Study design and participants
Our study includes a prospective cohort of 160 participants who were not previously found to be COVID-19 positive and received the second dose of the BNT162b2 mRNA COVID-19 vaccine between 1 January 2021 and 13 March 2021. This sample size of >150 participants was chosen to ensure a sufficient amount of participants will present substantial reactions (such as fever)8. Specifically, as reported reactions were considerably more severe after the second dose compared to the first8, we focused on the second dose of vaccine. Out of the 160 participants in this study, 90 (56.25%) were women and 70 (43.75%) were men. Their age ranged between 21 and 78 years, with a median age of 40. Participants were equipped with a chest-patch sensor and were monitored for a period of four days, starting one day prior to vaccine administration. In addition, participants installed a dedicated mobile application and were requested to fill in a daily questionnaire, starting one day prior to the inoculation, for a period of 15 days. For each participant, the measurements levels were compared to the levels observed on the 24-h period prior to vaccination.
In order to recruit participants and ensure they complete all the study’s requirements, we hired a professional survey company. Potential participants were recruited through advertisements in social media, online banners, and word-of-mouth. The survey company was responsible for guaranteeing the participants met the study’s requirements, in particular, that they agreed to wear the chest-patch sensor and fill in the daily questionnaires.
Participants were met in person, roughly 24 h prior to vaccination, and received a detailed explanation about the study, after which they were requested to sign an informed consent form. Then, participants were asked to complete a one-time enrollment questionnaire and install two applications on their mobile phones: an application that passively collects data from the chest-patch sensor and the PerMed application, allowing participants to fill the daily questionnaires.
To better understand the effects of the second vaccine dose on physiological measures, we also monitored 24 participants, with an identical procedure, when receiving their first vaccination dose.
The chest-patch sensor
The photoplethysmography (PPG)-based chest monitors purchased and used in this study collects the following 13 indicators of vital signs: heart rate (bpm), blood oxygen saturation (%), respiratory rate (br/min), systolic and diastolic blood pressure (mmHg), pulse pressure (mmHg), mean arterial pressure (mmHg), heart rate variability (HRV—the calculation is based on a time-domain method in which the root mean square of successive RR interval differences are measured for a segment of ten beats and are presented in %), stroke volume (mL/beat), cardiac output (L/min), cardiac index (L/min/m2), systemic vascular resistance (SVR) (dynes·sec·cm−5), and skin temperature (c). Together, these indicators of vital signs provide an accurate and comprehensive assessment of the respiratory, cardiovascular, and hemodynamic. The chest patch sensor received FDA clearance for measures of heart rate, blood oxygen saturation, and systolic and diastolic blood pressure (clearance number K190792) and CE Mark approval for all 13 measures (CE 2797) (Biobeat Technologies Ltd), (see also a technological validation study for blood pressure15). The sensor tracks vital signs derived from changes in the pulse contour, following calibration using an approved non-invasive, cuff-based device, and is based on Pulse Wave Transit Time (PWTT) technology, combined with pulse wave analysis (PWA) (see, for example, refs. 16,17). To increase its validity, the device has an inherent component that prevents showing values if the movement has crossed a pre-set threshold. To the best of our knowledge, this is the only cleared wearable wireless medical-grade device to provide all these measurements. As the chest patch sensors’ battery typically lasts for 4–5 days, participants were asked to remove the chest patch sensors 3 days after vaccination. Accordingly, the sensor continuously collected data at 10-min intervals for the entire duration of the 96-h experiment.
PerMed mobile application
Developed originally to support the PerMed study18, the PerMed mobile application allows participants to fill the daily questionnaires. The daily questionnaire we used included questions about clinical symptoms from a closed list of local and systemic reactions observed in the BNT162b2 mRNA Covid-19 clinical trial8, with an option to add other symptoms as free text.
In order to improve the quality and reliability of the data and to ensure its continuous collection, we applied the following two measures: (1) Participants who did not complete the daily questionnaire by 7 p.m. received a notification in their mobile app to fill the questionnaire; (2) We developed a dedicated dashboard that helped us identify when participants did not fill in the daily questionnaires. Those participants were contacted by the survey company and were encouraged to cooperate better.
Statistics and reproducibility
Before analyzing the data, we performed several preprocessing steps. With regard to the daily questionnaires, in cases where participants filled in the daily questionnaire more than once on a given day, only the last entry for that day was considered, as it was reasoned that the last one likely best represented the entire day. Self-reported symptoms that were entered as free text were manually categorized. With regard to the chest-patch indicators, data were first aggregated per hour (by taking the mean value). Then, to impute missing values, we performed a linear interpolation. To validate the consistency of our findings, we split the data into two groups in a balanced fashion in terms of their age group and gender. One group contained 80%, and the other one contained the other 20%. The final analyses presented are based on the entire sample. All data and code required to reproduce the results reported in this paper are available in the GitHub repository19.
To examine the changes in each chest-patch indicator over the 72 h post-vaccination compared with the 24-h period prior to vaccination, we performed the following steps. For each indicator, for each hour h of the 72 h post-vaccination, we calculated for each individual the mean value in the 5-h sliding window: [h−4, h−3, h−2, h−1, h]. Then, we calculated the relative change in the percentage of this value compared to the corresponding 5-h window in the day prior to vaccination. Finally, we calculated the mean value for hour h over all 160 participants, as well as the 90% confidence interval, corresponding to a significance level of 0.05 in a one-sided t-test (Fig. 1). We performed a similar analysis for the 24 participants who received the first vaccine dose (Supplementary Fig. S1).
Next, for each of the 3 days after the vaccination, we calculated the percentage of participants who reported new local or systemic reactions compared to their reports on the day prior vaccination (Fig. 2). For each reaction, a 90% confidence interval was calculated assuming a beta distribution, with parameter (alpha) corresponding to the number of participants reporting that reaction plus one (i.e., “successes”), and parameter (beta) corresponding to the number of participants who did not report that reaction plus one (i.e., “failures”).
Finally, we examined the difference between symptomatic and asymptomatic participants with regard to changes in the chest-patch indicators, stratified by the number of days post-vaccination (1–3) and part of the day (day or night) (Fig. 3). For a given day post-vaccination, symptomatic participants were defined as those who reported at least one reaction on that day that they did not report the day prior vaccination. Asymptomatic individuals were defined as those who reported no reactions on that day. We defined nighttime as the time interval between 12 a.m. and 7 a.m. and daytime between 7 a.m. and 12 a.m. This day-night definition is consistent with the observed movement patterns of the participants throughout the study. For each participant, we calculated the mean indicator value for each day and part of the day post-vaccination. Then, we calculated the relative change in percentages of these values compared to their corresponding values in the day prior vaccination. Next, we calculated the mean values of symptomatic participants and asymptomatic participants, as well as their corresponding 90% confidence intervals using a t distribution. Finally, unequal variances t-tests were used to evaluate the differences between symptomatic and asymptomatic participants.
Ethical approval
Before participating in the study, all subjects were advised, both orally and in writing, as to the nature of the study and gave written informed consent to the study protocol, which was approved by the Tel Aviv University Institutional Review Board (0002522-1). All data were de-identified and no personally identifiable information was gathered.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
