Effectiveness of Autumn 2023 COVID-19 vaccination and residual protection of prior doses against hospitalisation in England, estimated using a test-negative case-control study. (preprint)

IntroductionThe last COVID-19 vaccine offered to all adults in England became available from November 2021. The most recent booster programme commenced in September 2023. Bivalent BA.4-5 or monovalent XBB.1.5 boosters were given. During the study period, the JN.1 variant became dominant in England. MethodsVaccine effectiveness against hospitalisation was estimated throughout using the test-negative case-control study design where positive PCR tests from hospitalised individuals are cases and comparable negative PCR tests are controls. Multivariable logistic regression was used to assess vaccine effectiveness against hospitalisation with the test result as the outcome, vaccination status as the primary exposure variable of interest and confounder adjustment. ResultsThere was no evidence of residual protection for boosters given as part of previous campaigns. There were 28,916 eligible tests included to estimate the effectiveness of the autumn 2023 boosters in those aged 65 years and older. VE peaked at 50.6% (95% CI: 44.2-56.3%) after 2-4 weeks, followed by waning to 13.6% (95% CI: -11.7-33.2%). Estimates were generally higher for the XBB.1.5 booster than the BA.4-5 booster, but this difference was not statistically significant. Point estimates were highest against XBB sub-lineages. Effectiveness was lower against both JN.1 and EG.5.1 variants with confidence intervals non-overlapping with the effectiveness of the XBB sub-lineages at 2-4 weeks for EG.5.1 where VE was 44.5% (95% CI: 20.2-61.4%) and at 5-9 weeks for JN.1 where VE was 26.4% (95%CI: -3.4-47.6%). ConclusionsThe recent monovalent XBB.1.5 and bivalent BA.4-5 boosters provided comparable and good protection against hospitalisation, however there was evidence of lower VE against hospitalisation of these boosters against JN.1.

Covid-19 vaccine safety in pregnancy, a nested case-control study in births from April 2021 to March 2022, England (preprint)

Introduction: Vaccine safety in pregnancy is always of paramount importance. Current evidence of COVID-19 vaccine safety in pregnancy has been reassuring with no association found with negative maternal and neonatal outcomes. However, very few safety studies are conducted on a national level and investigate dosage, timing of vaccination as well as vaccine manufacturer. To fill this knowledge gap, we conducted a population based COVID-19 vaccine safety evaluation in England, including timing of vaccination by trimester, dosage and vaccine manufacturer received in pregnancy. Method: A matched case control study nested in a retrospective cohort where adverse maternal and neonatal pregnancy outcomes were compared across several COVID-19 vaccine exposures using conditional multivariable logistic regression, adjusting for a range of demographic and health characteristics. Eligible participants were identified from the national maternity services dataset (MSDS) and records were linked to hospital admission, national COVID-19 vaccine and COVID-19 testing databases. Matching criteria differed by outcome but included participant's age and estimated week of conception. Results: 514,013 pregnant individuals aged between 18 and 50 years were identified during the study period (births from 16th of April 2021- 31st March 2022). Receiving at least one dose of COVID-19 vaccine during pregnancy conferred lower odds of giving birth to a baby who was low birthweight (aOR=0.86, 95% CI: 0.79 - 0.93), preterm (aOR=0.89, 95% CI: 0.85 - 0.92) or who had an Apgar score less than 7 at five mins of age (aOR=0.89, 95% CI: 0.80 - 0.98). There was no association between vaccination in pregnancy and stillbirth (aOR=0.90, 95% CI: 0.76 - 1.07), neonatal death (aOR=1.27, 95% CI: 0.91 - 1.77) perinatal death (aOR=0.98, 95% CI: 0.83 - 1.16), and maternal venous thromboembolism in pregnancy (aOR=0.82, 95% CI: 0.43 - 1.56). The odds of maternal admission to intensive care unit were lower in vaccinated pregnant women (aOR=0.85, 95% CI: 0.76 - 0.95). Conclusion: COVID-19 vaccines are safe to use in pregnancy and they confer protection against SARS-CoV-2 infection which can lead to adverse outcomes for both the mother and the infant. Our findings generated important information to communicate to pregnant women and health professionals to support COVID-19 maternal vaccination programmes.

