Effect of the 2022 COVID-19 booster vaccination campaign in 50 year olds in England: regression discontinuity analysis in OpenSAFELY (preprint)

Background: SARS-CoV-2 vaccines are highly effective in preventing severe COVID-19 but require boosting to maintain protection. Changes to circulating variants and prevalent natural immunity may impact on real-world effectiveness of boosters in different time periods and in different populations. Methods: With NHS England approval, we used linked routine clinical data from >24 million patients to evaluate the effectiveness of the 2022 combined COVID-19 autumn booster and influenza vaccine campaign in non-clinically vulnerable 50-year-olds in England using a regression discontinuity design. Our primary outcome was a composite of 6-week COVID-19 emergency attendance, COVID-19 unplanned hospitalisation, or death. The secondary outcomes were: respiratory hospitalisations or death; any unplanned hospitalisation; and any death. Results: Our study included 1,917,375 people aged 45-54 years with no evidence of being in a high-risk group prioritised for vaccination. By 26 November 2022, booster vaccine coverage was 11.1% at age 49.75 years increasing to 39.7% at age 50.25 years. The estimated effect of the campaign on the risk of the primary outcome in 50-year-olds during weeks 7-12 after the campaign start was -0.4 per 100,000 (95% CI -7.8, 7.1). For the secondary outcomes the estimated effects were: -0.6 per 100,000 (95%CI -13.5, 12.3) for respiratory outcomes; 5.0 per 100,000 (95%CI -40.7, 50.8) for unplanned hospitalisations; and 3.0 per 100,000 (95%CI -2.7, 8.6) for any death. The results were similar when using different follow-up start dates, different bandwidths, or when estimating the effect of vaccination (rather than the campaign). Conclusion: This study found little evidence that the autumn 2022 vaccination campaign in England was associated with a reduction in severe COVID-19-related outcomes among non-clinically vulnerable 50-year-olds. Possible explanations include the low risk of severe outcomes due to substantial pre-existing vaccine- and infection-induced immunity. Modest booster coverage reduced the precision with which we could estimate effectiveness. The booster campaign may have had effects beyond those estimated, including reducing virus transmission and incidence of mild or moderate COVID-19.

Safety, reactogenicity, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons: A protocol for a living systematic review and meta-analysis (preprint)

Background Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding safety of these vaccines for the pregnant persons and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, efficacy or effectiveness, reactogenicity, and immunogenicity of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review (LSR) of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide information necessary to help guide vaccine policy decisions.Methods We aim to conduct a LSR based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety (i.e., impacts on obstetric and neonatal outcomes), efficacy or effectiveness of COVID-19 vaccines in pregnant persons. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including pre-specified subgroup and sensitivity analyses, and will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to evaluate the certainty of evidence.Conclusion This will be the first living systematic review (LSR) and meta-analysis assessing the safety, reactogenicity, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons. An online interactive dashboard for data visualization using Microsoft Power BI will be developed to regularly update and disseminate the latest findings (an in-progress version is available at https://safeinpregnancy.org/lsr/). In addition, the findings will be disseminated through publications and presentations.

Changes in COVID-19-related mortality across key demographic and clinical subgroups: an observational cohort study using the OpenSAFELY platform on 18 million adults in England (preprint)

Objectives To quantify in absolute and relative terms how population-level COVID-19 death rates have changed in demographic and clinical subgroups. Design Retrospective cohort study on behalf of NHS England. Setting Linked primary care and death registry data from the OpenSAFELY-TPP platform, covering the first three pandemic waves in England (wave 1: March 23 to May 30, 2020; wave 2: September 7, 2020 to April 24, 2021; and wave 3, delta: May 28 to December 14, 2021). Participants In total, 18.7, 18.8, and 18.7 million adults were included for waves 1, 2, and 3 respectively. Main outcome measures COVID-19-related mortality based on linked death registry records. Results The crude rate of COVID-19-related death per 1,000 person-years decreased from 4.48 in wave 1 (95%CI 4.41;4.55), to 2.70 in wave 2 (95%CI 2.67;2.73), to 0.64 in wave 3 (95%CI 0.63;0.66). The death rate decreased by 90% between waves 1 and 3 in patients aged 80+, but by only 20% in patients aged 18-39. This higher proportional reduction in death rates was also seen for other groups, such as neurological disease, learning disability and severe mental illness. Conversely, death rates in transplant recipients stayed constant across successive waves at 10 per 1,000 person-years. There was also only a small decrease in death rates between waves in people with kidney disease, haematological malignancies or conditions associated with immunosuppression. Consequently, the relative hazard of COVID-19-related death decreased over time for some variables (e.g. age), remained similar for some (e.g. sex, ethnicity), and increased for others (e.g. transplant). Conclusions COVID-19 death rates decreased over the first three pandemic waves. An especially large decrease was seen in older age groups and people with neurological disease, learning disability or severe mental illness. Some demographic inequalities in death rates persisted over time. Groups more likely to experience impaired vaccine effectiveness did not see the same benefit in COVID-19 mortality reduction.

Comparative effectiveness of BNT162b2 versus mRNA-1273 boosting in England: a cohort study in OpenSAFELY-TPP (preprint)

Introduction The COVID-19 booster vaccination programme in England used both BNT162b2 and mRNA-1273 vaccines. Direct comparisons of the effectiveness against severe COVID-19 of these two vaccines for boosting have not been made in trials or observational data. Methods On behalf of NHS England, we used the OpenSAFELY-TPP database to match adult recipients of each vaccine type on date of vaccination, primary vaccine course, age, and other characteristics. Recipients were eligible if boosted between 29 October 2021 and 31 January 2022, and followed up for 12 weeks. Outcomes were positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death. We estimated the cumulative incidence of each outcome, and quantified comparative effectiveness using risk differences (RD) and hazard ratios (HRs). Results 1,528,431 people were matched in each group, contributing a total 23,150,504 person-weeks of follow-up. The 12-week risks per 1,000 people of positive SARS-CoV-2 test were 103.2 (95%CI 102.4 to 104.0) for BNT162b2 and 96.0 (95.2 to 96.8) for mRNA-1273: the HR comparing mRNA-1273 with BNT162b2 was 0.92 (95%CI 0.91 to 0.92). For COVID-19 hospitalisations the 12-week risks per 1,000 were 0.65 (95%CI 0.56 to 0.75) and 0.44 (0.36 to 0.54): HR 0.67 (95%CI 0.58 to 0.78). COVID-19 deaths were rare: the 12-week risks per 1,000 were 0.03 (95%CI 0.02 to 0.06) and 0.01 (0.01 to 0.02): HR 1.23 (95%CI 0.59 to 2.56). Comparative effectiveness was generally similar within subgroups. Conclusion Booster vaccination with mRNA-1273 COVID-19 vaccine was more effective than BNT162b2 in preventing SARS-CoV-2 infection and COVID-19 hospitalisation during the first 12 weeks after vaccination.