Pfizer/BioNTech Comirnaty® Post-Authorisation Safety Study

Background: Comirnaty® received conditional marketing authorisation in the European Union (EU), United Kingdom (UK) and United States (US) in December 2020. We describe interim results from a post-authorisation safety study (PASS); a commitment to EU and US regulatory authorities.

Objectives: Determine the risk of 37 adverse events of special interest (AESIs) following ≥1 dose of Comirnaty in the general European population.

Methods: This is an ongoing retrospective cohort study, with Comirnaty vaccinated and unvaccinated matched 1:1 on age, sex and other demographic and clinical factors, from 6 electronic health record data sources in 5 countries: Italy (Pedianet, general practitioner, GP); Netherlands (PHARMO Data Network, GP); Norway (NHR, inpatient and outpatient); Spain (EpiChron, GP and inpatient and SIDIAP, GP and inpatient/outpatient specialist); and UK (CPRD Aurum, GP). Analyses were conducted using a common protocol, the ConcePTION common data model and common analytical programs. Propensity score-adjusted hazard ratios (HRs) were estimated for event-specific risk windows.

Results: From December 2020 to March 2022 (CPRD Aurum), December 2022 (Pedianet, NHR), June 2023 (PHARMO, SIDIAP) and July 2023 (EpiChron), 12,400,847 recipients of ≥1 dose of Comirnaty were matched (Pedianet: 10,500, NHR: 3,584,238, PHARMO: 992,144, EpiChron: 627,972, SIDIAP: 3,087,124, CPRD: 4,098,869).

There was no increased risk of most of the 37 AESIs associated with the vaccine, including myocarditis (21-day risk window) with HRs of 0.94 (95% CI: 0.46, 1.94) in NHR, 1.23 (95% CI: 0.13, 11.84) in PHARMO, 3.64 (95% CI: 0.41, 32.53) in EpiChron, 1.05 (95% CI: 0.35, 3.16) in SIDIAP, and 2.30 (95% CI: 0.94, 5.66) in CPRD. Results of note were arrhythmia with HRs of 1.36 (95% confidence interval [CI]: 1.29, 1.44) in PHARMO, 1.03 (95% CI: 1.00, 1.05) in NHR, 1.12 (95% CI: 1.04, 1.21) in EpiChron, and 1.27 (95% CI: 1.21, 1.33) in CPRD; heart failure 1.29 (95% CI: 1.13, 1.47) in PHARMO; coronary artery disease 1.49 (95% CI: 1.31, 1.69) in PHARMO, and 1.40 (95% CI: 1.30, 1.50) in CPRD. For secondary amenorrhoea, HRs were 1.71 (95% CI: 1.34, 2.18) in EpiChron and 1.24 (95% CI: 1.17, 1.30) in CPRD and for hypermenorrhoea 1.40 (95% CI: 1.23, 1.60) in EpiChron.

Conclusions: In this PASS which evaluated the safety of Comirnaty for 37 AESIs in >12 million vaccinated individuals, there was no increased risk for most AESIs. However, adjusted HRs for a few cardiac events and menstrual disorders were slightly elevated among vaccinated in some data sources. Potential explanations for these results include the divergence of cumulative incidence of cardiac events with long risk windows and differences in the composition of unvaccinated individuals over time.

BNT162b2, a mRNA-based vaccine for the prevention of COVID-19, has been authorised in the European Union (EU), United States and United Kingdom. Efficient and timely monitoring of adverse events of special interest (AESIs), is needed, particularly myocarditis and pericarditis which have been identified as potentially associated with the vaccine.

Objectives: To determine whether an increased risk of selected AESIs exists following vaccination with BNT162b2 in the general population and specific populations (immunocompromised, comorbidities, prior COVID-19 infection, pregnant individuals ) compared to unvaccinated, and to characterise utilisation patterns of BNT162b2 in Europe. In addition, a sub-study will describe the natural history of cases of myocarditis and pericarditis among vaccinated and unvaccinated individuals and will analyze risk factors.

Methods: A retrospective cohort design will be used to compare the incidence of AESIs in vaccinated versus unvaccinated individuals matched on relevant individual characteristics. A self-controlled risk interval study design will also be used for selected acute AESIs to control for time-invariant confounders. The natural history of myocarditis and pericarditis cases occurring in the cohort will be described. The study will be performed using electronic healthcare record (EHR) data in eight data sources in the Netherlands (PHARMO), Italy (ARS Toscana; Pedianet; Health Search Database), Spain (EpiChron; SIDIAP), United Kingdom (CPRD Aurum), and Norway (Norwegian health registers). The study consortium is coordinated by VAC4EU, and data analyses are planned biannually for three years. Recorded prescription, dispensing, or administration data will be used to assess vaccination with BNT162b2. AESIs will be identified using algorithms based on codes for diagnoses, procedures, and treatments. Outcome validation will be based on patient profile review of electronic records by healthcare professionals and a subset will undergo clinical validation through chart review.

Results: The study is conducted in a distributed manner using a common protocol, common data model (CDM), and common analytics programmes. The study will provide analyses of the occurrence of AESIs in 15,937,656 doses of the BNT162b2 that were included in the first data cut; 879,971 in PHARMO; 3,885,270 in ARS Toscana; 1,128 in PEDIANET; 621,795 in EpiChron; 3,164,906 in SIDIAP and 7,384,586 in CPRD Aurum.

Conclusions: Safety monitoring with biannual data cuts and clinical validation of AESIs is feasible in the participating data sources. The study will continue to monitor AESIs in the data sources through 2023.