Post-Authorization Active Surveillance Safety Study Using Secondary Data to Monitor Real-World Safety of Spikevax in Europe

Date of Approval
Application Number
Technical Summary

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) causes coronavirus disease-2019 (COVID-19) and has caused a global pandemic. The mRNA-1273 vaccine, developed by Moderna, Inc., and the US National Institute of Allergy and Infectious Diseases, combines mRNA delivery platform with the SARS-CoV-2 spike immunogen. The Spikevax vaccine was authorised across the EU to prevent COVID-19 in individuals aged 12 years and older.

This post-authorisation active surveillance safety study will monitor and assess the real-world safety of Spikevax using UK primary care data (CPRD Aurum) and linked datasets (HES, ONS death registration, COVID-19 datasets). The study aims to conduct signal detection followed, if necessary, by safety evaluation of identified possible signals.

Signal detection will use a cohort design and historical background rates of the AESI’s before the COVID-19 pandemic (2017-2019) will be used as expected rates in the unvaccinated. Incidence rates among Spikevax vaccinees will be compared against appropriate general population background AESI rates.

Signal evaluation will use either a self-controlled or parallel cohort design. Self-controlled designs are suitable for events with acute onset, short induction/latency, and a well-defined risk period, and where difficult to identify a suitable comparator or measure confounding. For AESI’s where these conditions are not fulfilled, cohort design will be used.

For the self-controlled designs, the incidence rate ratio between the risk and the control period will be computed using conditional Poisson regression. For parallel cohort designs, appropriate contrasts will be estimated in exposed vs. unexposed, while controlling for confounding.

The study includes three planned data extraction timepoints (January 2022, June 2022, March 2023); with repeat analyses conducted at each timepoint. Aggregate results from this UK study will be pooled with results generated by other Data Access Providers. The overall study is planned as analysis of routinely collected health data including the UK, Denmark, Italy, Norway, Spain.

Health Outcomes to be Measured

The outcomes to be measured include a list of AESIs, which are drawn from the ACCESS project ( or other published sources ( The AESIs are conditions primarily based on those defined by the Safety Platform for Emergency vACcines (SPEAC) and endorsed for COVID-19 vaccine safety assessment by the WHO Global Advisory Committee for Vaccine Safety, by the EMA, and by the US CDC. For most of the AESI, the Brighton Collaboration (2010) case definitions are available. The AESIs to be analysed in this study are:

Auto-immune diseases to include: Guillain-Barré Syndrome (GBS); Acute disseminated encephalomyelitis (ADEM); Narcolepsy; Acute aseptic arthritis; Diabetes type 1; (Idiopathic) Thrombocytopenia. Cardiovascular system outcomes to include: Microangiopathy; Heart failure; Stress-induced cardiomyopathy; Coronary artery disease;
Arrhythmia; Myocarditis; Pericarditis; Cerebrovascular disease. Circulatory system outcomes to include: Deep vein thrombosis (DVT); Pulmonary embolism (PE); Single Organ Cutaneous Vasculitis; Cerebral venous sinus thrombosis (CVST); Splanchnic vein thrombosis (SVT); Coagulation disorders; Disseminated intravascular coagulation (DIC); Kawasaki disease. Hepato-gastrointestinal and renal system outcomes to include:
Acute liver injury; Acute kidney injury. Nerves and central nervous system outcomes to include: Generalised convulsions; Encephalitis/meningoencephalitis; Transverse myelitis; Bell’s palsy. Respiratory system outcomes to include: Acute respiratory distress syndrome (ARDS). Skin and mucous membrane, bone and joints system outcomes to include: Erythema multiforme; Chilblain – like lesions. Other systems outcomes to include: Anosmia, ageusia; Anaphylaxis; Multisystem inflammatory syndrome in children; Multisystem inflammatory syndrome in adults; Vaccine-associated enhanced COVID-19 disease (VAED) or vaccine associated enhanced respiratory COVID-19 disease (VAERD) (if measurable in the participating databases); Vaccine-induced immune thrombotic thrombocytopenia (VITT); Sudden death; Death of any cause.

First in period (possible recurrent) events will be assessed and case definition algorithms will be based on codes for diagnoses, procedures, and treatments. Definitions, codes and proposed algorithms for the AESI have been published and the definitions have been used for estimation of pre-pandemic population background rates. These definitions will be reviewed and refined prior to the analysis based on expert input. The refinements may include specifications regarding the code types (procedure/diagnosis/drug), setting (inpatient/outpatient/emergency), and/or sector (primary/secondary). For the self-controlled analysis, definition of an AESI will include the length of the ‘clean window’ and lengths of the risk interval, as well as the lengths of the pre-vaccination and post-vaccination control intervals. Lengths of the risk intervals will be guided by previous literature on the specific AESI, biological plausibility, and the evidence from the signal detection phase of the time-periods after vaccination with the highest SMRs. For instance, for events of anaphylaxis, which are expected to have rapid onset after vaccination, we will likely propose the risk interval 0-2 days. The approach described in the published US PASS [1] will be used as the starting point and subsequently adapted to the EU setting. However, there is an inherent uncertainty about the true length of most risk intervals, which will be addressed by applying sensitivity analyses.

AESIs other than those listed above may be considered if relevant signals appear during the study conduct or if additional AESI become added to the ACCESS protocol or SPEAC.


Saad Shakir - Chief Investigator - Drug Safety Research Unit
Debabrata Roy - Corresponding Applicant - Drug Safety Research Unit
Catherine Fry - Collaborator - Drug Safety Research Unit
Hai Nguyen - Collaborator - Drug Safety Research Unit
Miranda Davies - Collaborator - Drug Safety Research Unit
Samantha Lane - Collaborator - Drug Safety Research Unit
Sandeep Dhanda - Collaborator - Drug Safety Research Unit


CHESS (Hospitalisation in England Surveillance System);HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ICNARC (COVID-19 Intensive Care National Audit and Research Centre);ONS Death Registration Data;COVID-19 Linkages