Long-term duration of protection of ancestral-strain monovalent vaccines and effectiveness of the bivalent BA.1 boosters against COVID-19 hospitalisation during a period of BA.5, BQ.1, CH.1.1. and XBB.1.5 circulation in England (preprint)

Abstract Background Bivalent BA.1 booster vaccines were offered to adults aged 50 years and older and clinically vulnerable individuals as part of the autumn COVID-19 booster vaccination programme 2022 in England. Methods A test-negative case-control study was used to estimate the duration of protection of the monovalent vaccines against hospitalisation as compared to those unvaccinated. In addition, the incremental VE of the bivalent BA.1 booster vaccines was estimated relative to those with waned immunity where the last dose was at least 6 months prior amongst those aged 50 years and older. Findings The protection conferred by the monovalent vaccines was well maintained long-term: absolute VE against hospitalisation amongst those aged 65 years and older who had received at least 3 doses plateaued from 6 months after the last dose at around 50%. Incremental VE (in addition to the protection from earlier vaccines) of the bivalent BA.1 boosters against hospitalisation peaked at 53.0% (95% C.I.; 47.9-57.5%) (equivalent to an absolute VE of approximately 75%) before waning to around 35.9% (95% C.I.; 31.4-40.1%) after 10 or more weeks. Interpretation This study provides evidence of the long-term duration of protection of the monovalent vaccines, suggesting individuals at lower risk of severe disease who did not receive a booster in autumn 2022 may not require regular re-vaccination. Furthermore, this study finds good evidence that the bivalent BA.1 booster vaccines are highly effective against hospitalisation amongst those aged 50 years and older with the sub-lineages of Omicron present in the autumn/winter of 2022 in England. Funding None.

Effectiveness of the COVID-19 vaccines against severe disease with Omicron sub-lineages BA.4 and BA.5 in England (preprint)

The Omicron sub-lineages BA.4 and BA.5 were first detected in England in April 2022. A case surge followed despite England having recently experienced waves with BA.1 and BA.2. This study used a whole population test-negative case-control study design to estimate the effectiveness of the vaccines currently in use as part of the UK COVID-19 vaccination programme against hospitalisation following infection with BA.4 and BA.5 as compared to BA.2 during a period of co-circulation. Incremental VE was estimated in those vaccinated with either a third or fourth dose as compared to individuals with waned immunity who had received their second dose at least 25 weeks prior. Vaccination status was included as an independent variable and effectiveness was defined as 1-odds of vaccination in cases/odds of vaccination in controls. During the study period, there were 32,845 eligible tests from hospitalised individuals. Of these, 25,862 were negative (controls), 3,432 were BA.2, 273 were BA.4, 947 were BA.5 and 2,331 were either BA.4 or BA.5 cases. There was no evidence of reduced VE against hospitalisation for BA.4 or BA.5 as compared to BA.2. The incremental VE was 56.8% (95% C.I.; 24.0-75.4%), 59.9% (95% C.I.; 45.6-70.5%) and 52.4% (95% C.I.; 43.2-60.1%) for BA.4, BA.5 and BA.2, respectively, at 2 to 14 weeks after a third or fourth dose. VE against hospitalisation with BA.4/5 or BA.2 was slightly higher for the mRNA-1273 booster than the BNT162b2 booster at all time-points investigated, but confidence intervals overlapped. These data provide reassuring evidence of the protection conferred by the current vaccines against severe disease with BA.4 and BA.5.

Protection against symptomatic disease with the delta and omicron BA.1/BA.2 variants of SARS-CoV-2 after infection and vaccination in adolescents: national observational test-negative case control study, August 2021 to March 2022, England (preprint)

Background Little is known about the protection following prior infection with different SARS-CoV-2 variants, COVID-19 vaccination, and a combination of the two (hybrid immunity) in adolescents. Methods We used national SARS-CoV-2 testing and COVID-19 mRNA vaccination data in England to estimate protection following previous infection and vaccination against symptomatic PCR-confirmed delta and omicron (BA.1 or BA.2) variants in 11-17-year-olds using a test-negative case-control design. Findings By 31 March 2022, 63.6% of 16-17-year-olds and 48.2% of 12-15-year-olds had received more than one COVID-19 mRNA vaccine dose. Between 08 August 2021 and 31 March 2022, 1,161,704 SARS-CoV-2 PCR-tests were successfully linked to COVID-19 vaccination status. In unvaccinated adolescents, prior infection with wildtype, alpha or delta provided greater protection against subsequent delta infection than subsequent omicron; prior omicron infection provided had the highest protection against omicron reinfection (59.3%; 95%CI: 46.7-69.0). In infection-naive adolescents, vaccination provided lower protection against symptomatic omicron infection than delta, peaking at 64.5% (95%CI; 63.6-65.4) 2-14 days after dose two and 62.9% (95%CI; 60.5-65.1) 2-14 weeks after dose three, with rapidly waning protection after each dose. Previously infected and vaccinated adolescents had the highest protection, irrespective of primary infecting SARS-CoV-2 strain. The highest protection against omicron was observed in vaccinated adolescents with prior omicron infection, reaching 96.4% (95%CI, 84.4-99.1) at 15-24 weeks post dose two. Interpretation All variants provide some protection against symptomatic reinfection and vaccination adds to protection. Vaccination provides low-to-moderate protection against symptomatic omicron infection, with waning protection after each dose, while hybrid immunity provides the most robust protection.

