key: cord-1051221-8iathlo8 authors: Quer, G.; Gadaleta, M.; Radin, J. M.; Andersen, K. G.; Baca-Motes, K.; Ramos, E.; Topol, E. J.; Steinhubl, S. R. title: The Physiologic Response to COVID-19 Vaccination date: 2021-05-04 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2021.05.03.21256482 sha: bae1df4de50b097306be67b13b25bbf51b356ed2 doc_id: 1051221 cord_uid: 8iathlo8 Two mRNA vaccines and one adenovirus-based vaccine against SARS CoV-2 are currently being distributed at scale in the United States. Objective evidence of a specific individual's physiologic response to that vaccine are not routinely tracked but may offer insights into the acute immune response and personal and/or vaccine characteristics associated with that. We explored this possibility using a smartphone app-based research platform developed early in the pandemic that enabled volunteers (38,911 individuals between 25 March 2020 and 4 April 2021) to share their smartwatch and activity tracker data, as well as self-report, when appropriate, any symptoms, COVID-19 test results and vaccination dates and type. Of 4,110 individuals who reported at least one mRNA vaccination dose, 3,312 provided adequate resting heart rate data from the peri-vaccine period for analysis. We found changes in resting heart rate with respect to an individual baseline increased the days after vaccination, peaked on day 2, and returned to normal on day 6, with a much stronger effect after second dose with respect to first dose (average changes 1.6 versus 0.5 beats per minute). The changes were more pronounced for individuals who received the Moderna vaccine (on both doses), those who previously tested positive to COVID-19 (on dose 1), and for individuals aged <40 years, after adjusting for possible confounding factors. Taking advantage of continuous passive data from personal sensors could potentially enable the identification of a digital fingerprint of inflammation, which might prove useful as a surrogate for vaccine-induced immune response. Due to an unprecedented effort in response to the COVID-19 pandemic, three vaccines are 48 currently authorized and distributed in the United States: two two-dose mRNA vaccines, 49 developed by Pfizer-BioNTech and Moderna, and one single-dose adenovirus-based vaccine, 50 developed by Janssen / Johnson & Johnson. 1-3 The population-wide efficacy of these vaccines 51 has been well established both through large-scale Phase 3 clinical trials, and reinforced by real-52 world data. 4-8 Although it is known that there is substantial variability in individuals' immune 53 response to vaccines, 9 and that some fully vaccinated individuals can still become infected, 10 54 there is currently no routinely available method to objectively identify a specific person's 55 response to a vaccine beyond self-reported side-effects, which are common. The Centers for 56 Disease Control and Prevention's (CDC) V-safe program found a majority (69%) of the 1.9 57 million enrolled individuals receiving the second dose of a mRNA vaccine reported some 58 systemic side effects. 11 Many of the reported symptoms were consistent with systemic 59 inflammation including fatigue, myalgias, chills, fever and joint pain being report in the range of 60 25.6% to 53.9% of individuals the day following their 2 nd dose. 12 61 In this analysis from the Digital Engagement and Tracking for Early Control and Treatment 62 (DETECT) study, 13 we collected daily wearable sensor data from the two-weeks before and after Individuals who had been vaccinated with the single dose Janssen vaccine were excluded as 83 there were too few (156 individuals) to allow for a meaningful comparison. We have included in 84 the analysis individuals wearing a Fitbit device (76%) and an Apple watch (20%), while 151 85 individuals with other devices were not included in this analysis. We also excluded 31 86 participants who reported a vaccine date before Dec. 11, 2020 -the official date of the first US 87 vaccine intake -and 6 participants who did not report age or gender. Individuals were excluded 88 if they had less than 4 days of recording in the 2 weeks before dose 1 vaccination, or less than 3 89 of the 5 days after vaccination, or less than 14 days during the baseline period (from 60 days to 7 90 days before vaccination). A number of individuals were excluded in the calculation of RHR 91 (454), sleep (1091) and activity (345) metrics because of missing data. 92 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. For each individual, we calculated the average of the absolute changes of RHR, sleep and 93 activity with respect to their individual baseline, which we have previously shown to be 94 relatively stable for an individual over time, but to vary substantially between individuals. 