Risk of thrombosis with thrombocytopaenia syndrome (TTS) after vaccination with AZD1222: a European VAC4EU post-authorisation safety study

A post-authorisation safety study was conducted for the AZD1222 COVID-19 vaccine. This paper presents one study outcome, thrombosis with thrombocytopenia syndrome (TTS), and estimates TTS risk in subjects administered ≥1 AZD1222 dose versus concurrent unvaccinated, pre-pandemic historical, or mRNA-vaccinated subjects.The cohort study used data from CPRD Aurum (UK), VID (Spain), SIDIAP (Spain) and PHARMO-GP database (PHARMO) (the Netherlands). AZD1222-vaccinated subjects were matched on age, sex, region, prior COVID-19, and special population status. Incident venous TTS was defined as a thromboembolic event and thrombocytopaenia within ±10 days and no TTS within the prior year.5,321,930 subjects were matched with concurrent unvaccinated comparators, 4,831,010 with historical comparators, and 4,028,091 with mRNA active comparators (CPRD only). In CPRD, 83% of subjects were vaccinated in Q1 2021; 64% were < 60 years. In VID, SIDIAP, and PHARMO, >59% were vaccinated after Q1 2021; most subjects were ≥ 60 years. Propensity score–weighted incidence rate ratios (IRRs) (95% confidence intervals) for TTS were CPRD, 1.14 (0.60–2.17); VID, 0.34 (0.10–1.18); SIDIAP, 0.66 (0.33–1.34); and zero events in PHARMO. Incidence rates (IRs) and IRRs for TTS, where available, were higher in AZD1222-vaccinated versus concurrent unvaccinated subjects <60 years or during shorter risk windows. After case validation, positive predictive value–adjusted IRRs were < 1. For historical comparators, meta-analysis resulted in an IRR of 1.78 (95% CI,1.12–2.82; I2 = 0%). For mRNA active comparators, the IRR was 1.12 (95% CI,0.61–2.05).Considering the magnitude, precision, and potential biases—such as selection bias due to informative censoring and potential outcome misclassification—the totality of evidence suggests a possible increased risk of TTS with post-AZD1222 vaccination that may be higher among subjects <60 years and 1–42 days after first AZD1222 dose, in line with the literature. Differential age distributions resulting from country-level differences in the risk minimisation measures may explain IRR disparities across data sources.