Background
To further monitor COVID-19 vaccine safety and complement pharmacovigilance measures, multi-national observational studies have been requested by the EMA: Incidences of patient-reported side effects after COVID-19 vaccination and adverse events of special interest are closely being monitored. The Covid-Vaccine-Monitor project will facilitate the rapid signal assessment of emerging safety concerns.
Hypothesis
These existing initiatives will provide important data on the incidence of adverse outcomes reported after vaccination and on potential risk factors for thromboembolic events in COVID-19 patients.
Objectives:
1-a)To quantify the association between the administration of a COVID-19 vaccine and the occurrence of thrombosis with thrombocytopenia syndrome/s (TTS) within pre-specified risk periods, stratified by vaccine type/brand, age and gender, while controlling for relevant confounding factors.
1b) To quantify the association between different COVID-19 vaccine types/brand (where possible/applicable), while controlling for relevant confounding factors.
2a) To quantify the association between the administration of a COVID-19 vaccine and the occurrence of thromboembolic events (TE) within pre-specified risk periods, stratified by vaccine type/brand, age and gender, while controlling for relevant confounding factors.
2b) To quantify the association between different COVID-19 vaccine types/brands (where possible/applicable), while controlling for relevant confounding factors.
3) To study the association between pre-specified potential risk factors and TTS in people receiving COVID-19 vaccine/s
4) To characterize the treatments used in patients with TTS, including the use of anticoagulants and other therapeutic products
Exploratory objective:
5) To develop a proof-of-concept study to support future genetic and pharmacogenomic analyses of the association between COVID-19 vaccines and thromboembolic events and TTS. The three specific subobjectives are:
Objective 5.1. To identify genetic variations associated with TE based on previous literature and a review of previous GWAS studies
Objective 5.2. To investigate whether the risk of TE following COVID vaccination is modified by genetic susceptibility
Objective 5.3. To assess the feasibility of identifying TTS in UK Biobank using linked hospital and primary care records to inform future pharmacogenetic studies
Methods:
Data will be obtained from five European primary care records, two outpatient records, and one inpatient records databases (UK,Spain,The Netherlands, France, Denmak). In addition, one US claims and one large US hospital records database will be accessed to maximise sample size and exposure to vaccines currently under-represented in European data.All of the data sources are previously mapped to the Observational Medical Outcomes Partnership (OMOP) common data model (CDM).
Distributed network cohort studies will be conducted to answer objectives 1-4. Propensity score matching based on large-scale propensity scores will be used to minimise confounding by indication for objectives 1-2 and 5
The study period will cover from Dec 2020 (first vaccine users) until the latest data extraction available in each of the contributing databases. For objectives 1-3, lags in hospital linkage will result in two different study periods for analyses based on primary care vs linked data in both CPRD AURUM, GOLD and SIDIAP.
For other objectives and data sources the study period will be unique and will go from cohort-specific index date to the latest data available.
Cohort-specific index dates are: For vaccinated people (and matched unvaccinated) [Objectives 1a-2a, 3, 5.2 and 5.3]: date of first dose vaccine (and same date for matched unvaccinated);For comparative cohorts [Objective 1b and 2b]: date of first dose of the corresponding vaccine type/Brand; For TTS cohorts [Objective 4]: date of TTS diagnosis.
Source and study population:
Target population: All persons registered in any of the contributing databases within the study period and with at least one year of data visibility before December 2020 will be eligible.
Study population for Objectives 1a-2a, 5.2 and5.3: Of these, people with at least one exposure to any COVID vaccine in the study period will be included in the ‘exposed’ cohort/s, with 1st and 2nd dose vaccine date as time-varying index dates. Unexposed matched groups will be pooled from the Target population.
Study populations for Objective 1b & 2b: Those with at least one exposure to viral vector-based vaccines will be included in the exposed group/s and those with at least one exposure to mRNA COVID-19 vaccines in the active comparator group/s. Similarly, those with Vaxzevria vaccine will be included in the exposed group and those with Comirnaty as the active comparator in the vaccine brand comparative safety analyses based on CPRD AURUM, GOLD, RCGP, and SIDIAP.
Study population for Objective 3: Those with at least one exposure to any COVID vaccine in the study period will be included in this cohort for the analysis of risk factors of post-vaccine TTS.
Study population for Objectives 4: Those with a TTS event in the up to 28 days post vaccination of any dose will be included as ‘TTS cases’ for Objective 4, with TTS date as index date.
Study population for Objective 5: UKBB participants with linkage to primary care and HES data and vaccine exposure identified in the primary care records will be included in the exposed group. Unexposed matched participants will be pooled from those with linked primary care and HES data
Data analysis
All the analyses detailed below will be conducted stratified by database and by age, gender and vaccine type/brand