Effectiveness of ChAdOx1-S COVID-19 Booster Vaccination against the Omicron and Delta variants in England (preprint)

BackgroundDespite the potential widespread global use of the ChAdOx1-S booster, to date there are no published data on the real-world effectiveness. VE studies have found one and two doses of the ChAdOx1-S vaccine to be highly effective, and clinical trial data have demonstrated enhanced immunity following a ChAdOx1-S booster. In England, some individuals received a ChAdOx1-S booster where vaccination with mRNA vaccines was clinically contraindicated. MethodsThe demographic characteristics of those who received a ChAdOx1-S booster were compared to those who received a BNT162b2 booster. A test-negative case control design was used to estimate vaccine effectiveness of the ChAdOx1-S booster against symptomatic disease and hospitalisation in England. FindingsThose who received a ChAdOx1-S booster were more likely to be female (adjusted odds ratio (OR) 1.67 (1.64-1.71)), in a clinical risk group (adjusted OR 1.58 (1.54-1.63)), in the CEV group (adjusted OR 1.84 (1.79-1.89)) or severely immunosuppressed (adjusted OR 2.05 (1.96-2.13)). Protection against symptomatic disease in those aged 65 years and older peaked at 66.1% (16.6 to 86.3%) and 68.5% (65.7 to 71.2%) amongst those who received the ChAdOx1-S and BNT162b2 booster vaccines, respectively. Protection waned to 44.5% (22.4 to 60.2%) and 54.1% (50.5 to 57.5%) after 5-9 weeks. Protection against hospitalisation following Omicron infection peaked at 82.3% (64.2 to 91.3%) after receiving a ChAdOx1-S booster, as compared to 90.9% (88.7 to 92.7%) for those who received a BNT162b2 booster. InterpretationDifferences in the population boosted with ChAdOx1-S in England renders direct comparison of vaccine effectiveness by manufacturer challenging. Nonetheless, this study supports the use of the ChAdOx1-S booster for protection against severe disease with COVID-19 in settings that have not yet offered booster doses and suggests that those who received ChAdOx1-S as a booster in England do not require re-vaccination ahead of others. FundingUKHSA

Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation: test negative case-control study (preprint)

Background The omicron (B.1.1.529) variant has been associated with reduced vaccine effectiveness (VE) against infection and mild disease with rapid waning, even after a third dose, nevertheless omicron has also been associated with milder disease than previous variants. With previous variants protection against severe disease has been substantially higher than protection against infection. Methods We used a test-negative case-control design to estimate VE against hospitalisation with the omicron and delta variants using community and in hospital testing linked to hospital records. As a milder disease, there may be an increasing proportion of hospitalised individuals with Omicron as an incidental finding. We therefore investigated the impact of using more specific and more severe hospitalisation indicators on VE. Results Among 18 to 64 year olds using all Covid-19 cases admitted via emergency care VE after a booster peaked at 82.4% and dropped to 53.6% by 15+ weeks after the booster; using all admissions for >= 2 days stay with a respiratory code in the primary diagnostic field VE ranged from 90.9% down to 67.4%; further restricting to those on oxygen/ventilated/on intensive care VE ranged from 97.1% down to 75.9%. Among 65+ year olds the equivalent VE estimates were 92.4% down to 76.9%; 91.3% down to 85.3% and 95.8% down to 86.8%. Conclusions With generally milder disease seen with Omicron, in particular in younger adults, contamination of hospitalisations with incidental cases is likely to reduce VE estimates against hospitalisation. VE estimates improve and waning and waning is more limited when definitions of hospitalisation that are more specific to severe respiratory disease are used.

