key: cord-0695129-oj13wicd authors: Kim, Min Seo; Jung, Se Yong; Ahn, Jong Gyun; Park, Se Jin; Shoenfeld, Yehuda; Kronbichler, Andreas; Koyanagi, Ai; Dragioti, Elena; Tizaoui, Kalthoum; Hong, Sung Hwi; Jacob, Louis; Salem, Joe‐Elie; Yon, Dong Keon; Lee, Seung Won; Ogino, Shuji; Kim, Hanna; Kim, Jerome H.; Excler, Jean‐Louis; Marks, Florian; Clemens, John D.; Eisenhut, Michael; Barnett, Yvonne; Butler, Laurie; Ilie, Cristian Petre; Shin, Eui‐Cheol; Il Shin, Jae; Smith, Lee title: Comparative safety of mRNA COVID‐19 vaccines to influenza vaccines: A pharmacovigilance analysis using WHO international database date: 2021-11-08 journal: J Med Virol DOI: 10.1002/jmv.27424 sha: e4862f5c5ae4576892bf61029c9e32e45008aaef doc_id: 695129 cord_uid: oj13wicd Two messenger RNA (mRNA) vaccines developed by Pfizer‐BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID‐19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID‐19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID‐19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID‐19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID‐19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47–65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62–24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain‐Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real‐world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines. In May 2020, the 42nd Global Advisory Committee on Vaccine Safety (GACVS) addressed pharmacovigilance preparedness for the launch of the future COVID-19 vaccines 1 ; experts have voiced that achieving herd immunity at the population level through mass vaccination is a potential strategy to control coronavirus disease . 2 Two vaccines, the Pfizer-BioNTech messenger RNA (mRNA) and the Moderna mRNA vaccine, have completed phase 3 trials, [2] [3] [4] [5] and are being actively rolled out. These mRNA vaccines are based on new technologies that have not been deployed to the general population, and as such, concerns about their safety in real-world settings intersect with optimism for their extraordinarily encouraging efficacy in clinical trials. 2, 3, 6 Although the safety profiles of mRNA vaccines have been evaluated in serial clinical trials, 4, 5, 7 concerns remain as the safety evaluations in clinical trials were limited to relatively healthy people, excluding vulnerable populations such as children, pregnant women, and individuals with severe underlying illnesses. 2, 3, 7 However, due to vaccine shortages, 3, 8, 9 vulnerable patients at high risk for severe courses of COVID-19 are prioritized for vaccination. 10 Therefore, the safety results from these trials may be unrepresentative of the populations that are prioritized to receive them. 11 This discrepancy between the trial settings and real-world roll-out strategy warrants urgent interim post-implementation surveillance. 3 Despite the high volume of emerging evidence regarding adverse The large post-implementation pharmacovigilance study was conducted using VigiBase, a WHO global deduplicated individual case safety reports (ICSR) database, 12 The baseline characteristics of individuals reported to VigiBase for any AEFI after mRNA COVID-19 and influenza vaccination are described in Table 1 . The VigiBase provides data on demographics (age, sex, and regions), drug history (components, dosage, regimen, indications, and duration of administration), AEs (MedDRA PT classification terms, time to onset, seriousness of AEs, fetal outcomes, and death), and general administrative information (date of report, reports from clinical trials, and reporter type). Common AEFI was defined as AEFI with a frequency ≥1% of all COVID-19 vaccinated individuals reported for any adverse reaction to VigiBase. A serious AEFI is defined as an AEFI that is associated with death, is life-threatening, involves hospitalization or its prolongation, results in chronic damage/disability, and requires interventions to prevent permanent impairment. 14 The selection process of common and serious AEFI is presented in Figures S1-2. Potentially false reports are partially prevented at an early data collection stage as most national centers review case reports before they are sent to UMC, and incoming reports to the VigiBase are systematically checked according to pre-defined quality criteria; unmet reports are flagged and subsequently inspected by UMC for reprocessing. 