key: cord-0804645-6pilt08d
authors: Gepner, Y.; Mofaz, M.; Oved, S.; Yechezkel, M.; Constantini, K.; Goldstein, N.; Shmueli, E.; Yamin, D.
title: Short-term effects of BNT162b2 mRNA COVID-19 vaccination on physiological measures: a prospective study
date: 2021-05-07
journal: nan
DOI: 10.1101/2021.05.06.21256587
sha: aaa5fb8820d4660de71c35489224c45838aaf859
doc_id: 804645
cord_uid: 6pilt08d

Background: Clinical 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. Methods: To 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. Findings: Within the first 48 hours post-vaccination, we identified significant changes (p-value <0.05) in nearly all 13 chest-patch indicators compared to their baseline levels. 48.5% (n=78) reported no local or systemic reaction. Nevertheless, we identified considerable changes in chest-patch indicators during the first 48 hours post-vaccination also in this group of presumably asymptomatic participants. Within three days from vaccination, these measures returned to baseline levels in both groups, further supporting the safety of the vaccine. Interpretation: Our 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. Funding: The European Research Council (ERC) project #949850.

Introduction clinical trials, particularly during an emergency, is crucial for a more comprehensive determination 88 of vaccine safety.

Study design and participants 92 Our study includes a prospective cohort of 160 participants who were not previously found to be In order to recruit participants and ensure they complete all the study's requirements, we hired a 105 professional survey company. Potential participants were recruited through advertisements in 106 social media, online banners, and word-of-mouth. The survey company was responsible for 107 guaranteeing the participants met the study's requirements, in particular, that they agreed to wear 108 the chest-patch sensor and fill in the daily questionnaires.

Participants were met in person, roughly 24 hours prior to vaccination, and received a detailed 111 explanation about the study, after which they were requested to sign an informed consent form. 112 Then, participants were asked to complete a one-time enrollment questionnaire and install two 113 applications on their mobile phones: an application that passively collects data from the chest-114 patch sensor and the PerMed application, allowing participants to fill the daily questionnaires. 115 To better understand the effects of the second vaccine dose on physiological measures, we also 116 monitored a subset of 25 participants, with an identical procedure, when receiving their first 117 vaccination dose.

The chest-patch sensor 119 The photoplethysmography (PPG)-based chest monitors purchased and used in this study collects 120 the following 13 indicators of vital signs: heart rate, blood oxygen saturation, respiratory rate, 121 systolic and diastolic blood pressure, pulse pressure, mean arterial pressure, heart rate variability, Technologies Ltd). To the best of our knowledge, this is the only cleared wearable wireless 128 medical-grade device to provide all these measurements. The sensor tracks vital signs derived from 129 changes in the pulse contour, following baseline calibration using an approved non-invasive, cuff- 134 Developed originally to support the PerMed study, 17 the PerMed mobile application passively 135 collects smartphone sensory data, as well as allows participants to fill the daily questionnaires. 136 The daily questionnaire we used included questions about: mood level (on a scale of -2 [awful] to an option to add other symptoms as free text). 141 In order to improve the quality and reliability of the data and to ensure its continuous collection, 142 we applied the following two measures: 1) Participants who did not complete the daily 143 questionnaire by 7 pm received a notification in their mobile app to fill the questionnaire; 2) We 144 developed a dedicated dashboard that helped us identify when participants did not fill in the daily 145 questionnaires. Those participants were contacted by the survey company and were encouraged to 146 cooperate better.

Statistical analysis 148 Before analyzing the data, we performed several preprocessing steps. With regard to the daily 149 questionnaires, in cases where participants filled in the daily questionnaire more than once on a 150 given day, only the last entry for that day was considered, as it was reasoned that the last one likely 151 best represented the entire day. Self-reported symptoms that were entered as free text were 152 manually categorized. With regard to the chest-patch indicators, data were first aggregated per 153 hour (by taking the mean value). Then, to impute missing values, we performed a linear 154 interpolation.

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. corresponding to the number of participants reporting that reaction plus one (i.e., "successes"), 170 and parameter β corresponding to the number of participants who did not report that reaction plus 171 one (i.e., "failures"). Then, we calculated the mean difference value over all participants and a 90% confidence interval 177 using a t distribution.

