Covid-19 vaccination in inflammatory conditions treated with immune suppressing drugs: a study of clinical effectiveness and vaccine safety using data from the Clinical Practice Research Datalink (CPRD).

Background: Immunosuppressed adults with inflammatory diseases are at an increased risk of hospitalisation and death from Covid-19 and were prioritised for vaccination in the UK.

However, the safety and effectiveness of the SARS-CoV-2 vaccines in this population is poorly understood as they were excluded from clinical trials.

Objectives: To answer the following questions on SARS-CoV-2 vaccines in adults treated with immune-suppressive medicines: [1] Is the clinical effectiveness of SARS-CoV-2 vaccines lower in adults treated with immune-suppressive medicines than in matched controls? [2] Is there a difference in the clinical effectiveness of SARS-CoV-2 vaccine technologies i.e. mRNA or vectored-DNA in this population? [3] Does SARS-CoV-2 vaccination associate with flare-up of inflammatory disease?

Methods: Data from Clinical Practice Research Datalink (CPRD) Aurum with linkage to Hospital Episode Statistics for hospitalisation data, and Office of National Statistics for mortality data will be used.

CPRD Aurum is a longitudinal anonymised electronic database and contains the health records of c.40 million people, of which 14 million are alive and registered in 1473 GP surgeries. It contains details of diagnoses, primary-care prescriptions, and immunisations including with the SARS-CoV-2 vaccines.

Dates of vaccination are recorded alongside the vaccine brand.

Clinical effectiveness (Objectives-1,2): Study design: Cohort study Study period: 01/12/2020 to 31/05/2022 Exposure: Age> 18-years, diagnosed with inflammatory bowel disease, autoimmune rheumatic disease, psoriasis or other skin disease prescribed immune-suppressing medicine(s).

Unexposed: One age (+/- 1-year), sex, technology of SARS-CoV-2 vaccine administered and vaccination date (+/-5 days) matched participants not meeting any of the criteria used to define exposure. Outcomes: Primary: Hospitalisation with Covid-19. Secondary: Primary-care diagnosis of Covid-19, death due to Covid-19.

Follow-up: From 14 days after the second dose to earliest of date of outcome, death, last data collection, leaving GP-surgery or 31/05/2022.

Analysis: Cox regression will be used to calculate hazard ratios and 95% confidence intervals (CI) with immunosuppression as the exposure of interest, adjusted for covariates. Interaction terms will be fitted for prognostic factors and stratified analysis performed if necessary.

Analyses will be restricted to 6, 9 and 12 months to examine the duration of health protection from SARS-CoV-2 vaccination. Disease flare (Objective-3): Study design: Self-controlled case series. Population: Vaccinated and outcome of interest. Exposed period: Three-weeks following each of the two SARS-CoV-2 vaccine doses.

Pre-exposure period: 2-weeks before the date of each of the two vaccinations. Unexposed period: Remaining follow-up time.

Analysis: Poisson model will be used to calculate incidence rate ratios and 95% CI for the exposed period compared to the unexposed period, including season as a covariate. Separate analyses will be performed for three disease areas. Timelines: CPRD-ISAC approval obtained prior-to study start. Data analysis and write-up month 12.

Impact and dissemination We will share our findings with the Joint Committee on Vaccination and Immunisation and Department of Health to advise health policy.

We will partner with national patient charities and professional societies to disseminate the findings to key stakeholders. A local dissemination event will be held with PPI. Results will be published open-access and presented at scientific meetings.