during the UKs Omicron wave now includes vaccination dose and prior SARS-CoV-2 infection and predicts COVID-19 mortality among people with a positive test. It has excellent performance and could be used for targeting COVID-19 vaccination and therapeutics. Although large disparities in risks of severe COVID-19 outcomes among ethnic minority groups were observed during the early waves of the pandemic, these are much reduced now with no increased risk of mortality by ethnic group. What is knownO_LIThe QCOVID risk assessment algorithm for predicting risk of COVID-19 death or hospital admission based on individual characteristics has been used in England to identify people at high risk of severe COVID-19 outcomes, adding an additional 1.5 million people to the national shielded patient list in England and in the UK for prioritising people for COVID-19 vaccination. C_LIO_LIThere are ethnic disparities in severe COVID-19 outcomes which were most marked in the first pandemic wave in 2020. C_LIO_LICOVID-19 vaccinations and therapeutics (monoclonal antibodies and antivirals) are available but need to be targeted to those at highest risk of severe outcomes. C_LI What this study addsO_LIThe QCOVID4 risk algorithm using data from the Omicron wave now includes number of vaccination doses and prior SARS-CoV-2 infection. It has excellent performance both for ranking individuals (discrimination) and predicting levels of absolute risk (calibration) and can be used for targeting COVID-19 vaccination and therapeutics as well as individualised risk assessment. C_LIO_LIQCOVID4 more accurately identifies individuals at highest levels of absolute risk for targeted interventions than the conditions-based approach adopted by NHS Digital based on relative risk of a list of medical conditions. C_LIO_LIAlthough large disparities in risks of severe COVID-19 outcomes among ethnic minority groups were observed during the early waves of the pandemic, these are much reduced now with no increased risk of mortality by ethnic group. C_LI
RESUMEN
Sotrovimab is a neutralising monoclonal antibody (nMAB), currently administrated in England to treat extremely clinically vulnerable COVID-19 patients. Trials have shown it to have mild or moderate side effects, however safety in real-world settings has not been yet evaluated. We used national databases to investigate its uptake and safety in community patients across England. We used a cohort study to describe uptake and a self-controlled case series design to evaluate the risks of 49 pre-specified suspected adverse events in the 2-28 days post-treatment. Between December 11, 2021 and May 24, 2022, there were 172,860 COVID-19 patients eligible for treatment. Of the 22,815 people who received Sotrovimab, 21,487 (94.2%) had a positive SARS-CoV-2 test and 5,999 (26.3%) were not on the eligible list. Between treated and untreated eligible individuals, the mean age (54.6, SD: 16.1 vs 54.1, SD: 18.3) and sex distribution (women: 60.9% vs 58.1%; men: 38.9% vs 41.1%) were similar. There were marked variations in uptake between ethnic groups, which was higher amongst Indian (15.0%; 95%CI 13.8, 16.3), Other Asian (13.7%; 95%CI 11.9, 15.8), White (13.4%; 95%CI 13.3, 13.6), and Bangladeshi (11.4%; 95%CI 8.8, 14.6); and lower amongst Black Caribbean individuals (6.4%; 95%CI 5.4, 7.5) and Black Africans (4.7%; 95%CI 4.1, 5.4). We found no increased risk of any of the suspected adverse events in the overall period of 2-28 days post-treatment, but an increased risk of rheumatoid arthritis (IRR 3.08, 95% CI 1.44, 6.58) and of systematic lupus erythematosus (IRR 5.15, 95% CI 1.60, 16.60) in the 2-3 days post-treatment, when we narrowed the risk period. FundingNational Institute of Health Research (Grant reference 135561)
RESUMEN
ObjectiveTo examine infants in Scotland aged 0-27 days with confirmed SARS-CoV-2 infection; the risk of neonatal infection by factors including maternal infection status and gestation at birth; and the need for hospital admission among infected neonates. DesignPopulation-based cohort study. Setting and populationAll live births in Scotland, 1 March 2020 to 31 January 2022. ResultsThere were 141 neonates with confirmed SARS-CoV-2 infection over the study period, giving an overall infection rate of 153 per 100,000 live births (141/92,009). Among infants born to women with confirmed infection around the time of birth, the infection rate was 1,811 per 100,000 live births (15/828). Nearly two-thirds (92/141, 65.2%) of