Risk of death following COVID-19 vaccination or positive SARS-CoV-2 test in young people in England

March 2023
Vahé Nafilyan, Charlotte R. Bermingham, Isobel L. Ward,1 Jasper Morgan, Francesco Zaccardi, Kamlesh Khunti, Julie Stanborough, Amitava Banerjee, and James C. Doidge

Abstract

Several studies have reported associations between COVID-19 vaccination and risk of cardiac diseases, especially in young people; the impact on mortality, however, remains unclear. We use national, linked electronic health data in England to assess the impact of COVID-19 vaccination and positive SARS-CoV-2 tests on the risk of cardiac and all-cause mortality in young people (12 to 29 years) using a self-controlled case series design. Here, we show there is no significant increase in cardiac or all-cause mortality in the 12 weeks following COVID-19 vaccination compared to more than 12 weeks after any dose. However, we find an increase in cardiac death in women after a first dose of non mRNA vaccines. A positive SARS-CoV-2 test is associated with increased cardiac and all-cause mortality among people vaccinated or unvaccinated at time of testing.

Subject terms: Cardiology, Infectious diseases, Vaccines, Epidemiology, SARS-CoV-2

Rare but serious cardiac disease side effects have been linked to COVID-19 vaccinations, especially in young people. Here, the authors find very little evidence of an association between vaccination and mortality, except for in females after a non mRNA vaccine, but show an increased risk of death following COVID-19 infection

Introduction

On the 8 December 2020, the United Kingdom (UK) began administering vaccines against COVID-19 according to the priority groups determined by the Joint Committee on Vaccination and Immunisation (JCVI)1. While the randomised clinical trials focused on short-term efficacy against symptomatic infection, which was subsequently found to wane and be escaped by SARS-CoV-2 variants2–7, real-world evidence has indicated stronger and more sustained effectiveness against severe disease and death due to COVID-196,8,9. However, it is also important to consider their safety, which can be difficult to assess in randomised clinical trials that are not powered to detect rare adverse events2,3,10.

There have been rare cases of serious adverse events reported with the COVID-19 vaccines. Previous studies have shown an increase in the risk of myocarditis and myopericarditis associated with mRNA vaccines including BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)8,11, and an increased risk of thrombotic and other rare cardiovascular events after the ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca)12,13. There is also evidence of a range of other rare neurological complications14. However, the absolute risk of severe complications is low and needs to be assessed against the increased risks associated with SARS-CoV-2 infection if unvaccinated15,16. The balance of risk and benefit is particularly important to determine in younger people, due to the lower risk of COVID-19 hospitalisation and death in this age group17.

Comparisons of the risk of death in vaccinated and unvaccinated young people are subject to confounding due to the vaccine prioritisation of, and higher vaccination rates among, those with underlying health conditions. To minimise potential confounding, we used a self-controlled case series (SCCS) design, where each participant acts as their own control, to compare the risk of death in the twelve weeks after vaccination (‘risk period’) to a subsequent reference period18. For comparison purposes, we assessed the impact of a positive test for SARS-CoV-2 on the same outcomes in vaccinated and unvaccinated individuals.

Here, we show that among the population of England aged 12–29, mortality is not significantly increased in the first twelve weeks after COVID-19 vaccination compared with more than 12 weeks after any dose. Observed reductions in all-cause mortality are consistent with a time-varying healthy vaccinee effect due to postponement of vaccination during periods of poor health. However, in subgroup analyses we find a significant elevation in the risk of cardiac death in women after a first dose of non-mRNA vaccines, and a smaller, non-significant increase in cardiac death after second dose of mRNA vaccines in men. By contrast, a positive SARS-CoV-2 test is associated with increased cardiac and all-cause mortality among both vaccinated and unvaccinated individuals.

Results

Characteristics of the study population

There were 3807 deaths of 12 to 29 year-olds in England that occurred between 8 December 2020 and 25 May 2022 and were registered by 8 June 2022 (Supplementary Fig. 1). Of these, 444 (11.7%) were due to a cardiac event and 1512 (39.7%) were linked to a vaccination record (1510 from NIMS and 2 from the supplementary NHS point of care extract) (Table 1). 62.8% (950) of first doses, 51.6% (505) of second doses and 98.8% (239) of third doses in the death registrations dataset were mRNA based (either the BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna vaccines), rather than non-mRNA based (the ChAdOx1 Oxford-AstraZeneca vaccine) or another vaccine or unknown. Of those who received both the first and second vaccination (979), 11.3% (111) received a different type of vaccine for each dose (Supplementary Table 1). Counts of deaths by sex and vaccine vector for people who received at least one dose of that vector are included (Supplementary Table 2).