12 Despite the effort, the noise safety signals may still exist, and we triaged to select validated safety signals using two approaches. First, we incorporated information component (IC), an indicator value for disproportionate reporting, that has been proven to be effective in avoiding false positive 15 and thus suitable for conducting pharmacovigilance studies using spontaneous adverse reaction reporting databases. [16] [17] [18] Second, we triaged to remove potentially false reports of adverse drug reactions (ADRs) using disproportionality analysis and clinical appraisal. Given that false reports by chance are less likely to survive in stringent association tests, we KIM ET AL. Table 2 and analyzed for the T A B L E 1 Baseline characteristics of participants vaccinated against COVID-19 and influenza reported to VigiBase for any adverse event following immunization (AEFI) Median days (IQR) Abbreviations: AEFIs, adverse events following immunization; IQR, interquartile range. a As denominator, all vaccinated participants with AEFIs reported rather than all vaccinated persons were used; we did not present percentile estimations given that they must be larger than those observed in real-world settings. The AEFIs for the COVID-19 and influenza vaccine were extracted from January 2020 to January 17, 2021. Values are presented as n (%) or n/N (%), unless otherwise indicated. Severe AEFI was defined as AEFI that is life-threatening, causes persistent or significant disability, requires hospitalization (first or prolonged), or results in death. T A B L E 2 Adverse events following immunization (AEFIs) associated with the COVID-19 and the influenza vaccine in the full database of the VigiBase from January, 2020 comparative safety between the vaccines (Figure 1 ). Our careful approach to using those reports deemed genuine and clinically meaningful for our comparative analyses minimized the risk of false reports driving the misleading results. The detailed triage process for AEFI is demonstrated in Figures S1-2. We have set influenza vaccines as a control given that they have endured iterative and thorough safety evaluations in the form of continued population-based post-market surveillance, 19 Given that VigiBase is composed of an extensive sample size (23 880 736 reports from inception), the data are eligible for disproportionality analysis (also known as case-non-case analysis), for which large sample size is essential to guarantee applicable power and resolution. 21 When individuals exposed to a particular drug or vaccine (cases) have higher odds of reporting for certain adverse reactions than those not exposed to the drug or vaccine (non-cases), the association between the intervention and the adverse reaction suggests a possible safety signal. As denominator, all vaccinated participants with AEFIs reported rather than all vaccinated persons were used; we did not present percentile estimations given that they must be larger than those observed in real-world settings. since 2020, respectively; and these reports were used as non-case. We identified safety signals associated with the vaccines, which are statistically significant (defined as IC 0.25 > 0) compared to non-cases (Tables 2 and S1). COVID-19 and influenza vaccines showed numerous statistically significant AEFIs, of which many were related to systemic reaction and injection site reactogenicity ( Table 2 ). The 10 most common AEFIs and deaths for the entire population are shown in Figure 1 . A more detailed list of total AEFIs after COVID-19 vaccination and the selection process of common AEFIs are presented in the Supplementary material. In Figure 1 , the cross-over pattern suggested that COVID-19-vaccinated individuals are more likely to experience systemic symptoms such as headache, myalgia, pyrexia, and fatigue, while influenza-vaccinated individuals were more likely to experience injection site reactogenicity events. Our analysis detected uncommon but serious AEFIs that were significantly associated with COVID-19 vaccines ( Guillain-Barre syndrome, gait disturbance, visual impairment, and dyskinesia were more prevalent with influenza vaccines (Figure 2 ). COVID-19-vaccinated individuals experienced fewer deaths compared to those not exposed to the vaccines, possibly indicating a protective effect of the vaccine (IC 0.25 , −1.66; ROR, 0.38; 95% CI, 0.31-0.46, Table 2 ). Influenza-vaccinated individuals also experienced fewer deaths compared to those not Table 2 ). To the best of our knowledge, this is the first post-implementation pharmacovigilance study to investigate a diverse range of adverse reactions and provide comparative views for the COVID-19 mRNA vaccine and influenza vaccine. This study has not identified significant safety concerns regarding mRNA vaccination in real-world settings. We have set influenza vaccines as a control given that they have undergone iterative and thorough safety evaluations in the form of continued population-based post-market surveillance, 19 which have deemed them acceptably safe. 19, 20 This interim safety surveillance data revealed that the safety profiles of novel mRNA vaccines may be divergent from those of influenza vaccines; the overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID-19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine (Figure 1 ). The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines (Figure 2 ). The two novel vaccines contain mRNAs that encode spike proteins of SARS-CoV-2 formulated in a lipid nanoparticle. In principle, mRNA vaccines have a unique mechanism compared to conventional vaccines in terms of immunogenicity. Exogenously administered mRNA can strongly stimulate the innate immune system through RNA-sensing pattern recognition receptors. 22 The World Health Orgnaization. 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All authors saw and approved the final submitted version.