babies with confirmed neonatal infection had an associated admission to neonatal or (more commonly) paediatric care. Of those admitted to hospital, 6/92 (6.5%) infants were admitted to neonatal or paediatric intensive care, however none of these six had COVID-19 recorded as the main diagnosis underlying their admission. There were no neonatal deaths among babies with confirmed infection. Implications and relevanceConfirmed neonatal SARS-CoV-2 infection is uncommon. Secular trends in the neonatal infection rate broadly follow those seen in the general population, albeit at a lower level. Maternal infection at birth increases the risk of neonatal infection, but most babies with neonatal infection are born to women without confirmed infection. A high proportion of neonates with confirmed infection are admitted to hospital, with resulting implications for the baby, family, and services, although their outcomes are generally good. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIThe incidence of SARS-CoV-2 infection in neonates is low, but some studies have suggested that age under 1 month is a risk factor for severe infection requiring admission to intensive care. C_LIO_LIAlmost all the studies of neonatal SARS-CoV-2 have focused on the transmission risk from SARS-CoV-2 positive women to their offspring and data are lacking on the level of neonatal SARS-CoV-2 infection in the whole population. C_LI What this study addsO_LIThis study includes all babies with confirmed SARS-CoV-2 in the neonatal period in Scotland during the first 22 months of the COVID-19 pandemic. C_LIO_LIConfirmed neonatal SARS-CoV-2 infection is uncommon, but a high proportion of neonates with confirmed infection are admitted to hospital. C_LIO_LIConfirmed maternal SARS-CoV-2 infection around the time of birth substantially increases the risk of neonatal infection, although the absolute risk of neonatal infection remains low (<2%) and most babies with neonatal infection are born to women without confirmed infection. C_LIO_LIOutcomes for neonates with confirmed SARS-CoV-2 infection are good; only 6.5% (6/92) of admitted neonates required intensive care, and COVID-19 was not the primary diagnosis recorded for these babies. There were no neonatal deaths among babies with confirmed infection. C_LI
RESUMEN
BackgroundCoronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is estimated to have caused more than 18 million deaths worldwide as of end-May 2022. MethodsCOVIDENCE UK is a longitudinal population-based study that investigates risk factors for, and impacts of, COVID-19 in UK residents aged [≥]16 years. A unique feature is the capacity to support trial-within-cohort studies to evaluate interventions for prevention of COVID-19 and other acute respiratory illnesses. Participants complete a detailed online baseline questionnaire capturing self-reported information relating to their socio-demographic characteristics, occupation, lifestyle, quality of life, weight, height, longstanding medical conditions, medication use, vaccination status, diet and supplemental micronutrient intake. Follow-up on-line questionnaires capturing incident symptoms of COVID-19 and other acute respiratory infections, incident swab test-confirmed COVID-19, doses of SARS-CoV-2 vaccine received, and quality of life are completed at monthly intervals. ResultsThe study was launched on 1st May 2020 and closed to recruitment on 6th October 2021. A total of 19,981 participants enrolled and consented to 5-year follow-up with medical record linkage. Their mean age was 59.1 years (range 16.0 to 94.4 years), 70.2% were female, and 93.7% identified their ethnic origin as White. Analyses conducted to date have provided key insights into risk factors for SARS-CoV-2 infection and COVID-19 disease, determinants of SARS-CoV-2 vaccine immunogenicity and efficacy, and impacts of COVID-19 on health economic outcomes. The cohort has also supported conduct of a Phase 3 randomised trial-within-cohort study (CORONAVIT) evaluating implementation of a test-and-treat approach to correcting sub-optimal vitamin D status on incidence and severity of acute respiratory infections, including COVID-19. ConclusionsThe COVIDENCE UK dataset represents a valuable resource containing granular information on factors influencing susceptibility to, and impacts of, COVID-19 in UK adults. Researchers wishing to access anonymised participant-level data should contacting the corresponding author for further information.
