The Comparative Risk of Thrombosis with Thrombocytopenia Associated with Different COVID-19 Vaccines: International Network Cohort Study Including 5 European Countries and the US

Background: Thrombosis with thrombocytopenia syndrome (TTS) is being investigated as an adverse effect of adenovirus-based COVID-19 vaccines. The comparative risk of TTS and thromboembolism (TE) following vaccination with different COVID-19 vaccines remains unclear.

Objectives: To quantify the comparative risk of TTS or TE associated with vaccination with adenovirus-based or mRNA-based covid-19 vaccines.

Methods: An international network cohort study using routinely collected data from the UK, Spain, Germany, France, Netherlands, and the US was conducted. We included individuals who received at least on dose of Vaxzevria, Comirnaty, Spikevax, or Janssen Covid 19 vaccines. Cohorts of first and second doses users were defined by vaccine brands in each database. The index date was the date of vaccination. Outcomes of interest were TTS or TE during 28 days following vaccination, defined by clinical codes and measurements based on the Brighton collaboration definition. Large-scale propensity score matching was used to control for observed confounding, and negative control outcomes to assess unobserved confounding. Empirical calibration was used to adjust for systematic error, and calibrated incidence rate ratios (cIRR) estimated to quantify risk of developing TTS or TE according to vaccination with adenovirus-based (Vaxzevria or Janssen Covid 19) vs mRNA vaccines (Comirnaty/Spikevax) using Poisson models. Random-effects meta-analysis was used to pool results across databases.

Results: We identified 4.0 million people vaccinated with a first dose of Vaxzevria, and 1.6 million people vaccinated with a second dose from all participating databases. We identified 1.1 million people vaccinated with single-dose Janssen covid-19 vaccine in three databases. We identified 10.6 million people vaccinated with a first dose of Comirnaty, and 7.7 million people vaccinated with a second dose. We identified 4.3 million people vaccinated with a first dose of Spikevax, and 3 million people vaccinated with a second dose. Comparing Vaxzevria to first-dose Comirnaty, we observed an increased risk of thrombocytopenia (pooled calibrated IRR 1.33 [1.18-1.50]) and TTS (pooled calibrated IRR 1.29 [0.94-1.77]). Risk of TTS with venous thromboembolism was higher in Janssen vs Comirnaty 1-dose vaccinees: pooled calibrated IRR 2.26 [0.93-5.52].

Conclusions: We observed a 30% increased risk of thrombocytopenia and TTS after first-dose Vaxzevria versus first-dose Comirnaty vaccination. We also identified an increased risk of TTS with venous thrombo-embolism after single-dose Janssen versus Comirnaty. Although TTS remained rare in all vaccine cohorts, the comparative risk between vaccines should be considered when planning immunisation campaigns.