14,15 A 95 single daily value is considered valid only if the device was worn for more than 15 hours during 96 the day. The RHR was based on the value of heart rate that would be obtained in a supine 97 position immediately after waking but before getting out of bed for Fitbit devices, 14 and by 98 considering heart rate values over the day by a proprietary algorithm for Apple watches. The 99 individual baseline was calculated using the period from 60 days to 7 days before vaccination, 100 using a decreasing exponential (with exponent α=0.05) to reduce the weight of days farthest in 101 the past. The baseline for the RHR was calculated as 102 The sleep and activity metrics were calculated accordingly using the total time asleep and the 106 number of steps recorded by the sensor in the 24 hours, respectively. In the figures, the mean 107 (over all individuals) and the 95% confidence interval for each metric (RHR, sleep and activity) 108 in the 15 days before and after the first and second dose of the vaccine are represented. The 109 cumulative distribution of the maximal variation in RHR in the 2 days after the vaccines is also 110 represented. 111 The cohort of vaccinated individuals (with first and second vaccine doses, treated separately) 112 was then split into subgroups according to gender, age (<40, 40-60, >60), vaccine type received, 113 and if they previously reported a COVID-19 positive test. For each subgroup and for each 114 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 4, 2021. ; https://doi.org/10.1101/2021.05.03.21256482 doi: medRxiv preprint metric, the mean (over all individuals) of the individual average value (calculated considering the 115 day of vaccination and the following 4 days), with the corresponding confidence interval was 116 calculated. The 95% confidence interval in the calculation of the mean is obtained with a 117 bootstrap method with 1000 iterations. 118 The demographic characteristics of these groups are reported in the Supplement (Table S.1) . 119 Unless stated otherwise, all the reported p-values refer to a two-sided t-test to quantify statistical 120 difference among different groups (Table 1) , and to a chi-squared test to evaluate significant 121 changes in the frequency of observation in each group ( We observed that the average RHR significantly increased the day following vaccination, 135 reaching a peak on day 2 with a population mean increase of +0.49 (CI: [0.38, 0.61], one-sided t-136 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. baseline, following the first and second dose, respectively. We found that the average RHR did 138 not return to baseline until day 4 after the first dose and day 6 after the second (Figure 1a The majority of vaccinated individuals, 70% and 76% after first and second dose, respectively, 140 experienced an increase in their RHR in the two days following the vaccine. (Figure 1c & d) 141 We explored several participant and vaccine characteristics that could impact immune response. 142 (Table 1 ) We found that average RHR changes with respect to baseline in the 5 days following 143 vaccination did not vary by gender (two-sided t-test, p = 0.44 and p = 0.28 for first and second 144 doses, respectively). In contrast, we found that RHR responses vary by age, with individuals age 145 < 40 years having the greatest increase in RHR. (Figure 2 ) We showed that < 60 years was 146 associated with a significantly higher RHR increase than 60+ years, but only after the second 147 dose of the vaccine (average 0.78 versus 0.53 BPM, p = 0.03). 148 We found that prior COVID-19 infection was associated with a significantly higher RHR (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. device, and prior COVID-19 infection. Age was also associated with RHR response, but only 165 after the second vaccine dose (p<0.01). We assessed the interaction between age and gender but 166 did not find it to be significant (p=0.53 and p=0.52 for first and second dose, respectively). 167 (Table S. We also observed that normal activity and sleep patterns among participants were minimally vaccinated. The present study demonstrates the ability, through widely available wearable 182 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. Individual response to vaccination is remarkably complex, incorporating components of innate, 185 humoral and cell-based immune system. A study of response to yellow fever vaccination found 186 significant modulation of expression in 97 genes in the days following vaccination. 16 Modern 187 improvements in a range of analytic tools have enabled a system biological approach to better 188 understand the immune responses to vaccination, which have shown promise in helping define 189 molecular signatures that may predict vaccine-induced immunity. 