RESUMEN
Obesity is associated with an increased risk of severe Covid-19. However, the effectiveness of SARS-CoV-2 vaccines in people with obesity is unknown. Here we studied the relationship between body mass index (BMI), hospitalization and mortality due to Covid-19 amongst 3.5 million people in Scotland. Vaccinated people with severe obesity (BMI>40 kg/m2) were significantly more likely to experience hospitalization or death from Covid-19. Excess risk increased with time since vaccination. To investigate the underlying mechanisms, we conducted a prospective longitudinal study of the immune response in a clinical cohort of vaccinated people with severe obesity. Compared with normal weight people, six months after their second vaccine dose, significantly more people with severe obesity had unquantifiable titres of neutralizing antibody against authentic SARS-CoV-2 virus, reduced frequencies of antigen-experienced SARS-CoV-2 Spike-binding B cells, and a dissociation between anti-Spike antibody levels and neutralizing capacity. Neutralizing capacity was restored by a third dose of vaccine, but again declined more rapidly in people with severe obesity. We demonstrate that waning of SARS-CoV-2 vaccine-induced humoral immunity is accelerated in people with severe obesity and associated with increased hospitalization and mortality from breakthrough infections. Given the prevalence of obesity, our findings have significant implications for global public health.
RESUMEN
OBJECTIVESTo determine whether population-level implementation of a test-and- treat approach to correction of sub-optimal vitamin D status (25-hydroxyvitamin D [25(OH)D] <75 nmol/L) influences risk of all-cause acute respiratory infection (ARI) or coronavirus disease 2019 (COVID-19). DESIGNPhase 3 open-label randomised controlled trial (CORONAVIT) utilising trials-within-cohorts (TwiCs) methodology. SETTINGUnited Kingdom. PARTICIPANTS6200 adults aged 16 years or older, who were not already taking vitamin D supplements at baseline. INTERVENTIONSOffer of a postal finger-prick test of blood 25(OH)D concentration with provision of a 6-month supply of higher-dose vitamin D (3200 IU/day, n=1550) or lower-dose vitamin D (800 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, vs. no offer of testing or supplementation (n=3100). Follow-up was from 17th December 2020 to 16th June 2021. MAIN OUTCOME MEASURESThe primary outcome was the proportion of participants experiencing at least one doctor- or swab test-confirmed ARI of any cause. Secondary outcomes included the proportion of participants developing swab test-confirmed COVID-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. RESULTSOf 3100 participants offered 25(OH)D testing, 2958 (95.4%) accepted, and 2690 (86.8%) had 25(OH)D <75 nmol/L and were sent vitamin D supplements (1356 higher-dose, 1334 lower-dose). 76 (5.0%) vs. 87 (5.7%) vs. 136 (4.6%) participants in higher-dose vs. lower-dose vs. no offer groups experienced at least one ARI of any cause (odds ratio [OR] for higher-dose vs. no offer 1.09, 95% CI 0.82-1.46; lower-dose vs. no offer 1.26, 0.96-1.66). 45 (3.0%) vs. 55 (3.6%) vs. 78 (2.6%) participants in higher-dose vs. lower-dose vs. no offer groups developed COVID-19 (OR for higher-dose vs. no offer 1.13, 0.78-1.63; lower-dose vs. no offer 1.39, 0.98-1.97). CONCLUSIONSAmong adults with a high baseline prevalence of sub-optimal vitamin D status, implementation of a population-level test-and-treat approach to vitamin D replacement did not reduce risk of all-cause ARI or COVID-19. TRIAL REGISTRATIONClinicalTrials.gov no. NCT04579640 SUMMARY BOXO_ST_ABSWhat is already known on this topic?C_ST_ABSVitamin D metabolites support innate immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory pathogens. Sub-optimal vitamin D status (25-hydroxyvitamin D <75 nmol/L) associates with increased susceptibility to all-cause acute respiratory infections (ARI) and coronavirus disease 2019 (COVID-19). Phase 3 randomised controlled trials of vitamin D to prevent COVID-19 have not yet reported. What this study addsThis phase 3 randomised controlled trial, including 6200 participants, shows that implementation of a population-level test-and-treat approach to oral vitamin D replacement at a dose of 800 IU or 3200 IU per day did not reduce risk of all-cause ARI or COVID-19 among adults with a high baseline prevalence of sub-optimal vitamin D status.
