Comparing reactions to COVID-19 and influenza vaccinations: data from patient self-reporting, smartwatches and electronic health records
Authors: Yechezkel Matan , Qian Gary , Levi Yosi , Davidovitch Nadav , Shmueli Erez , Yamin Dan , Brandeau Margaret L. 
Published: June 2023

Background

Public reluctance to receive COVID-19 vaccination is due in large part to safety concerns. We compare the safety profile of the BNT162b2 COVID-19 booster vaccine to that of the seasonal influenza vaccine, which has been administered for decades with a solid safety record and a high level of public acceptance.

Methods

We study a prospective cohort of 5,079 participants in Israel (the PerMed study) and a retrospective cohort of 250,000 members of Maccabi Healthcare Services. We examine reactions to BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 booster vaccinations and to influenza vaccination. All prospective cohort participants wore a Garmin Vivosmart 4 smartwatch and completed a daily questionnaire via smartphone. For the prospective cohort, we compare pre-vaccination (baseline) and post-vaccination smartwatch heart rate data and a stress measure based on heart rate variability, and we examine symptom severity from patient self-reports. For the retrospective cohort, we examine electronic health records (EHRs) for the existence of 28 potential adverse events during the 28-day period before and after each vaccination.

Findings

In the prospective cohort, 1,905 participants received COVID-19 vaccination; 899 received influenza vaccination. Focusing on those who received both vaccines yielded a total of 689 participants in the prospective cohort and 31,297 members in the retrospective cohort.Questionnaire analysis: For the COVID-19 vaccine, 39·7% [95% CI 36·4%–42·9%] of individuals reported no systemic reaction vs. 66·9% [95% CI 63·4%–70·3%] for the influenza vaccine. Individuals reporting a more severe reaction after influenza vaccination tended to likewise report a more severe reaction after COVID-19 vaccination (r=0·185, p<0·001).Smartwatch analysis: A statistically significant increase in heart rate and stress measure occurred during the first 3 days after COVID-19 vaccination, peaking 22 hours after vaccination with a mean increase of 4·48 (95% CI 3·94–5·01) beats per minute and 9·34 (95% CI 8·31–10·37) units in the stress measure compared to baseline. For influenza vaccination, we observed no changes in heart rate or stress measures. In paired analysis, the increase in both heart rate and stress measure for each participant was higher (p-value < 0·001) for COVID-19 vaccination than for influenza vaccination in the first 2 days after vaccination. On the second day after vaccination, participants had 1·5 (95% CI 0·68–2·20) more heartbeats per minute and 3·8 (95% CI 2·27–5·22) units higher stress measure, compared to their baseline. These differences disappeared by the third day after vaccination.EHR analysis: We found no elevated risk of non-COVID-19 or - influenza hospitalization following either vaccine. COVID-19 vaccination was not associated with an increased risk of any of the adverse events examined. Influenza vaccination was associated with an increased risk of Bell’s palsy (1·3 [95% CI 0·3–2·6] additional events per 10,000 people).

Interpretation

The more pronounced side effects after COVID-19 vaccination compared to influenza vaccination may explain the greater concern regarding COVID-19 vaccines. Nevertheless, our findings support the safety profile of both vaccines, as the reported side effects and physiological reactions measured by the smartwatches faded shortly after inoculation, and no substantial increase in adverse events was detected in the retrospective cohort.

Funding

This work was supported by the European Research Council, project #949850, and a Koret Foundation gift for Smart Cities and Digital Living.

RESEARCH IN CONTEXT

Evidence before this study

The unprecedented global impact of COVID-19 led to the rapid development and deployment of vaccines against the virus, including vaccines using novel mRNA technology. Despite the promising effectiveness of mRNA vaccines in preventing severe outcomes of COVID-19, concerns have been raised regarding the safety profile of these new vaccines. These concerns led to a notable global public reluctance to become vaccinated. By contrast, the seasonal influenza vaccine has been administered for decades with a well-established safety record and a high level of public acceptance. We searched Google Scholar, PubMed, and preprint services (including medRxiv, bioRrxiv, and SSRN) for studies comparing the safety profile of the two vaccines between March 1, 2023 (our study’s launch) and May 30, 2023, with no language restrictions, using the terms “safety of” AND (“COVID-19” OR “SARS-CoV-2”) AND (“vaccine” OR “BNT162b2 (Pfizer–BioNTech) mRNA vaccine”) AND “compared to” AND (“Influenza” OR “seasonal influenza” OR “flu”) AND “vaccine”. We found a study that compared the safety profile of the mRNA COVID-19 vaccine among 18,755 recipients with 27,895 recipients of the seasonal influenza vaccine using the WHO international database. The authors found a different safety pattern between the two vaccines with more systematic reactions following inoculation of the COVID-19 vaccine. Additionally, COVID-19 vaccines were associated with a higher risk of cardiovascular adverse events, while the influenza vaccine was associated with a higher risk of neurological adverse events. The remaining studies identified in our search compared the simultaneous administration of both vaccines to the administration of only COVID-19 vaccines. None of the studies conducted a paired analysis that compared reactions post-influenza vaccination and post-COVID-19 vaccination for the same individual; none examined the extent of physiological reaction (in terms of heart rate and heart rate variability) following the administration of COVID-19 or seasonal influenza vaccines; and none examined a cohort of individuals with data from before and after vaccination episodes or presented a comprehensive analysis to address concerns regarding the existence of potential rare adverse events following vaccination.

Added value of this study

We studied a prospective cohort of 5,079 participants in Israel (the PerMed study) from October 31, 2020 to September 30, 2022 and a retrospective cohort of 250,000 members of Maccabi Healthcare Services from July 31, 2021 and March 1, 2023. We examined reactions to BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccination (third or fourth shot) and to influenza vaccination. We compared the extent of reactions at the individual level, among individuals who received both vaccines separately. While the self-reported data and the continuous physiological measures from smartwatches revealed a higher rate of reactions following COVID-19 vaccination, these reactions faded soon after inoculation. We found no increase in risk of rare adverse events for either vaccine. We found a weak, albeit significant, correlation in the severity of the symptoms for the two vaccines (r=0·185, p<0·001): individuals who reported a more severe reaction after influenza vaccination tended to likewise report a more severe reaction after COVID-19 vaccination. We found no elevated risk of non-COVID-19 or - influenza hospitalization following the administration of either vaccine. COVID-19 vaccination was not associated with increased risk of any of the adverse events examined. Influenza vaccination was associated with an increased risk of Bell’s palsy (1·3 [95% CI 0·3–2·6] additional events per 10,000 people).

Implications of all the available evidence

Our study demonstrates the importance of accounting for continuous and objective surveillance of vaccines in both the clinical trial phase and the post-marketing phase, as it can aid in evaluating the safety profile of clinical trials and reduce vaccine hesitancy. The more pronounced side effects after COVID-19 vaccination compared to influenza vaccination may explain the greater concern regarding COVID-19 vaccines. Nevertheless, our findings support the safety profile of both vaccines, as the reported side effects and physiological reactions measured by the smartwatches faded shortly after inoculation, and no substantial increase in adverse events was detected in the retrospective cohort.