178 179 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Finally, we examined the difference between symptomatic and asymptomatic participants with 180 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) (Figure 3 ). For a given day post-vaccination, symptomatic 182 participants were defined as those who reported at least one reaction on that day that they did not 183 report in the baseline period. Asymptomatic individuals were defined as those who reported no 184 reactions on that day. We defined nighttime as the time interval between 12:00 am and 7:00 am 185 and daytime between 7:00 am and 12:00 am. This day-night definition is consistent with the 186 observed movement patterns of the participants throughout the study. For each participant, we 187 calculated the mean indicator value for each day and part of the day post-vaccination. Then, we 188 calculated the relative change in percentages of these values compared to their corresponding 189 values in the baseline period. Next, we calculated the mean values of symptomatic participants 190 and asymptomatic participants, as well as their corresponding 90% confidence intervals using a t 191 distribution. Finally, unequal variances t-tests were used to evaluate the differences between 192 symptomatic and asymptomatic participants.

Before participating in the study, all subjects were advised, both orally and in writing, as to the 195 nature of the study and gave written informed consent to the study protocol (appendix pp 25-35), 196 which was approved by the Tel-Aviv University Institutional Review Board (0002522-1). All data 197 were de-identified, and no personal identifiable information was gathered. The funders of the study had no role in data collection, data analysis, data interpretation, or 201 writing of the manuscripts. 202 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021.

Between 1 January 2021, and 13 March 2021, a total of 166 participants were recruited. Among 204 them, 160 participants completed the trial, and their data were analyzed; five participants left the 205 trial early, and one participant was provided with a malfunctioning chest-patch sensor. Among 206 these participants, 56.25% were females, 13.75% were obese (body-mass index of at least 30.0), 207 18.12% had high blood pressure, and 20.00% had at least one comorbidity. The median age was 208 40 years, and 10.63% of participants were older than 59 years of age (Table 1) . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. patch indicators compared to their baseline levels (figure 1 and appendix p 36). For example, at 225 their peak, the heart rate increased by 9.85% (90% CI, 7.71% to 11.99%), the systolic blood 226 pressure increased by 3.91% (90% CI, 2.97% to 4.87%), and the diastolic blood pressure increased 227 by 3.78% (90% CI, 2.82% to 4.74%), compared to baseline levels. By contrast, we observed no 228 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint significant differences in blood oxygen saturation (figure 1B). Following the initial 48 hours, these 229 changes faded, with measurements returning to their baseline levels. 

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

We also analyzed the changes in chest-patch indicators compared to baseline levels, stratified by 280 age group, gender, and vaccine dose. Participants 60 years old and above exhibited milder, albeit 281 not significant, changes than those below 60 years old in nearly all chest-patch indicators 282 (appendix pp 41-45). We found no differences between men and women in chest-patch indicators. Our key findings suggest that multiple physiological measures significantly increase following 289 BNT162b2 vaccine administration in both participants who reported and those who did not report We identified several aspects that strengthen the short-term safety of the BNT162b2 vaccine. First, 294 we found that all the physiological measures returned to their baseline levels within three days 295 from vaccination. Second, we observed no change in oxygen saturation levels compared to their 296 baseline levels, indicating that major adverse health consequences are less likely. Third, reports of 297 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. well-being indicators reported by the participants, including mood, sleep quality, and physical 299 activity, also returned to their baseline levels by the third day. Interestingly, the reported stress 300 levels significantly improved on the second and third days after vaccination, suggesting that 301 participants were concerned prior to vaccine administration. Thus, our study quells, in part, 302 concerns raised by those hesitant to be vaccinated on the grounds of potential adverse vaccination 303 consequences by demonstrating that such consequences are likely to fade after a few days. that the decrease is not necessarily directly related in this situation to inflammation. This could be 320 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. PubMed, Scopus, and Google Scholars for eligible studies using keywords such as "COVID-19 368 vaccine", "vaccine adverse effects", "vaccine reactions", "vaccine clinical trial". We also checked 369 the FDA guidelines and CE regulations regarding vaccine trails and approval. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Vaccination is widely accepted as the most prominent measure in the fight against COVID-19, posing the 500 greatest hope for ending this major global health pandemic and related economic crisis. 1 Consequently, an 501 unprecedented international effort by private and public institutions alike was directed at accelerating the 502 traditionally lengthy vaccine-development process. 2-4 503 504 On 2 December 2020, less than a year from the pandemic outbreak, the first vaccine, BNT162b2 mRNA 505 (Pfizer-BioNTech), was granted an Emergency Use Authorization (EUA) by the UK Medicines and 506