RESUMEN
BackgroundLittle is known about the relative influence of demographic, behavioural, and vaccine-related factors on risk of post-vaccination SARS-CoV-2 infection. We aimed to identify risk factors for SARS-CoV-2 infection after primary and booster vaccinations. MethodsWe undertook a prospective population-based study in UK adults ([≥]16 years) vaccinated against SARS-CoV-2, including data from Jan 12, 2021, to Feb 21, 2022. We modelled risk of post-vaccination SARS-CoV-2 infection separately for participants who had completed a primary course of vaccination (two-dose or, in the immunosuppressed, three-dose course of either ChAdOx1 nCoV-19 [ChAdOx1] or BNT1262b2) and for those who had additionally received a booster dose (BNT1262b2 or mRNA-1273). Cox regression models were used to explore associations between sociodemographic, behavioural, clinical, pharmacological, and nutritional factors and breakthrough infection, defined as a self-reported positive result on a lateral flow or reverse transcription PCR (RT-PCR) test for SARS-CoV-2. Models were further adjusted for weekly SARS-CoV-2 incidence at the local (lower tier local authority) level. Findings14,713 participants were included in the post-primary analysis and 10,665 in the post-booster analysis, with a median follow-up of 203 days (IQR 195-216) in the post-primary cohort and 85 days (66-103) in the post-booster cohort. 1051 (7.1%) participants in the post-primary cohort and 1009 (9.4%) participants in the post-booster cohort reported a breakthrough SARS-CoV-2 infection. A primary course of ChAdOx1 (vs BNT182b2) was associated with higher risk of infection, both in the post-primary cohort (adjusted hazard ratio 1.63, 95% CI 1.41-1.88) and in the post-booster cohort after boosting with mRNA-1273 (1.29 [1.03-1.61] vs BNT162b2 primary plus BNT162b2 booster). A lower risk of breakthrough infection was associated with older age (post-primary: 0.96 [0.96-0.97] per year; post-booster: 0.97 [0.96-0.98]), whereas a higher risk of breakthrough infection was associated with lower levels of education (post-primary: 1.66 [1.35-2.06] for primary or secondary vs postgraduate; post-booster: 1.36 [1.08-1.71]) and at least three weekly visits to indoor public places (post-primary: 1.38 [1.15-1.66] vs none; post-booster: 1.33 [1.10-1.60]). ConclusionsVaccine type, socioeconomic status, age, and behaviours affect risk of breakthrough SARS-CoV-2 infection following a primary schedule and a booster dose. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and Google Scholar for papers published up to Feb 18, 2022, using the search terms (breakthrough OR post-vaccin*) AND (SARS-CoV-2 OR COVID) AND (disease OR infection) AND (determinant OR "risk factor" OR associat*), with no language restrictions. Existing studies on risk factors for breakthrough SARS-CoV-2 infection among vaccinated individuals have found associations with age, comorbidities, vaccine type, and previous infection; however, findings have been inconsistent across studies. Most studies have been limited to specific subgroups or have focused on severe outcomes, and very few have considered breakthrough infections after a booster dose or have adjusted for behaviours affecting exposure to other people. Added value of this studyThis study is among the first to provide a detailed analysis of a wide range of risk factors for breakthrough SARS-CoV-2 infection, both after the primary course of vaccination and after a booster dose. Our large study size and detailed data have allowed us to investigate associations with various sociodemographic, clinical, pharmacological, and nutritional factors. Monthly follow-up data have additionally given us the opportunity to consider the effects of behaviours that may have changed across the pandemic, while adjusting for local SARS-CoV-2 incidence. Implications of all the available evidenceOur findings add to growing evidence that risk factors for SARS-CoV-2 infection after primary or booster vaccinations can differ to those in unvaccinated populations, with effects attenuated for previously observed risk factors such as body-mass index and Asian ethnicity. The clear difference we observed between the efficacies of ChAdOx1 and BNT162b2 as the primary course of vaccination appears to have been reduced by the use of BNT162b2 boosters, but not by mNRA-1273 boosters. As more countries introduce booster vaccinations, future population-based studies with longer follow-up will be needed to investigate our findings further.