COVID-19 Vaccine Effectiveness against the Omicron BA.2 variant in England (preprint)

The BA.1 sub-lineage of the Omicron (B.1.1.529) variant, first detected in the UK in mid-November 2021, rapidly became the dominant strain partly due to reduced vaccine effectiveness. An increase in a second Omicron sub-lineage BA.2 was observed in early January 2022. In this study we use a test-negative case control study design to estimate vaccine effectiveness against symptomatic disease with BA.1 and BA.2 after one or two doses of BNT162b2, ChAdOx1-S or mRNA-1273, and after booster doses of BNT162b2 or mRNA-1273 during a period of co-circulation. Overall, there was no evidence that vaccine effectiveness against symptomatic disease is reduced following infection with the BA.2 sub-lineage as compared to BA.1. Furthermore, similar rates of waning were observed after the second and booster dose for each sub-lineage. These data provide reassuring evidence of the effectiveness of the vaccines currently in use against symptomatic disease caused by BA.2.

Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern (preprint)

Abstract Background A rapid increase in cases due to the SARS-CoV-2 Omicron (B.1.1.529) variant in highly vaccinated populations has raised concerns about the effectiveness of current vaccines. Methods We used a test-negative case-control design to estimate vaccine effectiveness (VE) against symptomatic disease caused by the Omicron and Delta variants in England. VE was calculated after primary immunisation with two BNT162b2 or ChAdOx1 doses, and at 2+ weeks following a BNT162b2 booster. Results Between 27 November and 06 December 2021, 581 and 56,439 eligible Omicron and Delta cases respectively were identified. There were 130,867 eligible test-negative controls. There was no effect against Omicron from 15 weeks after two ChAdOx1 doses, while VE after two BNT162b2 doses was 88.0% (95%CI: 65.9 to 95.8%) 2-9 weeks after dose 2, dropping to between 34 and 37% from 15 weeks post dose 2.From two weeks after a BNT162b2 booster, VE increased to 71.4% (95%CI: 41.8 to 86.0%) for ChAdOx1 primary course recipients and 75.5% (95%CI: 56.1 to 86.3%) for BNT162b2 primary course recipients. For cases with Delta, VE was 41.8% (95%CI: 39.4-44.1%) at 25+ weeks after two ChAdOx1 doses, increasing to 93.8% (95%CI: 93.2-94.3%) after a BNT162b2 booster. With a BNT162b2 primary course, VE was 63.5% (95%CI: 61.4 to 65.5%) 25+ weeks after dose 2, increasing to 92.6% (95%CI: 92.0-93.1%) two weeks after the booster. Conclusions Primary immunisation with two BNT162b2 or ChAdOx1 doses provided no or limited protection against symptomatic disease with the Omicron variant. Boosting with BNT162b2 following either primary course significantly increased protection.

Risk of SARS-CoV-2 reinfections in children: prospective national surveillance, January 2020 to July 2021, England (preprint)

Background Reinfection after primary SARS-CoV-2 infection is uncommon in adults, but little is known about the risks, characteristics, severity or outcomes of reinfection in children. Methods We used national SARS-CoV-2 testing data in England to estimate the risk of reinfection >90 days after primary infection from 01 January 2020 to 31 July 2021, which encompassed both the Alpha and Delta waves in England. Disease severity was assessed by linking reinfection cases to national hospitalisation, intensive care admission and death registrations datasets. Findings Reinfection rates closely followed community infection rates, with a small peak during the Alpha wave and a larger peak during the Delta wave. In children aged <16 years, there were 688,418 primary infections and 2,343 reinfections. The overall reinfection rate was 66.88/100,000 population, being higher in adults (72.53/100,000) than in children (21.53/100,000). Reinfection rates after primary infection were 0.68% overall, 0.73% in adults and 0.34% in children. Of the 109 reinfections in children admitted to hospital, 78 (72%) had underlying comorbidities. Hospitalisation rates were similar for the first (64/2343, 2.73%) and second episode (57/2343, 2.43%). Intensive care admission was rare after primary infection (n=7) or reinfection (n=4), mainly in children with comorbidities. 44 deaths occurred after primary infection within 28 days of diagnosis (44/688,418, 0.01%), none after possible reinfections. Interpretation The risk of SARS-CoV-2 reinfection is strongly related to exposure due to community infection rates, especially during the Delta variant wave. Children had a lower risk of reinfection than adults, but reinfections were not associated with more severe disease or fatal outcomes. Funding PHE/UKHSA

Adolescent vaccination with BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine and effectiveness of the first dose against COVID-19: national test-negative case-control study, England (preprint)