17 There are no commercially 190 available tests for neutralizing antibodies to the spike protein or its components S1, S2, RBD, 191 that would provide quantitative evidence of an immune response. Beyond humoral immunity, the 192 early T-cell spike-specific response has recently been shown to be important, 18 yet is only rarely vaccination. 22 Consistent with that, we identified a rapid rise in heart rate the day after 205 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 4, 2021. ; https://doi.org/10.1101/2021.05.03.21256482 doi: medRxiv preprint vaccination, and one that was more robust after the second dose, unless the participant had prior 206 COVID-19 infection, mirroring the significantly higher incidence of systemic symptoms 207 following the second dose found in V-safe. 23 We also observed a more pronounced increase after 208 a Moderna vaccine, in accordance to a recent analysis of V-safe data that identified a higher 209 incidence of side effects relative to those receiving the Pfizer-BioNTech vaccine, especially after Immunosenescence or waning response to vaccination as someone ages has been described for 214 many vaccines and is a concern for COVID-19. 25 We found that individuals in the younger age 215 group (<40 years) had a significantly higher RHR response to the second dose compared to older 216 individuals. Overall, women also reported more side effects to V-Safe compared to men. 23 217 Immune response to other vaccines has varied by gender, possibly because of differences in 218 hormones, genetics, or differences in dosing by weight. A prior flu vaccine study found that 219 vaccine induced immunity in mice was increased by estradiol in females and decreased by 220 testosterone in males 26 and that as age increased, sex differences in vaccine efficacy was 221 declined. Although the RHR differences we saw was not significant, it is possible that a greater 222 change would be identified when younger age groups are vaccinated. 223 We found that the observable variables (age, gender, previously COVID-19 infection, device 224 used, vaccine type) can explain only 2% of the variance in terms of average changes in RHR 225 (and less than 24% of the variance in terms of peak changes in RHR). It is possible that with 226 further investigation it may be found that RHR response to vaccines may correlate with 227 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 4, 2021. ; https://doi.org/10.1101/2021.05.03.21256482 doi: medRxiv preprint individual immune response and therefore wearables may offer a way to easily quantify 228 someone's protection. 229 The presence of a fever has previously been shown to be associated with an increase in heart 230 rate, with an ~8.5 BPM increase for every degree Celsius increase in body temperature. 27 While 231 ~30% of V-safe participants reported having a fever after their second dose and ~9% after the 232 first, we showed that the vast majority of participants experienced an increase in RHR after both 233 vaccination doses, suggesting that inflammation unassociated with an elevated temperature also 234 influences heart rate, albeit much more subtly. 12 Inflammation, outside of that associated with 235 fever, and its influence on heart rate has been previously described, but primarily at a population 236 level. 28, 29 Similarly, inflammation has also been shown to lead to increase in sleep and a 237 decrease in activity, with a more rapid return to normal with treatment. 30,31 By taking advantage 238 of wearable sensors we were able to recognize subtle, but significant deviations from an 239 individual's unique, normal resting heart rate due to vaccination. We were able to also 240 demonstrate substantial interindividual variability in that heart rate increase that was only related 241 to the mRNA vaccine type and prior COVID-19 infection in our population. The significantly 242 greater heart rate response at the time of vaccination, especially the first dose, in those with prior 243 infection is consistent with a greater immune response for these individuals. 32 Although this 244 response is clearly multifactorial, future work coupling continuous sensory data with a "systems 245 vaccinology" approach 17 could enable the identification of easily scalable, sensor-based markers 246 of the desired immune response. 247 The data collected as part of the DETECT study depends entirely on the participants' willingness 249 to use their wearable device and accurately reporting vaccination date and type. While we do not 250 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 4, 2021. ; https://doi.org/10.1101/2021.05.03.21256482 doi: medRxiv preprint have direct control on self-reported information, the DETECT app provides an intuitive tool to 251 self-report vaccination information, and an optional reminder to report information on the second 252 dose after first one has been reported. While the information collected may not be as accurate as 253 in a controlled laboratory setting, we rely on previous work confirming that self-reported 254 symptoms and sensor data provide valuable information. 