RESUMEN
BackgroundAntibody responses to SARS-CoV-2 vaccination vary for reasons that remain poorly understood. MethodsWe tested for presence of combined IgG, IgA and IgM (IgGAM) anti-spike antibodies before and after administration of two doses of ChAdOx1 nCoV-19 (ChAdOx1, Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) in UK adults participating in a population-based longitudinal study who received their first dose of vaccine from December 15, 2020 to July 10, 2021. Information on sixty-six potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of serological response to vaccination was captured using serial online questionnaires. We used logistic regression to estimate multivariable-adjusted odds ratios (aORs) for associations between independent variables and risk of seronegativity following two vaccine doses. Participants who were seronegative after receiving two vaccine doses were offered an additional antibody test following subsequent administration of a booster dose of BNT162b2 or mRNA-1273 (Moderna) from September 23 to December 12, 2021. FindingsSerology results following two vaccine doses were available for 9,101 participants, of whom 5,770 (63.4%) received ChAdOx1 and 3,331 (36.6%) received BNT162b2. Anti-spike IgGAM was undetectable in 378 (4.2%) participants at a median of 8.6 weeks (IQR 6.4-10.7 weeks) after their second dose of vaccine. Seronegativity following two doses of SARS-CoV-2 vaccination was associated with administration of ChAdOx1 vs BNT162b2 (aOR 7.03, 95% CI 4.39-11.24), shorter interval between first and second vaccine doses (aOR 2.37, 1.06-5.26, for <6 weeks vs >10 weeks; aOR 1.59, 1.18-2.13, for 6-10 weeks vs >10 weeks), poorer self-assessed general health (aOR 3.33, 1.49-7.46, for poor vs excellent), immunodeficiencies (aOR 6.75, 2.63-17.35) and prescription of systemic immunosuppressants (aOR 3.76, 2.44-5.78). By contrast, pre-vaccination SARS-CoV-2 seropositivity (aOR 0.16, 0.04-0.70, for symptomatic seropositives vs seronegatives) and supplemental vitamin D intake (aOR 0.73, 0.53-0.99) were associated with reduced risk of post-vaccination seronegativity. 247/378 (65.3%) of participants who were seronegative after two doses of ChAdOx1 vs BNT162b2 provided a third sample at a median of 7.8 weeks (IQR 5.8-10.4) after receiving a booster dose of BNT162b2 or mRNA-1273: eight (3.2%) of them remained seronegative after three vaccine doses, all of whom either had a primary immunodeficiency or were taking systemic immunosuppressant drugs. InterpretationWe identify multiple determinants of antibody responses to two doses of ChAdOx1 or BNT162b2, many of which are potentially modifiable. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in those who failed to mount antibody responses following two doses of ChAdOx1 or BNT162b2. Study registrationhttps://clinicaltrials.gov/ct2/show/NCT04330599 FundingBarts Charity, Fischer Family Trust, The Exilarchs Foundation, DSM Nutritional Products, Health Data Research UK Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and Google Scholar for papers published from January 1, 2020, to February 1, 2022, using the search terms (antibody OR humoral OR serologic* OR immunogenic*) AND (SARS-CoV-2 vaccine OR ChAdOx1 or BNT162b2 coronavirus), with no language restrictions. Population-based studies investigating multiple potential determinants of vaccine immunogenicity in people with known pre-vaccination SARS-CoV-2 serostatus are lacking. Added value of this studyThis large population-based study, conducted in a population with known pre-vaccination SARS-CoV-2 serostatus, examines a comprehensive range of potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of antibody responses to administration of two major SARS-CoV-2 vaccines (i.e., ChAdOx1 or BNT162b2), many of which have not previously been investigated. It is also the first population-based study to characterise antibody responses to booster doses of SARS-CoV-2 vaccines in adults who were seronegative after their primary course of vaccination. Implications of all the available evidenceIncreased risk of seronegativity following two doses of SARS-CoV-2 vaccines was associated with administration of ChAdOx1 vs BNT162b2, shorter interval between first and second vaccine doses, poorer self-assessed general health, immunocompromise and SARS-CoV-2 seronegativity pre-vaccination. Regular intake of vitamin D supplements was associated with reduced risk of post-vaccination seronegativity. Randomised controlled trials are now needed to test for causality. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in the majority of people who failed to mount antibody responses following a primary course of vaccination, the few exceptions being a subset of those with primary immunodeficiency or systemic immunosuppressant drugs.
RESUMEN
In an updated self-controlled case series analysis of 42,200,614 people aged 13 years or more, we evaluate the association between COVID-19 vaccination and myocarditis, stratified by age and sex, including 10,978,507 people receiving a third vaccine dose. Myocarditis risk was increased during 1-28 days following a third dose of BNT162b2 (IRR 2.02, 95%CI 1.40, 2.91). Associations were strongest in males younger than 40 years for all vaccine types with an additional 3 (95%CI 1, 5) and 12 (95% CI 1,17) events per million estimated in the 1-28 days following a first dose of BNT162b2 and mRNA-1273, respectively; 14 (95%CI 8, 17), 12 (95%CI 1, 7) and 101 (95%CI 95, 104) additional events following a second dose of ChAdOx1, BNT162b2 and mRNA-1273, respectively; and 13 (95%CI 7, 15) additional events following a third dose of BNT162b2, compared with 7 (95%CI 2, 11) additional events following COVID-19 infection. An association between COVID-19 infection and myocarditis was observed in all ages for both sexes but was substantially higher in those older than 40 years. These findings have important implications for public health and vaccination policy. FundingHealth Data Research UK.