Adolescents in the UK were recommended to have their first dose of mRNA vaccine during a period of high community transmission due to the highly transmissible Delta variant, followed by a second dose at an extended interval of 8-12 weeks. We used national SARS-CoV-2 testing, vaccination and hospitalisation data to estimate vaccine effectiveness (VE) using a test-negative case-control design, against PCR-confirmed symptomatic COVID-19 in England. VE against symptomatic disease increased to 80% within two weeks of the first dose of BNT162b2 vaccine (higher than in adults aged 18-64 years) and then declines rapidly to 40% within 8 weeks (similar to adults). Early data in 16-17-year-olds also indicate high protection against hospitalisation and a rapid increase in VE against symptomatic COVID-19 after the second dose. Our data highlight the importance of the second vaccine dose for protection against symptomatic COVID-19 and raise important questions about the objectives of an adolescent immunisation programme. If prevention of infection is the primary aim, then regular COVID-19 vaccine boosters will be required.

Effectiveness of BNT162b2 (Comirnaty, Pfizer-BioNTech) COVID-19 booster vaccine against covid-19 related symptoms in England: test negative case-control study (preprint)

Background In September 2021, the UK Government introduced a booster programme targeting individuals over 50 and those in a clinical risk group. Individuals were offered either a full dose of the BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine or a half dose of the mRNA-1273 (Spikevax, Moderna) vaccine, irrespective of the vaccine received as the primary course Methods We used a test-negative case-control design to estimate the Vaccine Effectiveness (VE) of the booster dose BNT162b2 (Comirnaty, Pfizer-BioNTech) in those aged over 50 against symptomatic disease in post booster time intervals compared to individuals at least 140 days post a second dose with no booster dose recorded. In a secondary analysis, we also compared to unvaccinated individuals and to the 2 to 6 day period after a booster dose was received. Analyses were stratified by which primary doses had been received and any mixed primary courses were excluded. Results The relative VE estimate in the 14 days after the BNT162b2 (Comirnaty, Pfizer-BioNTech) booster dose, compared to individuals that received a two-dose primary course, was 87.4 (95% confidence interval 84.9-89.4) in those individuals who received two doses ChAdOx1-S (Vaxzevria, AstraZeneca) as a primary course and 84.4 (95% confidence interval 82.8-85.8) in those individuals who received two doses of BNT162b2 (Comirnaty, Pfizer-BioNTech) as a primary course. Using the 2-6 day period post the booster dose as the baseline gave similar results. The absolute VE from 14 days after the booster, using the unvaccinated baseline, was 93.1(95% confidence interval 91.7-94.3) in those with ChAdOx1-S (Vaxzevria, AstraZeneca) as their primary course and 94.0 (93.4-94.6) for BNT162b2 (Comirnaty, Pfizer-BioNTech) as their primary course. Conclusions Our study provides real world evidence of significant increased protection from the booster vaccine dose against symptomatic disease in those aged over 50 year of age irrespective of which primary course was received.

Monitoring the COVID-19 immunisation programme through a National Immunisation Management System- Englands experience (preprint)

In England, the National Immunisation Management System (NIMS) has been used to deliver COVID-19 vaccinations across England, monitor vaccine coverage, and assess vaccine effectiveness and safety. The NIMS was developed by a joint collaboration between a range of health and digital government agencies. Vaccinations delivered at large vaccination sites, pharmacies, hospitals and in primary care are entered on a point of care application which is verified using the unique NHS number in a centralised system containing information for everyone resident and registered with a GP in England. Vaccination details and additional data from hospital and GP records (such as priority groups) are sent to NHS Digital for data linkage. The NIMS constantly receives updated details from NHS Digital for all individuals and these data are provided to Public Health England (PHE) in a secure environment. PHE primarily use the NIMS for vaccine coverage, vaccine effectiveness and safety. Daily access to individual-level vaccine data has allowed PHE to rapidly and accurately estimate vaccine coverage and provide some of the worlds first vaccine effectiveness estimates. Other countries evaluating the roll-out and effect of COVID-19 vaccine programmes should consider a vaccine register or immunisation information system similar to the NIMS.

Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK (preprint)

BackgroundCOVID-19 vaccines have been used for 9 months in the UK. Real world data have demonstrated the vaccines to be highly effective against COVID-19, severe disease and death. Here, we estimate vaccine effectiveness over time since the second dose of Comirnaty, Vaxzevria and Spikevax in England. MethodsWe used a test-negative case-control design to estimate vaccine effectiveness against symptomatic disease, hospitalisation and mortality by age, comorbidity status and over time after the second dose to investigate waning separately for Alpha and Delta variants. ResultsVaccine effectiveness against symptomatic disease peaked in the early weeks after the second dose and then fell to 47.3 (95% CI 45 to 49.6) and 69.7 (95% CI 68.7 to 70.5) by 20+ weeks against the Delta variant for Vaxzevria and Comirnaty, respectively. Waning of vaccine effectiveness was greater for 65+ year-olds compared to 40-64 year-olds. Vaccine effectiveness fell less against hospitalisations to 77.0 (70.3 to 82.3) and 92.7 (90.3 to 94.6) beyond 20 weeks post-vaccination and 78.7 (95% CI 52.7 to 90.4) and 90.4 (95% CI 85.1 to 93.8) against death for Vaxzevria and Comirnaty, respectively. Greater waning was observed among 65+ year-olds in a clinically extremely vulnerable group and 40-64-year olds with underlying medical conditions compared to healthy adults. ConclusionsWe observed limited waning in vaccine effectiveness against hospitalisation and death more than 20 weeks post-vaccination with Vaxzevria or Comirnaty. Waning was greater in older adults and those in a clinical risk group, suggesting that these individuals should be prioritised for booster doses.

Characteristics associated with COVID-19 vaccine uptake among adults in England (08 December to 17 May 2021) (preprint)

ObjectiveTo determine characteristics associated with COVID-19 vaccine coverage among individuals aged 50 years and above in England since the beginning of the programme. DesignObservational cross-sectional study assessed by logistic regression and mean prevalence margins. SettingCOVID-19 vaccinations delivered in England from 08 December 2020 - 17 May 2021. Participants30,624,257/ 61,967,781 (49.4%) and 17,360,045/ 61,967,781 (28.1%) individuals in England were recorded as vaccinated in the National Immunisation Management System with a first dose and a second dose of a COVID-19 vaccine, respectively. InterventionsVaccination status with COVID-19 vaccinations. Main Outcome MeasuresProportion, adjusted odds ratios and mean prevalence margins for individuals not vaccinated with dose 1 among those aged 50-69 years old and dose 1 and 2 among those aged 70 years old and above. ResultsAmong individuals aged 50 years and above, Black/African/Caribbean ethnic group was the least likely of all ethnic groups to be vaccinated with dose 1 of the COVID-19 vaccine. However, among those aged 70 years and above, the odds of not having dose 2 was 5.53 (95% CI 5.42 to 5.63) and 5.36 (90% CI 5.29 to 5.43) greater among Pakistani and Black/African/Caribbean compared to White British ethnicity, respectively. The odds of not receiving dose 2 was 1.18 (95% CI 1.16 to 1.20) higher among individuals who lived in a care home compared to those who did not. This was the opposite to that observed for dose 1, where the odds of not being vaccinated was significantly higher among those not living in a care home (0.89 (95% CI 0.87 to 0.91)). ConclusionsWe found that there are characteristics associated with low COVID-19 vaccine coverage. Inequalities, such as ethnicity are a major contributor to suboptimal coverage and tailored interventions are required to improve coverage and protect the population from SARS-CoV-2. Article summaryO_ST_ABSStrengths and Limitations of this studyC_ST_ABSO_LIThis is the is the first study assessing characteristics associated with COVID-19 vaccine coverage for all individuals aged 50 years and above in England. C_LIO_LIThis study uses data from the National Immunisation Management System (NIMS) which is based on all individuals in England with a registered NHS number. C_LIO_LIThis centralised national system captures individual level data for both vaccination status and demographic characteristics and allows for linkage to other datasets such as health care worker and care home resident status. C_LIO_LIThis study does not include those without an NHS number and, therefore, it is possible we have underestimated the number of vaccines delivered and odds of not being vaccinated for characteristics such as ethnic groups where we have seen the greatest impact. C_LIO_LIResidual errors in data entry on the point of care apps at the vaccination sites may have also occurred, though these errors are not likely to be widespread. C_LI

Higher serological responses and increased vaccine effectiveness demonstrate the value of extended vaccine schedules in combatting COVID-19 in England (preprint)

