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. 2024 Mar 7;42(7):1731-1737.
doi: 10.1016/j.vaccine.2024.02.032. Epub 2024 Feb 22.

Mortality risk after COVID-19 vaccination: A self-controlled case series study

Stanley Xu  1 , Lina S Sy  2 , Vennis Hong  2 , Paddy Farrington  3 , Sungching C Glenn  2 , Denison S Ryan  2 , Abraelle M Shirley  2 , Bruno J Lewin  2 , Hung-Fu Tseng  2 , Gabriela Vazquez-Benitez  4 , Jason M Glanz  5 , Bruce Fireman  6 , David L McClure  7 , Laura P Hurley  8 , Onchee Yu  9 , Michael Wernecke  10 , Ning Smith  11 , Eric S Weintraub  12 , Lei Qian  2
Affiliations

Mortality risk after COVID-19 vaccination: A self-controlled case series study

Stanley Xu et al. Vaccine. .

Abstract

Background: Although previous studies found no-increased mortality risk after COVID-19 vaccination, residual confounding bias might have impacted the findings. Using a modified self-controlled case series (SCCS) design, we assessed the risk of non-COVID-19 mortality, all-cause mortality, and four cardiac-related death outcomes after primary series COVID-19 vaccination.

Methods: We analyzed all deaths between December 14, 2020, and August 11, 2021, among individuals from eight Vaccine Safety Datalink sites. Demographic characteristics of deaths in recipients of COVID-19 vaccines and unvaccinated individuals were reported. We conducted SCCS analyses by vaccine type and death outcomes and reported relative incidences (RI). The observation period for death spanned from the dates of emergency use authorization to the end of the study period (August 11, 2021) without censoring the observation period upon death. We pre-specified a primary risk interval of 28-day and a secondary risk interval of 14-day after each vaccination dose. Adjusting for seasonality in mortality analyses is crucial because death rates vary over time. Deaths among unvaccinated individuals were included in SCCS analyses to account for seasonality by incorporating calendar month in the models.

Results: For Pfizer-BioNTech (BNT162b2), RIs of non-COVID-19 mortality, all-cause mortality, and four cardiac-related death outcomes were below 1 and 95 % confidence intervals (CIs) excluded 1 across both doses and both risk intervals. For Moderna (mRNA-1273), RI point estimates of all outcomes were below 1, although the 95 % CIs of two RI estimates included 1: cardiac-related (RI = 0.78, 95 % CI, 0.58-1.04) and non-COVID-19 cardiac-related mortality (RI = 0.80, 95 % CI, 0.60-1.08) 14 days after the second dose in individuals without pre-existing cancer and heart disease. For Janssen (Ad26.COV2.S), RIs of four cardiac-related death outcomes ranged from 0.94 to 0.98 for the 14-day risk interval, and 0.68 to 0.72 for the 28-day risk interval and 95 % CIs included 1.

Conclusion: Using a modified SCCS design and adjusting for temporal trends, no-increased risk was found for non-COVID-19 mortality, all-cause mortality, and four cardiac-related death outcomes among recipients of the three COVID-19 vaccines used in the US.

Keywords: All-cause mortality; COVID-19 vaccines; Cardiac-related mortality; Self-controlled case series; non-COVID-19 mortality.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Scenarios for the timeline of administering one or two doses of a 2-dose primary series of mRNA COVID-19 vaccines, risk intervals and control intervals$ $Individual A received two doses of mRNA vaccines and died during the control interval after dose 2; Individual B received two doses of mRNA vaccines and died during the second risk interval; Individual C received two doses of mRNA vaccines with dose 2 being administered before the end of the first risk interval, and died during the control interval after dose 2; Individual D received two doses of mRNA vaccines with dose 2 be administered before the end of the first risk interval, and died during the second risk interval; Individual E received only one dose of mRNA vaccine and died during the control interval after dose 1; Individual F received only one dose of mRNA vaccine and died during the first risk interval; Individual G was not vaccinated and died during the observation period. Dashed line represents person-time after death. In a modified self-controlled cases series design, follow-up continues after death.
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