Healthcare products Regulatory Agency (MHRA). 5 This initial authorization was followed by rapid 507 authorizations for emergency use in several countries, with the US Food and Drug Administration (FDA) 508 among the first to do so. 6 509 510 Safety data from a randomized controlled trial suggests a favorable safety profile for the BNT162b2 511 vaccine. 7 Specifically, the local and systemic self-reported reactions during the first seven days after 512 vaccination were mainly mild to moderate, with a median onset of 0-2 days after vaccine administration 513 and a median duration of 1-2 days. The most frequently reported reactions were fatigue, headache, muscle 514 pain, chills, joint pain, and fever. 7 The incidence of serious adverse events was low and was similar between 515 vaccine-and placebo-treated participants. The safety of the new vaccine over a median of two months post-516 vaccination was similar to that of other viral vaccines. A considerable fraction of the participants did not 517 report any reaction or adverse event. Likewise, several other vaccine candidates, including ChAdOx1 518 nCoV-19 (Oxford/AstraZeneca) and mRNA-1273 (Moderna), received EUAs following similar 519 encouraging safety results by randomized controlled trials. 8-10 520

Nevertheless, concerns regarding potential adverse effects from vaccines have recently led to the 521 suspension of the ChAdOx1 nCoV-19 vaccination campaigns in Europe. 11 They may have reinforced the 522 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint public hesitancy towards COVID-19 vaccines. These concerns underscore the importance of extracting as 523 much information as possible from clinical trials. 524

The World Health Organization (WHO) has defined vaccine hesitancy as one of the 10 major health threats 525 worldwide. 12 However, clinical trial guidelines for assessing the safety of vaccines, including the FDA 526 criteria, 13 are primarily rely on subjective, self-reported questionnaires. Despite the tremendous 527 technological advances in recent years, objective, continuous assessment of physiological measures post-528 vaccination is rarely performed. 529

This short-term prospective clinical study aims to document symptoms among COVID-19 vaccinated 530 subjects and cross it with physiological signs derived from continuous remote monitoring before, during, 531 and after receiving the vaccine, looking at any potential hidden layers of the safety of the vaccine. 532 533

This prospective observational study will be conducted during the mass-vaccination campaign expected to 536 be implemented in Israel in early 2021. The study design is outlined in Figure S1 . Participants will be 537 equipped with a chest-patch sensor and will be monitored for four days, starting one day before vaccination. 538

In addition, participants will install a dedicated mobile application and will be requested to fill a daily 539 questionnaire, starting one day before the inoculation, for 15 days. For each participant, the 24-hour period 540 prior to vaccination will be served as the baseline period. 541 542 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint Up to 200 participants will be recruited for the study, all before receiving the BNT162b2 mRNA COVID-545 19 vaccine. Inclusion criteria will include those aged > 18 years who were eligible to receive the vaccine. 546

Individuals who are not eligible to give and sign a consent form of their free will or those previously 547 diagnosed with COVID-19 will be excluded. To recruit participants and ensure they complete all the study's 548 requirements, we will hire a professional survey company. Potential participants will be recruited through 549 advertisements in social media, online banners, and word-of-mouth. The survey company is responsible for 550 guaranteeing the participants meet the study's requirements, in particular, that they agree to wear the chest-551 patch sensor and fill in the daily questionnaires. 552

Several days before receiving the vaccine, a study investigator personally meets with each participant to 554 explain the study procedure. Before participation in the study, all participants will be advised orally and in 555 writing about the nature of the experiments and give written, informed consent. At this time, participants 556 will be asked to complete enrollment questionnaire that includes demographic information and health 557 status. In addition, participants will be asked to install two applications on their mobile phones: an 558 application that passively collects data from the chest-patch sensor and the PerMed application, which 559 allows participants to fill in the daily questionnaires. Participants will be given instructions regarding the 560 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint self-reported symptoms questionnaires and how to operate the wireless chest-patch sensor, which they will 561 wear for four consecutive days, starting 24 hours prior to receiving the vaccine. 562

As mentioned, all the participants filled a one time enrollment questionnaire that includes demographic 564 questions and questions about the participant's health condition in general. The questionnaire we will use 565 includes the following: age, gender, height, weight, household size and comorbidities. Other questions such 566 as name, address, phone and email were included as well and were used by the survey company in order to 567 contact the participants. The answers were inserted by the study investigator to the study's secured 568 dashboard. 569

Starting 24 hours prior to receiving the vaccine, participants will wear a chest-patch sensor attached, 571 continuously measuring 13 physiological parameters: heart rate, blood oxygen saturation, respiratory rate, 572 systolic and diastolic blood pressure, pulse pressure, mean arterial pressure, heart rate variability, stroke 573 volume, cardiac output, cardiac index, systemic vascular resistance, and body temperature. Participants will 574 wear the monitoring sensor for three days following the vaccine. 575