IntroductionIn January 2021, the UK decided to prioritise the delivery of the first dose of BNT162b2 (Pfizer/BioNTech) and AZD1222 (AstraZeneca) vaccines by extending the interval until the second dose up to 12 weeks. MethodsSerological responses were compared after BNT162b2 and AZD1222 vaccination with varying intervals in uninfected and previously-infected adults aged 50-89 years. These findings are evaluated against real-world national vaccine effectiveness (VE) estimates against COVID-19 in England. ResultsWe recruited 750 participants aged 50-89 years, including 126 (16.8%) with evidence of previous infection; 421 received BNT162b2 and 329 and AZD1222. For both vaccines, over 95% had seroconverted 35-55 days after dose one, and 100% seroconverted 7+ days after dose 2. Following a 65-84 day interval between two doses, geometric mean titres (GMTs) at 14-34 days were 6-fold higher for BNT162b2 (6703; 95%CI, 5887-7633) than AZD1222 (1093; 806-1483), which in turn were higher than those receiving BNT162b2 19-29 days apart (694; 540 - 893). For both vaccines, VE was higher across all age-groups from 14 days after dose two compared to one dose, but the magnitude varied with interval between doses. Higher two-dose VE was observed with >6 week intervals between BNT162b2 doses compared to the authorised 3-week schedule, including [≥]80 year-olds. ConclusionOur findings support the UK approach of prioritising the first dose of COVID-19 vaccines, with evidence of higher protection following extended schedules. Given global vaccine constraints, these results are relevant to policymakers, especially with highly transmissible variants and rising incidence in many countries. FundingPublic Health England

Effectiveness of BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on mortality following COVID-19 (preprint)

We estimated risk of death in vaccinated compared to unvaccinated COVID-19 cases. Cases vaccinated with 1 dose of BNT162b2 had 44% reduced risk of death, 55% with 1 dose of ChAdOx1, and 69% with 2 doses of BNT162b2. This is on top of the protection provided against becoming a case.

Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England (preprint)

Objectives To estimate the real-world effectiveness of the Pfizer/BioNTech BNT162b2 vaccine and Astrazeneca ChAdOx1 vaccine against Confirmed COVID-19, hospitalisations and deaths. To estimate effectiveness on the UK variant of concern. Design Test negative case control design Setting Community COVID-19 PCR testing in England Participants All adults in England aged 70 years and older (over 7.5 million). All COVID-19 testing in the community among eligible individuals who reported symptoms between 8 th December 2020 and 19 th February 2021 was included in the analysis. Interventions One and two doses of BNT162b2 vaccine. One dose of ChAdOx1 vaccine. Main outcome measures Symptomatic PCR confirmed SARS-CoV-2 infection, hospitalisations and deaths with COVID-19. Results Individuals aged >=80 years vaccinated with BNT162b2 prior to 4 th January, had a higher odds of testing positive in the first 9 days after vaccination (odds ratio up to 1.48, 95%CI 1.23-1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore estimated relative to the baseline post-vaccination period. Vaccine effects were noted from 10-13 days after vaccination, reaching an effectiveness of 70% (95% CI 59-78%) from 28-34 days, then plateauing. From 14 days after the second dose a vaccine effectiveness of 89% (95%CI: 85-93%) was seen. Individuals aged >=70 years vaccinated from 4 th January had a similar underlying risk of COVID-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (95%CI 51-69%) from 28-34 days after vaccination then plateaued. With the ChAdOx1 vaccine, vaccine effects were seen from 14-20 days after vaccination reaching an effectiveness of 60% (95%CI 41-73%) from 28-34 days and further increasing to 73% (95%CI 27-90%) from day 35 onwards. On top of the protection against symptomatic disease, cases who had been vaccinated with one dose of BNT162b2 had an additional 43% (95%CI 33-52%) lower risk of emergency hospitalisation and an additional 51% (95%CI 37-62%) lower risk of death. Cases who had been vaccinated with one dose of ChAdOx1 had an additional 37% (95% CI 3-59%) lower risk of emergency hospitalisation. There was insufficient follow-up to assess the effect of ChAdOx1 on mortality due to the later rollout of this vaccine. Combined with the effect against symptomatic disease, this indicates that a single dose of either vaccine is approximately 80% effective at preventing hospitalisation and a single dose of BNT162b2 is 85% effective at preventing death with COVID-19. Conclusion Vaccination with either a single dose of BNT162b2 or ChAdOx1 COVID-19 vaccination was associated with a significant reduction in symptomatic SARS-CoV2 positive cases in older adults with even greater protection against severe disease. Both vaccines show similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 provides further protection against symptomatic disease but second doses of ChAdOx1 have not yet been rolled out in England. There is a clear effect of the vaccines against the UK variant of concern.

Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study) (preprint)

Background: BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK. We determined the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in our healthcare worker (HCW) cohort study of staff undergoing regular asymptomatic testing.Methods: The SIREN study is a prospective cohort study among staff working in publicly funded hospitals. Baseline risk factors, vaccination status (from 8/12/2020-5/2/2021), and symptoms are recorded at 2 weekly intervals and all SARS-CoV-2 polymerase chain reaction (PCR) and antibody test results documented. A mixed effect proportional hazards frailty model using a Poisson distribution was used to calculate hazard ratios to compare time to infection in unvaccinated and vaccinated participants to estimate the impact of the BNT162b2 vaccine on all (asymptomatic and symptomatic) infection.Findings: Vaccine coverage was 89% on 5/2/2021. Significantly lower coverage was associated with prior infection (aOR 0.59 95% confidence interval [CI] 0.54-0.64), female (aOR 0.72, 95% CI 0.63-0.82), aged under 35 years, being from minority ethnic groups (especially Black, aOR 0.26, 95% CI 0.21-0.32), porters/security guards (aOR 0.61, 95% CI 0.42-0.90),or midwife (aOR 0.74, 95% CI 0.57-0.97), and living in more deprived neighbourhoods (IMD 1 (most) vs. 5 (least) (aOR 0.75, 95% CI 0.65-0.87). A single dose of BNT162b2 vaccine demonstrated vaccine effectiveness of 72% (95% CI 58-86) 21 days after first dose and 86% (95% CI 76-97) seven days after two doses in the antibody negative cohort.Conclusion: Our study demonstrates that the BNT162b2 vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults; this cohort was vaccinated when the dominant variant in circulation was B1.1.7 and demonstrates effectiveness against this variant.Trial Registration: IRAS ID 284460, REC reference 20/SC/0230 Berkshire Research Ethics Committee, Health Research Authority and Health and Care Research Wales approval granted 22 May 2020. Trial registered with ISRCTN, Trial ID: ISRCTN11041050. https://www.isrctn.com/ISRCTN11041050Funding: The study is funded by the United Kingdom’s Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments. Funding is also provided by the National Institute for Health Research (NIHR) as an Urgent Public Health Priority Study (UPHP). SH, VH are supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE) (NIHR200915). AC is supported by NIHR HealthProtection Research Unit in Behavioural Science and Evaluation at University of Bristol in partnership with Public Health England. MR, NA, AC are supported by NIHR HealthProtection Research Unit in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England.Conflict of Interest: The Immunisation and Countermeasures Division has provided vaccine manufacturers(including Pfizer) with post-marketing surveillance reports on pneumococcal andmeningococcal infection which the companies are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports.Ethical Approval: The study was approved by the Berkshire Research Ethics Committee, Health Research Authority (IRAS ID 284460, REC reference 20/SC/0230) on 22 May 2020; the vaccine amendment was approved on 12/1/2021.

Interactions between SARS-CoV-2 and Influenza and the impact of coinfection on disease severity: A test negative design (preprint)

Background: The potential impact of COVID-19 alongside influenza on morbidity, mortality and health service capacity is a major concern as the Northern Hemisphere winter approaches. This study investigates the interaction between influenza and COVID-19 during the latter part of the 2019-20 influenza season in England. Methods: Individuals tested for influenza and SARS-CoV-2 were extracted from national surveillance systems between 20/01/2020 and 25/04/2020. To estimate influenza infection on the risk of SARS-CoV-2 infection, univariable and multivariable analyses on the odds of SARS-CoV-2 in those who tested positive for influenza compared to those who tested negative for influenza. To assess whether a coinfection was associated with severe SARS-CoV-2 outcome, univariable and multivariable analyses on the odds of death adjusted for age, sex, ethnicity, comorbidity and coinfection status. Findings: The risk of testing positive for SARS-CoV-2 was 68% lower among influenza positive cases, suggesting possible pathogenic competition between the two viruses. Patients with a coinfection had a risk of death of 5.92 (95% CI, 3.21-10.91) times greater than among those with neither influenza nor SARS-CoV-2 suggesting possible synergistic effects in coinfected individuals. The odds of ventilator use or death and ICU admission or death was greatest among coinfection patients showing strong evidence of an interaction effect compared to SARS-CoV-2/influenza acting independently. Interpretation: Cocirculation of these viruses could have a significant impact on morbidity, mortality and health service demand. Testing for influenza alongside SARS-CoV-2 and maximising influenza vaccine uptake should be prioritised to mitigate these risks.