Safety of COVID-19 Monovalent and Bivalent BNT162b2 mRNA Vaccine Boosters for Adults 60 Years and Above: A Large-Scale Retrospective Study

Abstract

Background: COVID-19 continues to constitute a major health threat, particularly among the elderly. Despite the adoption of a follow-up (timed) vaccine booster strategy for this age group by many countries, most of them have witnessed a graduate decline in vaccine coverage, including in the US, the UK, and Israel. The absence of sufficient vaccine safety information is one of the key contributors to vaccine refusal. In this study, we evaluated the safety profile of the first and second monovalent and bivalent BNT162b2 mRNA booster vaccines in older adults.

Methods: We analyzed the medical records of 863,886 members aged 60 years and above of the largest healthcare organization in Israel (Clalit Healthcare Services) who received the first, second monovalent and/or bivalent BNT162b2 mRNA COVID-19 vaccine boosters between July 30, 2021, and November 1, 2022. We examined the occurrence of non-COVID-19 hospitalizations and 27 adverse events potentially associated with the vaccinations, with special focus on the cardiovascular system. Specifically, we used a self-control methodology to evaluate the risk differences between 28 days before vaccination (baseline period: 35 days until 8 days before vaccination), and after vaccination (post vaccination: the day of inoculation until day 27) for each adverse event in a pairwise method using non-parametric percentile bootstrap. We also assessed the safety profile in the subgroups 60–70, 70–80, >80 years of age, and with the added layer of with vs. without a previous cardiovascular background.

Findings: The cohort consisted of 702,490 recipients of the first monovalent booster, 369,859 recipients of the second monovalent booster, and 49,502 recipients of the bivalent booster. Overall, we found no indication of an elevated risk of non-COVID-19 hospitalizations following the administration of any of the booster vaccines. With the exception of a weak signal in pericarditis following the second monovalent booster (risk difference, 0·19 events per 10,000 individuals [95% CI: 0·03 to 0·38]), the monovalent and bivalent boosters were not associated with any of the adverse events we investigated, including myocardial infarction (first monovalent 2·25 [CI: 3·93 to 8·98], second monovalent  0·24 [-0·59 to 1·08], bivalent 0·81[-0·2 to 2·02]), ischemic-stroke (first monovalent -0·48[-1·12 to 0·17], second monovalent 0·19[-0·7 to1·08], bivalent -0·61[ -2·02 to 0·81]) and heart failure (first monovalent -0·61[-1·21tp 0·0], second monovalent 0·38[-0·68 to 1·46], bivalent 0·4 [ -1·41 to 2·22]). Our subgroup analysis further confirmed no elevated risk of hospitalizations post vaccination in all six subgroups considered, including in individuals aged 80 years and above with a previous cardiovascular background. 

Interpretation: Our analysis supports the safety of the monovalent and bivalent BNT162b2 mRNA booster vaccines, in subjects aged 60 and above.

Funding: ISRAEL SCIENCE FOUNDATION (grant no. 3409/19), within the Israel Precision Medicine Partnership program.

Declaration of Interest: The authors declare no competing interests

Ethics Approval: As the retrospective data was pseudonymized, the institutional Helsinki review board and data utilization committee approved the use of the retrospective cohort data without requiring specific consent from the members of Clalit Healthcare Services (protocol number 0139-21-CHS).

Keywords: COVID-19 vaccine, COVID-19 booster vaccine, BNT162b2, adverse events, bivalent vaccine, vaccine safety, cardiovascular disease, ischemic stroke