The photoplethysmography (PPG)-based chest monitors (Biobeat Technologies Ltd) that will be purchased 576 and used in this study has FDA clearance (clearance number K190792) and CE Mark approval (CE 2797). 577

The sensor tracks vital signs derived from changes in the pulse contour, following baseline calibration using 578 an approved non-invasive, cuff-based device, and is based on Pulse Wave Transit Time (PWTT) 579 technology, combined with Pulse Wave Analysis (PWA). The sensor will continuously collect data at 10-580 minute intervals for the entire duration of the 96-hour experiment. 581

All participants will complete the daily self-reported questionnaire in a dedicated application (the PerMed 583 mobile application). The daily questionnaire we will use includes the following questions: 584 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

The data will be exported securely through the MD Clone secure data platform or a secured locked database 609 only after receipt of consent forms from participants. Data from the mobile phone application of the 610 prospective study population will be stored on a secure server within Tel Aviv University facilities. The 611 server (bdl7.eng.tau.ac.il) runs a CentOS operating system and is located in Software Engineering Building 612 at Tel Aviv University. This server is protected behind the university's firewall and is not connected to 613 external networks. In addition, a secure connection through an SSL protocol and a trusted certificate will 614 be obtained for the transfer of information from the mobile phone application into the secured server. 615

Access will be restricted to investigators in the study. The information from the mobile application will be 616 stored in a structured manner on the secured server without any explicitly identifying information (name, 617 ID number, email). Each participant will be assigned a coded participant number that will be used to identify 618 the subject in the database. The code with the identified information will be stored in an encrypted form on 619 a separate secured server that only the research manager will have access to. Access to all servers is 620 restricted with username and password. 621

All (non-digital) questionnaires and signed informed consent documents will be stored in a secured cabinet 622

in Tel Aviv University, to which only the research manager and the principal investigators will have access. 623

No data collected as part of the study will be added to individuals' medical charts. 624

All signed informed consent and printed questionnaires will be stored in a secured cabinet at Tel Aviv 625

University with restricted access. Only the PIs will have access to this cabinet. 626

All individual clinical test results that are generated as part of this study will be shared with participants as 627 explained above. 628 629 630 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

We will perform several preprocessing steps. Concerning the daily questionnaires, in cases where 632 participants will fill in the daily questionnaire more than once on a given day, only the last entry for that 633 day will be considered, as it is reasoned that the last one likely best represented the entire day. Self-reported 634 symptoms that are entered as the free text will be manually categorized. Concerning the chest-patch 635

indicators, data will first be aggregated per hour (by taking the mean value). Then, to impute missing values, 636

we will perform a linear interpolation. 637 638

We will examine the changes in each chest-patch indicator over the 72 hours post-vaccination compared 640 with the 24-hour baseline period prior to vaccination. To do so, we will perform the following steps. For 641 each indicator, for each hour ℎ of the 72 hours post-vaccination, we will calculate for each individual the 642 mean value in the five-hour sliding window: [ℎ − 4, ℎ − 3, ℎ − 2, ℎ − 1, ℎ]. Then, we will calculate the 643 relative change in the percentage of this value compared to the corresponding five-hour window in the 644 baseline period. Finally, we will calculate the mean value for hour ℎ over all 160 participants, as well as 645 the 90% confidence interval, corresponding to a significance level of 0.05 in a one-sided t-test. 646

We will also examine the changes in the daily questionnaire. For each of the three days after the vaccination, 648

we will calculate the percentage of participants who reported new local or systemic reactions compared to 649 their baseline period. For each reaction, a 90% confidence interval will be calculated assuming a beta 650 distribution, with parameter corresponding to the number of participants reporting that reaction plus one 651 (i.e., "successes"), and parameter corresponding to the number of participants who did not report that 652 reaction plus one (i.e., "failures"). Similarly, we will calculate the changes in the well-being indicators 653 reported post-vaccination compared to those reported in the baseline period. Specifically, we will calculate 654 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint the difference between the value in each day and the corresponding value in the baseline period for each 655

indicator. Then, we will calculate the mean difference value over all participants and a 90% confidence 656 interval using a t distribution. 657 658 Finally, we will examine the difference between symptomatic and asymptomatic participants with regard 659 to changes in the chest-patch indicators, stratified by the number of days post-vaccination (1-3) and part of 660 the day (day or night). For a given day post-vaccination, symptomatic participants will be defined as those 661 who reported at least one reaction on that day that they did not report in the baseline period. Asymptomatic 662 individuals will be defined as those who reported no reactions on that day. We will define nighttime and 663 daytime based on the observed movement patterns of the participants throughout the study. For each 664 participant, we will calculate the mean indicator value for each day and part of the day post-vaccination. 665