RESUMEN
BackgroundThere are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. MethodsPHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35{middle dot}6% were female, mean age 58{middle dot}7 (SD 12{middle dot}5) years, and 27{middle dot}8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/1965 (25{middle dot}5%) and one year 232/804 (28{middle dot}9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0{middle dot}68 (95% CI 0{middle dot}46-0{middle dot}99), obesity OR 0{middle dot}50 (95%CI 0{middle dot}34-0{middle dot}74) and IMV OR 0{middle dot}42 (95%CI 0{middle dot}23-0{middle dot}76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0{middle dot}88 (0{middle dot}74-1{middle dot}00), five months 0{middle dot}74 (0{middle dot}60-0{middle dot}88) to one year: 0{middle dot}74 (0{middle dot}59-0{middle dot}88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. InterpretationThe sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. FundingUKRI & NIHR Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Embase databases for large studies reporting one-year follow-up data for hospitalised COVID-19 patients published between January 1, 2021 and November 7, 2021, without language restrictions. Search terms related to COVID-19, hospitalisation and long-term follow-up were used. A large prospective cohort study from Wuhan, China (n = 1276) showed that 49% of patients reported at least one persistent symptom during a follow-up clinic visit at 12 months post COVID-19; no significant improvement in exercise capacity was observed between six- and 12-month visits. Another two large cohort studies in China (n = 2433) and Spain (n = 1950) with one-year follow-up data from telephone interviews showed that 45% and 81% of patients reported at least one residual COVID-19 symptom, respectively. However, no previous studies have compared the trajectories of COVID-19 recovery in patients classified by different clinical phenotypes, and there are no large studies investigating the relationship between systemic inflammation and ongoing health impairments post COVID-19. Added value of this studyIn a diverse population of adults post-hospital admission with COVID-19, our large UK prospective multi-centre study reports several novel findings: the minority felt fully recovered at one year with minimal recovery from five months across any health domain; female sex and obesity are associated with being less likely to feel fully recovered at one year; several inflammatory mediators were increased in individuals with the most severe physical, mental health, and cognitive impairments compared to individuals with milder ongoing impairments. Implications of all the available evidenceBoth pharmacological and non-pharmacological interventions are urgently needed to improve the ongoing burden following hospitalisation for COVID-19 both for individuals and healthcare systems; our findings support the use of a precision medicine approach with potential treatable traits of systemic inflammation and obesity.
RESUMEN
BackgroundProspective population-based studies investigating multiple determinants of pre-vaccination antibody responses to SARS-CoV-2 are lacking. MethodsWe did a prospective population-based study in SARS-CoV-2 vaccine-naive UK adults recruited between May 1 and November 2, 2020, without a positive swab test result for SARS-CoV-2 prior to enrolment. Information on 88 potential sociodemographic, behavioural, nutritional, clinical and pharmacological risk factors was obtained through online questionnaires, and combined IgG/IgA/IgM responses to SARS-CoV-2 spike glycoprotein were determined in dried blood spots obtained between November 6, 2020 and April 18, 2021. We used logistic and linear regression to estimate adjusted odds ratios (aORs) and adjusted geometric mean ratios (aGMRs) for potential determinants of SARS-CoV-2 seropositivity (all participants) and antibody titres (seropositive participants only), respectively. Results1696 (15.2%) of 11,130 participants were seropositive. Factors independently associated with increased risk of SARS-CoV-2 seropositivity included frontline health/care occupation (aOR 1.86, 95% CI 1.48-2.33), international travel (1.20, 1.07-1.35), number of visits to shops and other indoor public places ([≥]5 vs. 0/week: 1.29, 1.06-1.57, P-trend=0.01), body mass index (BMI) [≥]25 vs <25 kg/m2 (1.24, 1.11-1.39), Asian/Asian British vs White ethnicity (1.65, 1.10-2.49), and alcohol consumption [≥]15 vs 0 units/week (1.23, 1.04-1.46). Light physical exercise associated with decreased risk (0.80, 0.70-0.93, for [≥]10 vs 0-4 h/week). Among seropositive participants, higher titres of anti-Spike antibodies associated with factors including BMI [≥]30 vs <25 kg/m2 (aGMR 1.10, 1.02-1.19), Asian/Asian British vs White ethnicity (1.22, 1.04-1.44), frontline health/care occupation (1.24, 95% CI 1.11-1.39), international travel (1.11, 1.05-1.16), and number of visits to shops and other indoor public places ([≥]5 vs. 0/week: 1.12, 1.02-1.23, P-trend=0.01); these associations were not substantially attenuated by adjustment for COVID-19 disease severity. ConclusionsHigher alcohol consumption and reduced light physical exercise represent new modifiable risk factors for SARS-CoV-2 infection. Recognised associations between Asian/Asian British ethnic origin and obesity and increased risk of SARS-CoV-2 seropositivity were independent of other sociodemographic, behavioural, nutritional, clinical and pharmacological factors investigated. Among seropositive participants, higher titres of anti-Spike antibodies in people of Asian ancestry and in obese people were not explained by greater COVID-19 disease severity in these groups. FundingBarts Charity, Health Data Research UK.
