A post-authorisation (post-marketing) observational study using existing secondary health data sources to evaluate the association between exposure to the AstraZeneca COVID-19 vaccine (AZD1222) and safety concerns

Date of Approval
Application Number
Technical Summary

The Covid-19 vaccine AstraZeneca AZD1222 (called Vaxzevria® in Europe) has been authorised for use in the European Union (EU), for prevention of COVID-19. Due to the shortened pre-authorisation development period and the limited clinical trials for COVID-19 vaccines, post-authorisation safety studies (PASS) are required to continue monitoring safety. This CPRD study, conducted in Aurum database, forms the UK component of this multi-database multi-country study conducted in Europe, fulfilling European Medicines Agency (EMA) requirements.

The study aims to determine whether there is an increased risk of prespecified adverse events of special interest (AESI) after vaccination with AZD1222. A retrospective cohort design and a self-controlled risk interval (SCRI) design will be used to compare individuals who have received at least one dose of AZD1222 with those who have not yet received any COVID-19 vaccine for the occurrence of AESIs. The cohort study design will be used to estimate incidence rates of prespecified AESI among individuals who receive at least one dose of AZD1222.

A cohort study and SCRI design will be used to describe incidence rates and determine whether an increased risk of prespecified AESI exists following at least one dose of AZD1222 compared with a matched comparator group with no COVID 19 vaccination, within sub-cohorts of interest with missing information. Areas of missing information include use of AZD1222 in pregnant or breastfeeding women, use in immunocompromised individuals, use in frail individuals with comorbidities, use in those with autoimmune or inflammatory disorders, and interactions with other vaccines and long-term safety.

In addition, the study will characterise utilisation patterns of AZD1222 by estimating the proportion of individuals receiving the vaccine; two-dose vaccine completion rate and distribution of time gaps between the first and second dose, demographics and clinical characteristics of recipients, overall and among sub-cohorts of interest.

Health Outcomes to be Measured

Safety outcomes:

Outcomes include the safety concerns and other AESIs listed in the current approved AZD1222 EU Risk Management Plan (RMP) and also new safety events of interest raised by the EMA after evaluation of cases involving thrombocytopenia with thrombosis or bleeding. The AESIs differ in terms of latency, acuity of onset, availability of empirical estimates for appropriate risk periods, and the effect of the event on subsequent likelihood of vaccination. The AESIs to be analysed in this study are: Vaccine-associated enhanced disease, including vaccine-associated enhanced respiratory disease (e.g. acute respiratory distress syndrome, ARDS); Multisystem inflammatory syndrome in adults/children; Sudden death; Autoimmune thyroiditis; Anosmia, ageusia; Anaphylaxis; Type III hypersensitivity reactions; ARDS; Guillain-Barré syndrome; Other peripheral and polyneuropathies; Multiple sclerosis, transverse myelitis, and other demyelinating disorders; Optic neuritis/neuromyelitis optic spectrum disorder; Encephalitis (including acute disseminated encephalomyelitis); Myasthenia gravis; Bell’s palsy; Generalised convulsions; Narcolepsy; Myocarditis/Pericarditis; Postural orthostatic tachycardia syndrome; Myocardial infarction; Acute cardiac injury including microangiopathy, cardiogenic shock, heart failure, stress cardiomyopathy; Thrombocytopenia; Thrombocytopenia with associated bleeding; Thrombosis (embolic and thrombotic events) without thrombocytopenia; Thrombosis with thrombocytopenia syndrome; Capillary leak syndrome; Acute kidney injury; Acute liver injury; Acute pancreatitis; Acute aseptic arthritis; Fibromyalgia; Rhabdomyolysis; Chronic fatigue syndrome/ME/PVFS; Erythema multiforme; and Chilblain-like skin lesions.

The study will also estimate the incidence rates of AESIs. 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 all AESI will incorporate definitions developed by the ACCESS project (http://www.encepp.eu/encepp/viewResource.htm?id=37274) (https://drive.google.com/drive/folders/1Y_3cuGRN1g-jBv2ec1fC0aYcpxEjtrY9).

If feasible, algorithms to determine selected AESIs will be validated in a sample of cases based on manual review of electronic records (electronic records here relates to the data from CPRD Aurum and linked datasets, extracted as part of this study). This will be conducted by clinicians blinded to COVID-19 vaccine exposure, which will also involve use of a validation case report form (CRF) for cases that will be subject to an event or case verification and validation procedure. Information to complete the validation CRF will only be obtained from data extracted as part of the study i.e., CPRD Aurum and linked datasets. This study will not involve any further contact with GPs or patients. If validation is performed, certainty of an event diagnosis will be classified against existing and as-yet developed standardised definitions such as those created by the Brighton Collaboration.


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);CPRD Mother-Baby Link;HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ICNARC (COVID-19 Intensive Care National Audit and Research Centre);ONS Death Registration Data;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation;Pregnancy Register;COVID-19 Linkages