Then, we will calculate the relative change in percentages of these values compared to their corresponding 666 values in the baseline period. Next, we will calculate the mean values of symptomatic participants and 667 asymptomatic participants and their corresponding 90% confidence intervals using a t distribution. Finally, 668 unequal variances t-tests will be used to evaluate the differences between symptomatic and asymptomatic 669 participants. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint Symptomatic vs. asymptomatic participants -additional chest-patch indicators 750 During the daytime of the first two days post-vaccination, nearly all chest-patch indicators significantly changed 751 not only for symptomatic participants but also for asymptomatic participants (Figure 3 in the main text and Figure  752 S4). Moreover, the changes observed for symptomatic participants were found to be significantly higher than those 753 of asymptomatic individuals in most chest-patch indicators during the first day and the first night post-vaccination. 754 758 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint Horizontal dashed lines represent no change compared to the baseline levels. Significant differences from baseline at a 0.05 759 level are marked with * . Significant differences between symptomatic and asymptomatic participants at a 0.05 level are marked 760 with #.

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint Gender groups differences in chest-patch indicators 763 During the daytime and nighttime of the first two days post-vaccination, all four chest-patch indicators significantly 764 changed for both males and females ( Figure S5 ). There was no significant change between the two genders. 765 768 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint Age groups differences in chest-patch indicators 769 During the daytime and nighttime of the first two days post-vaccination, all four chest-patch indicators significantly 770 changed for the younger age group but not necessary for the older group ( Figure S6) . 771 772 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint 778 In contrast to the second vaccine dose, examining the participants who were monitored when receiving their first 779 vaccine dose revealed no difference in vitals during the first 48 hours post-inoculation. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 7, 2021. ; https://doi.org/10.1101/2021.05.06.21256587 doi: medRxiv preprint

No potential risks arising from the sensors are expected, as the device is already commercialized with no 679 known adverse reactions. Following the instructions for use

After 685 completion of the study, all participants will receive a detailed report containing information regarding their 686 fluctuations in blood pressure during the baseline monitoring period (i.e., 24 hours prior to receiving the 687 vaccine

No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

Signed and dated informed consent forms, as well as data 702 recording sheets (e.g., case report forms) will be stored in locked cabinets during the study and following 703 its completion. A file containing the personal details of the participants will be coded to help preserve 704 confidentiality and separated from all other data collected throughout the study. This file will be kept by 705 the principal investigator

The data obtained from the sensor used in this study will be anonymous and coded. The sensor does not 707 include a GPS, as required from any medical-grade monitoring device. The data collected by the PerMed 708 application arrive to PerMed back-end servers and are stored securely

No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

Within the first 48 hours post-vaccination, we identified significant changes in nearly all chest-patch physiological 715 measures compared to their baseline levels (Figure 1 in the main text and Figure S2). Following the initial 48 hours, 716 these changes faded

Percentage of change in respiratory, cardiovascular, and physiological chest-patch indicators recorded by the chest-720 patch sensor, compared to their baseline levels: (A) pulse arterial pressure, (B) mean arterial pressure, (C) stroke volume, (D) 721 cardiac index, (E) heart rate variability. Mean values are depicted as solid lines

Additional days for self-reported local and systemic reactions 727 We observe a sharp decline in reported local and systemic reactions following three days post-vaccination and 728 nearly a complete halt within 14 days post-vaccination (Figure 2 in the main text and Figure S3). Fatigue and 729 headache were the most frequent reactions

No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted

K) stroke volume, (L) cardiac index, and (M) heart rate variability. Mean values are depicted as 784 solid lines, 90% confidence intervals are presented as shaded regions, and horizontal dashed lines represent no change 785 compared to the baseline levels

A Review of the Progress and Challenges of Developing a 791 Vaccine for COVID-19

Keeping track of the SARS-CoV-2 vaccine pipeline

SARS-CoV-2 vaccines in development

FDA Takes Key Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for First 799 COVID-19 Vaccine | FDA

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Background document on mRNA vaccine BNT162b2 (Pfizer-BioNTech) against COVID-19

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine 809 (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, 810 South Africa, and the UK

Covid-19: WHO says rollout of AstraZeneca vaccine should continue, as Europe divides over 812 safety

Development and Licensure of Vaccines to Prevent COVID-19 | FDA

No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity