key: cord-0425881-fkx24jx2 authors: Pradhan, P. M.; Li, C.; Shen, Z.; Remucal, M. J. title: Comparison of adverse events between COVID-19 and Flu vaccines date: 2021-09-25 journal: nan DOI: 10.1101/2021.09.22.21263711 sha: 0db513a9215f73ecdb7788122bffa4572408786d doc_id: 425881 cord_uid: fkx24jx2 BACKGROUND Among the various driving factors for vaccine hesitancy, confidence in the safety associated with the vaccine constitutes as one of the key factors. This study aimed at comparing the adverse effects of COVID-19 vaccines with the Flu vaccines. METHODS The VAERS data from 01/01/2020 to 08/20/2021 were used. The MedDRA terms coded by VAERS were further aggregated by a clinician into clinically meaningful broader terms. RESULTS Various common adverse events between Flu and COVID-19 vaccines have been identified. Adverse events such as headache and fever were very common across all age groups. Among the common adverse events between Flu and COVID-19 vaccine, the relative risk along with 95% CI indicated that such common adverse events were more likely to be experienced by COVID-19 vaccine users than Flu vaccine users. Our study also quantified the proportion of rare adverse events such as Guillain Barre Syndrome and Gynecological changes in the VAERS database for COVID-19 vaccines. CONCLUSIONS Based on the available data and results, it appears that there were some common adverse events between Flu vaccines and COVID-19 vaccines. These identified common adverse events warrant further investigations based on the relative risk and 95% CI. report also has suggested that vaccine hesitancy has been decreasing to 16% [10] . Another study estimated that 3 in 10 adults were not sure about their acceptance of vaccination and 1 in 10 did not intend to be vaccinated against COVID-19 [11] . Vaccine hesitancy reduces the impact of COVID-19 vaccination and exacerbates existing disparities in COVID-19 health outcomes [12] . Therefore, to avoid this unfavorable outcome, the government has incentivized the uptake of COVID-19 vaccine [13, 14] . However, multiple studies characterize vaccine hesitancy as a multilayer problem [15, 16] which requires a multi-faceted approach to address. Some of the common COVID-19 vaccine hesitancy reasons are political affiliations [15] , safety, and concerns of vaccine side effects [12, 17, 18] , trust-related with information from public health experts [17] , evidence-based communications; accelerated vaccine or haste of vaccine development [16, 19] , and concerns around the novelty of available vaccines [20] . A U.S. government report claimed that fear of side effects was the most commonly cited reason for vaccine hesitancy [10] . The same report also cited that the pause on Janssen COVID-19 vaccine impacted some demographic groups more than others [21] . On the other hand, Flu vaccines have been around for more than 75 years and are widely trusted and considered safe. Under such circumstances, it is natural for the public and clinicians to compare the safety profiles, including Adverse Events (AEs), between COVID-19 and Flu vaccines. While several studies are being conducted to monitor the adverse events of COVID-19 vaccines prospectively. Based on our literature review, this is the first study that compares the three popular COVID-19 vaccines (Pfizer, Moderna, and Janssen) and flu vaccine's AE using an observational study design with the VAERS database. This study first aimed to compare the top 10 common adverse events of COVID-19 vaccines with the Flu vaccines among persons who reported at least the first dose of receiving COVID-19 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 25, 2021. ; https://doi.org/10.1101/2021.09. 22.21263711 doi: medRxiv preprint or Flu vaccine as reported to VAERS database. Among those top 10 common adverse events, relative risk and associated 95% confidence intervals were calculated as a measure of association. These comparisons will be useful to address the evidence gap in communicating the risk associated with COVID-19 vaccination and thus overcome one of the component of vaccine hesitancy. VAERS is a passive national surveillance system administered by the CDC, the FDA, and agencies of the Department of Health and Human Services (DHHS) [22] . While anyone can report adverse effect information to VAERS, health care providers and vaccine manufacturers have certain obligations to report a subset or all adverse effects that they become aware of to VAERS. Adverse event reports in the VAERS database are indicative of a potential association between vaccine and adverse events but these associations should not be implied as causal associations [23] . As with any passive surveillance system it is also susceptible to underreporting and incomplete data [23] . However, the VAERS database can help in identifying safety signals that may indicate potential safety issues which can lead to further detailed examination. Reported adverse events from each report were coded in the VAERS using Medical Dictionary for Regulatory Activities (MedDRA) [23] . The VAERS data from 01/01/2020 to 08/20/2021 were used for this descriptive study. Additional eligibility criteria were an age of 12 years or older and an indication of either COVID-19 or Flu vaccination in the data. Records with missing age data, or records where a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 25, 2021. ; https://doi.org/10.1101/2021.09.22.21263711 doi: medRxiv preprint manufacturer of the first vaccine dose could not be ascertained (e.g., cases where information was only available on the second dose of the vaccine) and records that indicated use of COVID-19 vaccines from two different manufacturers (e.g., cases where person received Moderna for their first dose and Pfizer for their second dose) were excluded. A study flow diagram illustrating cohort sizes is shown in Figure 1 . The MedDRA terms coded by VAERS were further aggregated by a clinician into clinically meaningful broader terms. The reported adverse events in the results section used these broader terms. Mapping of MedDRA terms to broader categories are included in the Supplementary table (Supplementary table-S1). All preprocessing of the data was informed by the VAERS Data Use Guide [23] . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Demographic information and pregnancy characteristics were described for persons who reported adverse events related to COVID-19 and Flu vaccine use. After stratification of the data based on age-group, we gathered a list of Adverse Events and then reported the top 10 most frequently reported adverse events for each age group and vaccine type. The top 10 AE for each age group and vaccine type are presented in Table 2 whereas, full list of reported adverse events have been included as supplementary tables. Given the intuitive interpretation and other benefits of risk ratios [24, 25] , relative risks and associated 95 % confidence intervals (CI) were calculated for top 10 AE for each age group and vaccine type. Data preprocessing and descriptive analyses were conducted using R version 4.0.2, running in RStudio Version 1.2.5033. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Altered level of consciousness 1669 (9) (15) 115 (12) 2444 (12) 96 (12) 1586 (23) 15 (17) 0 (0) 70 (11) Nonspecific musculoskeletal pain 2245 (12) 181 (19) 2834 (14) 140 (18) 1143 (16) 13 (12) 390 (8) 12163 (17) 392 (12) 1434 (8) 27 (11) (15) 204 (9) 4128 (12) 227 (13) 465 (17) 14 (16) 2539 (13) 230 (10) 4456 (13) 246 (14) 390 (14) 15 (18) (7) 172 (10) 297 (11) 10 (12) 1 (16) 222 (11) The common vaccine manufacturers reported in the data differed by age groups. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The most frequently reported adverse event for Janssen vaccine was Fever (20%) for the first dose. The most frequently reported adverse event for the Unknown COVID vaccine were fever (26%) for the first dose and fatigue (33%) for the second dose. The most frequently reported adverse event for the Flu vaccine was injection site complications (33%). At this age group, the most common adverse events across the five-vaccine cohort were fever, injection site . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 25, 2021. ; https://doi.org/10.1101/2021.09.22.21263711 doi: medRxiv preprint complication, nonspecific musculoskeletal pain, and fatigue (Table 2) . Supplemental tables list risk percentages for additional adverse events reported in the VAERS (Supplemental Table S3 ). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint (Table 3) . Persons receiving first dose of Janssen vaccine were 0.23 times more likely to experience fever (95% CI: 0.08 to 0.64), 0.12 times more likely to experience weakness (95% CI: 0.02 to 0.87), and 0.09 times more likely to experience central neuropathy (95% CI: 0.03 to 0.29) than persons receiving the Flu vaccine (Table 3) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Table 3) . Persons receiving the Janssen vaccine were 2.03 times more likely to experience Nausea vomiting (95% CI: 1.63 to 2.55), 1.31 times more likely to experience central neuropathy (95% CI: 1.13 to 1.51), and 0.4 times more likely to experience injection site complications (95% CI: . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint (Table 3) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint (Table 3) . Apart from the frequently reported adverse events (Table 3) , some adverse events were worth mentioning due to the growing concerns in the media, such as Guillain Barre Syndrome [26] , and gynecologic changes [27] . Since these concerns were specific to COVID-19 vaccine and rarely reported as adverse events for the Flu vaccines, relative risk statistics were not calculated. Such rare events have been identified in our study and have been listed in the Supplemental table (Supplemental table S3). As mentioned previously, the interpretation of the results is subjected to limitations of passive surveillance system. Moderna had the highest number of reports in VAERS among all cohorts. Most of the reports were from the 31-64 age group which is likely due to the initial authorization of vaccine for the 31-64 age group. The proportion of reports were equally divided among having recovered and not recovered from the adverse event across all cohorts. The proportion of death across COVID vaccines cohorts were comparable and may indicate the high fatality rate of the disease rather than the vaccines especially given that the COVID-19 vaccines were recently introduced and those with severe symptoms had earlier access to them than the general population. Across the five cohorts and age groups, common adverse events could be summarized as: central neuropathy, fever, headache, injection site, nonspecific musculoskeletal pain, chest pain. Except . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 25, 2021. for chest pain, most of the adverse events were already identified in randomized controlled clinical trials of COVID-19 vaccines. Our study provides an age-wise distribution of adverse events as reported in the VAERS database (Table 2 ). It is hoped that this information will assist some in overcoming their vaccine hesitancy due to safety concerns. Investigating rare side effects of any vaccine is a difficult task [28] due to the rarity of some sideeffects, the longer period of manifestation for some side-effects, and lack of evidence for causation Observational studies like that reported here is often is a good starting point to higher quality research. A robust surveillance system (usually a combination of active and passive surveillance systems) is key in documenting rare adverse events and generating hypotheses for randomized controlled trials or case-control studies. It is important to interpret these results considering their limitations. The lack of availability of time to each adverse event reported prevented time-to-event analysis such as survival analysis (i.e., Kaplan-Meier Survival curves and Cox proportional hazard regression). Potential selection bias could apply to adverse event reporting in cases of COVID-19 vaccinations compared to adverse events reported in cases of Flu vaccinations. Finally, reporting of adverse events to VAERS does not imply that the adverse event is caused by the immunization event. Based on the available data and results, it appears that there were some common adverse events between Flu vaccines and COVID-19 vaccines. These identified common adverse events warrant further investigations based on the relative risk and 95% CI. Continued vaccine safety monitoring and ongoing advocacy targeting public for reporting of any adverse events associated with available COVID-19 vaccines to the VAERS will help . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 25, 2021. ; https://doi.org/10.1101/2021.09.22.21263711 doi: medRxiv preprint researchers to identify adverse events related with vaccines and generate hypotheses for further investigations. The current study can be used by laypersons to inform decision-making about COVID-19 and Flu vaccinations to overcome one aspect of vaccine hesitancy. ) than a person receiving the Flu vaccine (Table 3). headache (95% CI: 1.49 to 2.04), 1.68 times more likely to experience dermatitis NOS (95% CI: 1.46 to 1.92), 0.88 times more likely to experience injection site complications (95% CI: 0.82 to 0.94), 0.73 times more likely to experience nonspecific musculoskeletal pain Persons receiving second dose of the Moderna vaccine were 1.51 times more likely to experience headache (95% CI: 1.24 to 1.85), 1.28 times more likely to experience central neuropathy (95% CI: 1.07 to 1.53), 0.64 times more likely to experience nonspecific musculoskeletal pain to 2.68), 1.65 times more likely to experience central neuropathy (95% CI: 1.42 to 1.93), 1.39 times more likely to experience nausea vomiting (95% CI: 1.16 to 1.66), 0.69 times more likely to experience dermatitis NOS (95% CI: 0.57 to 0.84), and 0.66 times more likely to experience nonspecific musculoskeletal pain COVID-19) Dashboard FDA. 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SSRN (2020) Covid-19: Biden tells states to offer $100 vaccine incentive as cases rise COVID-19 and vaccine hesitancy: A longitudinal study Letter to the Editor: COVID-19 and Vaccine Hesitancy A challenge the United States Must Overcome COVID-19 vaccine hesitancy among medical students Time trends and factors related to COVID-19 vaccine hesitancy from Escaping Catch-22 -Overcoming Covid Vaccine Hesitancy COVID-19 Vaccine Monitor KFF COVID-19 Vaccine Monitor Vaccine Adverse Event Reporting System. VAERS Home VAERS Data Use Guide The relative merits of risk ratios and odds ratios When to use the odds ratio or the relative risk? News Release: Coronavirus (COVID-19) update COVID-19 Vaccines and the menstrual cycle Why is it so hard to investigate the rare side effects of COVID vaccines? The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.