RESUMEN
BackgroundConcerns have been expressed about a number of drugs that potentially worsen outcomes in patients with COVID-19. We sought to identify all potentially deleterious drug groups in COVID-19 and critically assess the underpinning strength of evidence pertaining to the harmful effects of these drugs. Methods and findingsWe performed a rapid systematic review, searching Medline, Embase and two COVID-19 portfolios (WHO COVID-19 database and NIH iSearch COVID-19 portfolio) for papers and preprints related to primary studies investigating drugs identified as potentially deleterious. Primary outcomes were direct measures of susceptibility to infection, disease severity and mortality. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tools. Random-effects meta-analyses were used for data synthesis with further subgroup analyses where possible for specific outcome, study design, statistical adjustment and drug groups when two were combined. Sensitivity analyses were performed by removing any studies at high risk of bias and by publication status. 49 observational studies (15 peer-reviewed papers and 34 preprints) reported primary outcomes for eight drug groups hypothesised to be deleterious. Meta-analysis showed that acute inpatient corticosteroid use was associated with increased mortality (OR 2.22, 95% CI 1.26-3.90), however this result appeared to have been biased by confounding via indication. One subgroup analysis indicated an association between immunosuppressant use and susceptibility to COVID-19 among case control and cross-sectional studies (OR 1.29, 95% CI 1.19-1.40) but this was not found with cohort studies (OR 1.11, 95% CI 0.86-1.43). Studies which adjusted for multiple confounders showed that people taking angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) required a lower level of care (OR 0.85, 95% CI 0.74-0.98). Furthermore, studies which combined these two drug groups in their analysis demonstrated an association with a lower mortality (OR 0.68, 95% CI 0.55-0.85). ConclusionsWe found minimal high quality or consistent evidence that any drug groups increase susceptibility, severity or mortality in COVID-19. Converse to initial hypotheses, we found some evidence that regular use of ACEIs and ARBs prior to infection may be effective in reducing the level of care required, such as requiring intensive care, in patients with COVID-19.
RESUMEN
BackgroundIn 2020, the COVID-19 pandemic and control measures such as national lockdowns threatened to disrupt routine childhood immunisation programmes. Initial reports from the early weeks of lockdown in the UK and worldwide suggested that uptake could fall putting children at risk from multiple other infectious diseases. In Scotland and England, enhanced surveillance of national data for childhood immunisations was established to inform and rapidly assess the impact of the pandemic on infant and preschool immunisation uptake rates. Methods and findingsWe undertook an observational study using routinely collected data for the year prior to the pandemic (2019), and immediately before, during and after the first period of the UK lockdown in 2020. Data were obtained for Scotland from the Public Health Scotland "COVID19 wider impacts on the health care system" dashboard (https://scotland.shinyapps.io/phs-covid-wider-impact/) and for England from ImmForm. Five vaccinations delivered at different ages were evaluated; three doses of the 6-in-1 DTaP/IPV/Hib/HepB vaccine and two doses of MMR. Uptake in the periods in 2020 compared to that in the baseline year of 2019 using binary logistic regression analysis. For Scotland, we analysed timely uptake of immunisations, defined as uptake within four weeks of the child becoming eligible by age for each immunisation and data were also analysed by geographical region and indices of deprivation. For both Scotland and England, we assessed whether immunisations were up to date at approximately 6 months (all doses 6-in-1) and 16-18 months (first MMR) of age. We found that uptake rates within four weeks of eligibility in Scotland for all the five vaccine visits were higher during the 2020 lockdown period than in 2019. The difference ranged from 1.3% for the first dose of the 6-in-1 vaccine (95.3 vs 94%, OR 1.28, CI 1.18-1.39) to 14.3% for the second MMR dose (66.1 vs 51.8 %, OR 1.8, CI 1.74-1.87). Significant increases in uptake were seen across all deprivation levels, though, for MMR, there was evidence of greater improvement for children living in the least deprived areas. In