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The 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.To 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.The 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 (p0·0001), 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).Both 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.European Research Council (ERC).

SummaryCOVID-19 remains a global concern due to vaccine protection waning and the emergence of immuneevasive variants. While the effectiveness of a second booster vaccine dose (i.e., fourth inoculation) is well proven, its safety has yet to be fully understood, and vaccine compliance remains low. We conducted a prospective observational study to compare the short-term effects of the first and second BNT162b2 mRNA COVID-19 vaccine booster doses. 2,019 participants received smartwatches and filled in a daily questionnaire on systemic reactions to the vaccine. We found substantial changes from baseline levels in the 72 hours post-vaccination with the second booster in both self-reported and physiological reactions measured by the smartwatches. However, no significant difference in reactions was observed between the first and second boosters. We also found that participants who experienced more severe reactions to the first booster tended to likewise experience more severe reactions to the second booster. Our work supports the safety of the second booster from both subjective (self-reported questionnaires) and objective (physiological measurements) perspectives.

BackgroundThe rapid rise in hospitalizations associated with the Delta-driven COVID-19 resurgence, and the imminent risk of hospital overcrowding, led the Israeli government to initialize a national third (booster) COVID-19 vaccination campaign in early August 2021, offering the BNT162b2 mRNA vaccine to individuals who received their second dose over five months ago. However, the safety of the third (booster) dose has not been fully established yet.ObjectiveEvaluate the short-term, self-reported and physiological reactions to the third BNT162b2 mRNA COVID-19 (booster) vaccine dose.DesignA prospective observational study, in which participants are equipped with a smartwatch and fill in a daily questionnaire via a dedicated mobile application for a period of 21 days, starting seven days before the vaccination.SettingAn Israel-wide third (booster) vaccination campaign.ParticipantsA group of 1,609 (18+ years of age) recipients of at least one dose of the BNT162b2 vaccine between December 20, 2020, and September 15, 2021, out of a larger cohort of 2,912 prospective study participants. 1,344 of the participants were recipients of the third vaccine dose.MeasurementsDaily self-reported questionnaires regarding local and systemic reactions, mood level, stress level, sport duration, and sleep quality. Heart rate, heart rate variability and blood oxygen saturation level were continuously measured by Garmin Vivosmart 4 smartwatches.ResultsThe extent of systemic reactions reported following the third (booster) dose administration is similar to that reported following the second dose (p-value=0.305) and considerably greater than that reported following the first dose (p-valueLimitationsParticipants may not adequately represent the vaccinated population in Israel and elsewhere.ConclusionOur work further supports the safety of a third COVID-19 BNT162b2 mRNA (booster) vaccine dose from both a subjective and an objective perspective, particularly in individuals 65+ years of age and those with underlying medical conditions.Primary funding sourceEuropean Research Council (ERC) project #949850

BackgroundClinical trial guidelines for assessing the safety of vaccines, including the FDA criteria, are primarily based on subjective, self-reported questionnaires. Despite the tremendous technological advances in recent years, objective, continuous assessment of physiological measures post-vaccination is rarely performed.MethodsTo evaluate the short-term effects of the BNT162b2 COVID-19 vaccine on physiological measures, we conducted a prospective observational study during the mass vaccination campaign in Israel. 160 individuals >18 years who were not previously found to be COVID-19 positive and who received the second dose of the COVID-19 vaccine between 1 January, 2021, and 13 March, 2021 were equipped with a chest-patch sensor and a dedicated mobile application. The chest-patch sensor continuously measured 13 physiological vitals one day before the inoculation (baseline), for four days: heart rate, blood oxygen saturation, respiratory rate, systolic and diastolic blood pressure, pulse pressure, mean arterial pressure, heart rate variability, stroke volume, cardiac output, cardiac index, systemic vascular resistance, and body temperature. The mobile application collected daily self-reported questionnaires starting one day before the inoculation, for 15 days on local and systemic reactions, sleep quality, stress levels, physical activity, and mood levels.FindingsWithin the first 48 hours post-vaccination, we identified significant changes (p-value InterpretationOur work underscores the importance of obtaining objective physiological data in addition to self-reported questionnaires when performing clinical trials, particularly in ones conducted in very short time frames.FundingThe European Research Council (ERC) project #949850.

The unprecedented restrictions imposed due to the COVID-19 pandemic, including movement control orders and lockdowns, altered our daily habits, and severely affected our well-being and physiology. The effect of these changes is yet to be fully understood. Here, we analyzed highly detailed data on 169 participants for 2-6 months, before and during the second COVID-19 lockdown in Israel. Our entire study was conducted during the COVID-19 pandemic, and therefore is the first to decipher the specific effects of the lockdown from the general effects of the pandemic. We extracted 12 well-being indicators from sensory data of smartwatches and from self-reported questionnaires, filled on a daily basis using a designated mobile application. We used a mixed ANOVA model to study the interplay between age, gender, and chorotype on well-being before and after lockdowns. We found that at the population level, lockdowns resulted in significant changes in mood, sleep duration, sport duration, social encounters, resting heart rate, and the number of steps. The lockdown's adverse effects were greater for young early chronotypes who did not increase their sleep duration, reduced activity level and suffered from significantly reduced mood, and for women, who further suffered an increase in stress levels and a greater decline in social encounters. Our findings underscore that while lockdowns severely impacted our well-being and physiology in general, greater damage has been identified in certain subpopulations. Based on the observed effects, special attention should be given to younger people, who are usually not in the focus of social support, and to women.