• This multinational retrospective review encompassing over 6 million patients compared the incidence of thromboembolic events or thrombosis with thrombocytopenia syndrome among adults receiving mRNA-based versus adenovirus-based COVID-19 vaccines. Although the events occurred infrequently, compared with BNT162b2 (Pfizer–BioNTech), the first dose of ChAdOx1-S (Oxford–AstraZeneca) was associated with a statistically significant 30% increased risk of thrombocytopenia. A non-statistically significant increase in the risk of venous thrombosis with thrombocytopenia syndrome was noted after receiving Ad26.COV2.S (Janssen/Johnson & Johnson) compared with BNT162b2.
• Prior to this study, real-world data regarding the incidence and comparative risk of thrombosis with thrombocytopenia syndrome among patients receiving adenovirus versus mRNA vaccines were lacking. The increased risk noted with one of the adenovirus vaccines may inform subsequent recommendations and public health efforts.

OBJECTIVE

To quantify the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with use of adenovirus based covid-19 vaccines versus mRNA based covid-19 vaccines.

DESIGN

International network cohort study.

SETTING

Routinely collected health data from contributing datasets in France, Germany, the Netherlands, Spain, the UK, and the US.

PARTICIPANTS

Adults (age ≥18 years) registered at any contributing database and who received at least one dose of a covid-19 vaccine (ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen/Johnson & Johnson)), from December 2020 to mid-2021.

MAIN OUTCOME MEASURES

Thrombosis with thrombocytopenia syndrome or venous or arterial thromboembolic events within the 28 days after covid-19 vaccination. Incidence rate ratios were estimated after propensity scores matching and were calibrated using negative control outcomes. Estimates specific to the database were pooled by use of random effects meta-analyses.

RESULTS

Overall, 1 332 719 of 3 829 822 first dose ChAdOx1-S recipients were matched to 2 124 339 of 2 149 679 BNT162b2 recipients from Germany and the UK. Additionally, 762 517 of 772 678 people receiving Ad26.COV2.S were matched to 2 851 976 of 7 606 693 receiving BNT162b2 in Germany, Spain, and the US. All 628 164 Ad26.COV2.S recipients from the US were matched to 2 230 157 of 3 923 371 mRNA-1273 recipients. A total of 862 thrombocytopenia events were observed in the matched first dose ChAdOx1-S recipients from Germany and the UK, and 520 events after a first dose of BNT162b2. Comparing ChAdOx1-S with a first dose of BNT162b2 revealed an increased risk of thrombocytopenia (pooled calibrated incidence rate ratio 1.33 (95% confidence interval 1.18 to 1.50) and calibrated incidence rate difference of 1.18 (0.57 to 1.8) per 1000 person years). Additionally, a pooled calibrated incidence rate ratio of 2.26 (0.93 to 5.52) for venous thrombosis with thrombocytopenia syndrome was seen with Ad26.COV2.S compared with BNT162b2.

CONCLUSIONS

In this multinational study, a pooled 30% increased risk of thrombocytopenia after a first dose of the ChAdOx1-S vaccine was observed, as was a trend towards an increased risk of venous thrombosis with thrombocytopenia syndrome after Ad26.COV2.S compared with BNT162b2. Although rare, the observed risks after adenovirus based vaccines should be considered when planning further immunisation campaigns and future vaccine development.

When interpreting vaccine safety studies, it is important to keep the background in mind.  Adverse events following vaccination can be due to the vaccine exposure, simple coincidence, or in response to an infection-related process emerging despite vaccination (vaccine failure).  Safety studies using random allocation of vaccine or placebo provide the best evidence of causation but are uncommon outside of initial evaluations needed for authorization or licensure and are not powered to allow evaluation of rare outcomes.  More often, we are presented with larger studies comparing vaccinated and unvaccinated individuals or individuals receiving one vaccine to those receiving another, and we are left with assessments of relative rates and not necessarily causation.

A recent evaluation of thrombosis with thrombocytopenia syndrome (TTS) and thromboembolic events associated with different COVID-19 vaccines [1] fits into this last category.  First, remember that—in the background—infection with SARS-CoV-2 can result in arterial and venous and thromboembolism [2]; characteristics of SARS-CoV-2 surface proteins likely elicit thrombosis.  Accordingly, intentional use of similar proteins within a vaccine may trigger this effect.

Using routinely collected data from five European nations and the United States, researchers were able to compare the rates of TTS and thromboembolic events in the 28-days following two adenovirus-vectored, COVID-19 vaccines (Oxford-AstraZeneca [not available in the U.S.] and Janssen/Johnson & Johnson) to those following two mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna).  Compared to Pfizer-BioNTech, Oxford-AstraZeneca recipients had a 30% increase in thrombocytopenia.  Although there was a trend for increased risk, no significant increase in thrombosis occurred in individuals receiving Janssen/Johnson & Johnson as compared to those Pfizer-BioNTech. 

The takeaway here is that rare cases of TTS and thrombosis occur at greater frequency with the adenovirus-vectored vaccines than with the mRNA vaccines.  Considerations for their use should be based on multiple factors, and CDC guidance states, “Because of this risk, vaccination with COVID-19 vaccines other than J&J/Janssen vaccine is preferred.”[3] 

References

1. Li X, Burn E, Duarte-Salles T, Yin C, et al. Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US. BMJ. 2022 Oct 26;379:e071594. doi: 10.1136/bmj-2022-071594. PMID: 36288813; PMCID: PMC9597610.
2. Malas MB, Naazie IN, Elsayed N, et al. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine. 2020 Dec;29:100639. doi: 10.1016/j.eclinm.2020.100639. Epub 2020 Nov 20. PMID: 33251499; PMCID: PMC7679115.
3. CDC. Overview of COVID-19 Vaccines.  Accessed 11/10/2022 at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/overview-COVID-19-vaccines.html