Safety of the fourth COVID-19 BNT162b2 mRNA (second booster) vaccine: a prospective and retrospective cohort study.

backgroundThe effectiveness of the second BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 booster vaccine dose (ie, fourth inoculation) is well established, but its safety has yet to be fully understood. The absence of sufficient vaccine safety information is one of the key contributors to vaccine hesitancy. In this study, we aimed to evaluate the safety profile of the second BNT162b2 mRNA COVID-19 booster vaccine using data from a retrospective cohort and a prospective cohort.

methodsTo evaluate the safety profile of the second booster vaccine, we analysed its short-term effects and compared them to those of the first booster by using data from, first, a retrospective cohort of 250 000 random members of the second-largest health-care organisation in Israel (Maccabi Healthcare Services) and, second, a prospective cohort (the PerMed study) of 4698 participants from all across Israel. Individuals who were aged 18 years or older who received the second BNT162b2 mRNA COVID-19 vaccine booster during the vaccination campaign, from Dec 30, 2021, to July 22, 2022, were eligible for inclusion in the retrospective cohort analysis. To be included in the PerMed study, participants needed to be 18 years or older, members of Maccabi Healthcare Services at the time of enrolment, using their own smartphone, and be able to give informed consent by themselves. Participants from the prospective cohort received smartwatches, downloaded a dedicated mobile application, and granted access to their medical records. The smartwatches continuously monitored several physiological measures, including heart rate. For analysis of the prospective cohort data, we used the Kruskal-Wallis test to compare heart rate levels observed before and after vaccination. The mobile application collected daily self-reported questionnaires on local and systemic reactions. Medical records of the retrospective cohort were accessed to examine the occurrence of 25 potential adverse events, and we evaluated the risk differences between 42 days in the periods before and after vaccination in a pairwise method using non-parametric percentile bootstrap.

findingsThe retrospective cohort included 94 169 participants who received the first booster and 17 814 who received the second booster. Comparing the 42 days before and after vaccination, the second booster was not associated with any of the 25 adverse events investigated, including myocardial infarction (risk difference, 2·25 events per 10 000 individuals [95% CI -3·93 to 8·98]) and Bell's Palsy (-1·68 events [-5·61 to 2·25]). None of the individuals was diagnosed with myocarditis or pericarditis following vaccination with the second booster. The prospective cohort included 1785 participants who received the first booster and 699 who received the second booster. We found no significant differences after inoculation with the first booster compared with the second booster (heart rate: day 2 [p=0·3], day 6 [p=0·89]; extent of self-reported reactions [p=0·06]). We found a significant increase in mean heart rate relative to that observed during the week before vaccination (baseline) levels during the first 3 days following the second booster (p<0·0001), peaking on day 2 (mean difference of 1·61 bpm [1·07 to 2·16] compared with baseline). Mean heart rate values returned to baseline levels by day 6 (-0·055 bpm [-0·56 to 0·45] compared with baseline).

interpretationBoth our retrospective and prospective analyses support the safety of the second booster, with our findings reflecting physicians' diagnoses, patients' objective physiological measures, and patients' subjective reactions. We believe this study provides safety assurances to the global population who are eligible to receive an additional COVID-19 booster inoculation. These assurances can help increase the number of high-risk individuals who opt to receive this booster vaccine and thereby prevent severe outcomes associated with COVID-19.

fundingEuropean Research Council (ERC).