33-35 Only daily sensor data is considered 255 in this analysis, excluding intra-day data provided by some wearable sensor. These once-a-day (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. to identify the small proportion of people (approximately 5%) who do not have an adequate 274 immune response to vaccines, and who may benefit by more in-depth assessment and re-275 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. 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. 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. 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. 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. 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. 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. 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 4, 2021. ; https://doi.org/10.1101/2021.05.03.21256482 doi: medRxiv preprint The Advisory Committee on Immunization Practices' Interim 356 Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine -United States The Advisory Committee on Immunization Practices' Interim 359 Recommendation for Use of Moderna COVID-19 Vaccine -United States The Advisory Committee on Immunization Practices' Interim 362 Recommendation for Use of Janssen COVID-19 Vaccine -United States Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Estimating real-world COVID-19 vaccine effectiveness in Israel using 367 aggregated counts. medRxiv Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl 369 Interim Results of a Phase 1-2a Trial of Ad26 Interim Estimates of Vaccine Effectiveness of BNT162b2 and 373 mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health 374 Care Personnel, First Responders, and Other Essential and Frontline Workers -375 Factors That Influence the Immune Response to 377 Vaccination Failure to Reach the Goal of Measles Elimination: 379 Apparent Paradox of Measles Infections in Immunized Persons. Archives of Internal 380 Reactogenicity Following Receipt of mRNA-384 Based COVID-19 Vaccines Wearable sensor data and self-reported symptoms for COVID-19 386 detection Inter-and 388 intraindividual variability in daily resting heart rate and its associations with age, 389 sex, sleep, BMI, and time of year: Retrospective, longitudinal cohort study of 92,457 390 adults Association of Sleep Duration and Variability With Body Mass 392 Index: Sleep Measurements in a Large US Population of Wearable Sensor Users Systems biology approach predicts immunogenicity of the yellow 395 fever vaccine in humans 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 Early T cell and binding antibody responses are associated with 399 Covid-19 RNA vaccine efficacy onset Human immune system variation COVID-19 vaccines: modes of immune activation and 403 future challenges COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell 405 responses Preclinical and Clinical Demonstration of Immunogenicity by mRNA 407 Vaccines against H10N8 and H7N9 Influenza Viruses First Month of COVID-19 Vaccine Safety Monitoring -United States A preliminary report of a randomized controlled phase 2 trial of the 413 safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine Tackling immunosenescence to improve COVID-19 outcomes and 415 vaccine response in older adults Age-associated changes in the impact of sex steroids on influenza 417 vaccine responses in males and females Fever and cardiac rhythm Association between resting heart rate and inflammatory 421 biomarkers (high-sensitivity C-reactive protein, interleukin-6, and fibrinogen) (from 422 the Multi-Ethnic Study of Atherosclerosis) Association between Resting Heart 424 Rate and Inflammatory Markers (White Blood Cell Count and High Reactive Protein) in Healthy Korean People Sick and tired: does sleep have a vital role in the 427 immune system? Impact of influenza treatment with oseltamivir on health, sleep and 429 daily activities of otherwise healthy adults and adolescents Antibody responses to the BNT162b2 mRNA vaccine in 432 individuals previously infected with SARS-CoV-2 The impact of patient-reported outcome (PRO) data from clinical 434 trials: a systematic review and critical analysis Overall Survival Results of a Trial Assessing Patient-Reported 439 Outcomes for Symptom Monitoring During Routine Cancer Treatment COVID-19 and digital inequalities: 442 Reciprocal impacts and mitigation strategies About one-in-five Americans use a smart watch or fitness tracker 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