First dose ChAdOx1 and BNT162b2 COVID-19 vaccinations and cerebral venous sinus thrombosis: A pooled self-controlled case series study of 11.6 million individuals in England, Scotland, and Wales.

Background: Several countries restricted the administration of ChAdOx1 to older age groups in 2021 over safety concerns following case reports and observed versus expected analyses suggesting a possible association with cerebral venous sinus thrombosis (CVST). Large datasets are required to precisely estimate the association between Coronavirus Disease 2019 (COVID-19) vaccination and CVST due to the extreme rarity of this event. We aimed to accomplish this by combining national data from England, Scotland, and Wales. Methods and findings: We created data platforms consisting of linked primary care, secondary care, mortality, and virological testing data in each of England, Scotland, and Wales, with a combined cohort of 11,637,157 people and 6,808,293 person years of follow-up. The cohort start date was December 8, 2020, and the end date was June 30, 2021. The outcome measure we examined was incident CVST events recorded in either primary or secondary care records. We carried out a self-controlled case series (SCCS) analysis of this outcome following first dose vaccination with ChAdOx1 and BNT162b2. The observation period consisted of an initial 90-day reference period, followed by a 2-week prerisk period directly prior to vaccination, and a 4-week risk period following vaccination. Counts of CVST cases from each country were tallied, then expanded into a full dataset with 1 row for each individual and observation time period. There was a combined total of 201 incident CVST events in the cohorts (29.5 per million person years). There were 81 CVST events in the observation period among those who a received first dose of ChAdOx1 (approximately 16.34 per million doses) and 40 for those who received a first dose of BNT162b2 (approximately 12.60 per million doses). We fitted conditional Poisson models to estimate incidence rate ratios (IRRs). Vaccination with ChAdOx1 was associated with an elevated risk of incident CVST events in the 28 days following vaccination, IRR = 1.93 (95% confidence interval (CI) 1.20 to 3.11). We did not find an association between BNT162b2 and CVST in the 28 days following vaccination, IRR = 0.78 (95% CI 0.34 to 1.77). Our study had some limitations. The SCCS study design implicitly controls for variables that are constant over the observation period, but also assumes that outcome events are independent of exposure. This assumption may not be satisfied in the case of CVST, firstly because it is a serious adverse event, and secondly because the vaccination programme in the United Kingdom prioritised the clinically extremely vulnerable and those with underlying health conditions, which may have caused a selection effect for individuals more prone to CVST. Although we pooled data from several large datasets, there was still a low number of events, which may have caused imprecision in our estimates. Conclusions: In this study, we observed a small elevated risk of CVST events following vaccination with ChAdOx1, but not BNT162b2. Our analysis pooled information from large datasets from England, Scotland, and Wales. This evidence may be useful in risk–benefit analyses of vaccine policies and in providing quantification of risks associated with vaccination to the general public. In a pooled self-controlled case series study, Steven Kerr and colleagues assess the association between first dose ChAdOx1 and BNT162b2 COVID-19 vaccination with cerebral venous sinus thrombosis in England, Scotland and Wales. Author summary: Why was this study done?: There have been indications of a possible association between Coronavirus Disease 2019 (COVID-19) vaccines—in particular, Oxford/AstraZeneca (ChAdOx1)—and cerebral venous sinus thrombosis (CVST), which is a rare type of blood clot in the brain. Further evidence on this topic is required in order to inform vaccine policy deliberations. What did the researchers do and find?: We estimated the rate of CVST events in the 4 weeks following first dose vaccination compared with a 90-day period prior to vaccination. The rate of CVST events in the 4 weeks following vaccination with Oxford/AstraZeneca was approximately twice as high compared to the baseline rate, implying an additional 0.25 events on average in this period per million people vaccinated. We did not find an association between Pfizer-BioNTech (BNT162b2) and CVST. What do these findings mean?: We found evidence of a slight increased risk of CVST following first dose vaccination with ChAdOx1, but not BNT162b2. Public health authorities may wish to take this evidence into account when communicating the benefits and risks associated with COVID-19 vaccines to the general public. Our study had some limitations. Although the cohort was large, CVST is an extremely rare event, and this may have caused some imprecision in our estimates. In addition, there is a possibility that our model assumptions were not satisfied. [ABSTRACT FROM AUTHOR]