England, fewer children who had been due to receive their immunisations during the lockdown period were up to date at 6 months (6-in-1) or 18 months (first dose MMR). The fall in percentage uptake ranged from 0.5% for first 6-in1 (95.8 vs 96.3%, OR 0.89, CI 0.86-0.91) to 2.1% for third 6-in-1 (86.6 vs 88.7%, OR 0.82, CI 0.81-0.83). ConclusionsThis study suggests that the national lockdown in Scotland was associated with a positive effect on timely childhood immunisation uptake, however in England a lower percentage of children were up to date at 6 and 18 months. Reason for the improve uptake in Scotland may include active measures taken to promote immunisation at local and national level during this period. Promoting immunisation uptake and addressing potential vaccine hesitancy is particularly important given the ongoing pandemic and COVID-19 vaccination campaigns.
RESUMEN
BackgroundEstimating real-world vaccine effectiveness is vital to assess the impact of the vaccination programme on the pandemic and inform the ongoing policy response. However, estimating vaccine effectiveness using observational data is inherently challenging because of the non-randomised design and the potential for unmeasured confounding. MethodsWe used a Regression Discontinuity Design (RDD) to estimate vaccine effectiveness against COVID-19 mortality in England, exploiting the discontinuity in vaccination rates resulting from the UKs age-based vaccination priority groups. We used the fact that people aged 80 or over were prioritised for the vaccine roll-out in the UK to compare the risk of COVID-19 and non-COVID-19 death in people aged 75-79 and 80-84. FindingsThe prioritisation of vaccination of people aged 80 or above led to a large discrepancy in vaccination rates in people 80-84 compared to those 75-79 at the beginning of the vaccination campaign. We found a corresponding difference in COVID-19 mortality, but not in non-COVID-19 mortality, suggesting that our approach appropriately addresses the issue of unmeasured confounding factors. Our results suggest that the first vaccine dose reduced the risk of COVID-19 death by 52.6% (95% Cl 26.6-84.2) in those aged 80. InterpretationsOur results support existing evidence that a first dose of a COVID-19 vaccine has a strong protective effect against COVID-19 mortality in older adults. The RDD estimate of vaccine effectiveness is comparable to previously published studies using different methods, suggesting that unmeasured confounding factors are unlikely to substantially bias these studies. FundingOffice for National Statistics. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for studies reporting on the real-world effectiveness of the COVID-19 vaccination on risk of death using terms such as "COVID-19", "vaccine effectiveness", "mortality" and "death". The relevant published studies on this topic report vaccine effectiveness estimates against risk of death ranging from 64.2% to 98.7%, for varying times post-vaccination. All of these are observational studies and therefore potentially subject to bias from unmeasured confounding. We found no studies that used a quasi-experimental method such as regression discontinuity design, which is not subject to bias from unmeasured confounding, to calculate the effectiveness of the COVID-19 vaccination on risk of COVID-19 death, or on other outcomes such as hospitalisation or infection. Added value of this studyThe estimates of vaccine effectiveness based on observational data may be biased by unmeasured confounding. This study uses a regression discontinuity design to estimate vaccine effectiveness, exploiting the fact that the vaccination campaign in the UK was rolled out following age-based priority groups. This enables the calculation of an unbiased estimate of the effectiveness of the COVID-19 vaccine against risk of death. The vaccine effectiveness estimate of 52.6% (95% Cl 26.6-84.2) is slightly lower but similar to previously published estimates, therefore suggesting that these estimates are not substantially affected by unmeasured confounding factors and confirming the effectiveness of the COVID-19 vaccine against risk of COVID-19 death. Implications of all the available evidenceObtaining an unbiased estimate of COVID-19 vaccine effectiveness is of vital importance in informing policy for lifting COVID-19 related measures. The regression discontinuity design provides confidence that the existing estimates from observational studies are unlikely to be substantially biased by unmeasured confounding.
