Reactogenicity of Simultaneous COVID-19 mRNA Booster and Influenza Vaccination in the US | Infectious Diseases | JAMA Network Open | JAMA Network
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Table 1.  Demographic Characteristics of v-safe Respondentsa
Demographic Characteristics of v-safe Respondentsa
Table 2.  Reactions Reported by v-safe Respondentsa
Reactions Reported by v-safe Respondentsa
Table 3.  Most Common Reactions Reported by v-safe Respondentsa
Most Common Reactions Reported by v-safe Respondentsa
Table 4.  Reactions and Health Impacts Reported in v-safe Respondents
Reactions and Health Impacts Reported in v-safe Respondents
1.
Woodworth  KR, Moulia  D, Collins  JP,  et al.  The Advisory Committee on Immunization Practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine in children aged 5-11 years - United States, November 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(45):1579-1583. doi:10.15585/mmwr.mm7045e1 PubMedGoogle ScholarCrossref
2.
Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. US Department of Health and Human Services, CDC; 2021. Accessed November 23, 2021. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html
3.
US Food and Drug Administration. Pfizer-BioNTech COVID-19 vaccine letter of authorization. US Food and Drug Administration; 2021. Accessed November 23, 2021. https://www.fda.gov/media/150386/download
4.
US Food and Drug Administration. Moderna COVID-19 vaccine letter of authorization. US Food and Drug Administration; 2021. Accessed November 23, 2021. https://www.fda.gov/media/144636/download
5.
US Food and Drug Administration. Janssen COVID-19 vaccine letter of authorization. US Food and Drug Administration; 2021. Accessed November 23, 2021. https://www.fda.gov/media/146303/download
6.
Grohskopf  LA, Alyanak  E, Ferdinands  JM,  et al.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 influenza season.   MMWR Recomm Rep. 2021;70(5):1-28. doi:10.15585/mmwr.rr7005a1 PubMedGoogle ScholarCrossref
7.
Centers for Disease Control and Prevention. v-safe after vaccination health checker. Accessed Jun 13, 2022. https://vsafe.cdc.gov/en/
8.
Lazarus  R, Baos  S, Cappel-Porter  H,  et al; ComfluCOV Trial Group.  Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial.   Lancet. 2021;398(10318):2277-2287. doi:10.1016/S0140-6736(21)02329-1 PubMedGoogle ScholarCrossref
9.
Schwarz  TF, Aggarwal  N, Moeckesch  B,  et al.  Immunogenicity and safety of an adjuvanted herpes zoster subunit vaccine coadministered with seasonal influenza vaccine in adults aged 50 years or older.   J Infect Dis. 2017;216(11):1352-1361. doi:10.1093/infdis/jix481 PubMedGoogle ScholarCrossref
10.
Falsey  AR, Treanor  JJ, Tornieporth  N, Capellan  J, Gorse  GJ.  Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older.   J Infect Dis. 2009;200(2):172-180. doi:10.1086/599790 PubMedGoogle ScholarCrossref
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    Original Investigation
    Infectious Diseases
    July 15, 2022

    Reactogenicity of Simultaneous COVID-19 mRNA Booster and Influenza Vaccination in the US

    Author Affiliations
    • 1CDC COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Georgia
    • 2Rollins School of Public Health, Emory University, Atlanta, Georgia
    JAMA Netw Open. 2022;5(7):e2222241. doi:10.1001/jamanetworkopen.2022.22241
    Key Points

    Question  Are systemic reactions more common after simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines than after COVID-19 mRNA booster alone?

    Findings  In this cohort study of self-reported data from 981 099 persons aged 12 years or older, simultaneous administration of a COVID-19 mRNA booster dose and an influenza vaccine was associated with 8% to 11% increases, respectively, in systemic reaction compared with COVID-19 mRNA booster alone. These differences were statistically significant.

    Meaning  Findings from this study suggest that simultaneous administration of COVID-19 mRNA booster and influenza vaccines may be associated with increased likelihood of systemic reactions.

    Abstract

    Importance  COVID-19 and seasonal influenza vaccines are essential in preventing respiratory infections and their potentially severe complications. Simultaneous administration of vaccines is efficient and may improve coverage with each vaccine. However, the safety of simultaneous administration of COVID-19 and influenza vaccines has not been well described.

    Objective  To evaluate adverse events and health impacts associated with simultaneously administered COVID-19 mRNA booster and seasonal influenza vaccines in the US population.

    Design, Setting, and Participants  In this retrospective cohort study, self-reported vaccine data were collected on days 0 to 7 after vaccination from September 22, 2021, through May 1, 2022, through v-safe, a voluntary smartphone-based monitoring system established by the Centers for Disease Control and Prevention. Participants were persons who voluntarily registered in v-safe following COVID-19 vaccination.

    Exposure  Receipt of simultaneously administered COVID-19 mRNA booster and seasonal influenza vaccines or COVID-19 mRNA booster alone.

    Main Outcomes and Measures  Local injection site and systemic reactions (eg, fatigue, headache, and myalgia) and health impacts reported by v-safe respondents in the week following COVID-19 mRNA booster vaccination. Adjusted odds ratios (aORs) were estimated for simultaneous administration compared with booster dose alone, controlling for sex, age, and week of vaccination.

    Results  Of a total of 981 099 persons aged 12 years or older registered with v-safe, simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines was reported by 92 023 (9.4%) v-safe respondents; of these respondents, 54 926 (59.7%) were female, 36 234 (39.4%) were male, and sex was unknown for 863 (0.9%). In the week following vaccination, any systemic reactions were reported by 36 144 (58.9%) of 61 390 respondents who simultaneously received Pfizer-BioNTech booster and influenza vaccines and 21 027 (68.6%) of 30633 respondents who simultaneously received Moderna booster and influenza vaccines. Respondents who simultaneously received influenza and Pfizer-BioNTech booster vaccines (aOR, 1.08; 95% CI, 1.06-1.10) or influenza and Moderna booster vaccines (aOR, 1.11; 95% CI, 1.08-1.14) were slightly more likely to report any systemic reaction in the week following simultaneous vaccination than respondents who received only a COVID-19 mRNA vaccine booster.

    Conclusions and Relevance  In this study, compared with administration of COVID-19 mRNA booster vaccines alone, simultaneous administration of COVID-19 mRNA booster and seasonal influenza vaccines was associated with significant increases in reports of systemic reactions during days 0 to 7 following vaccination. These results may help better characterize the outcomes associated with simultaneously administered COVID-19 booster and influenza vaccines in the US population.

    Introduction

    COVID-19 vaccination is recommended by the Centers for Disease Control and Prevention (CDC) for all persons aged 5 years or older in the US.1 Current clinical guidance indicates that COVID-19 vaccines may be administered without regard to timing of other vaccines, including simultaneous administration of COVID-19 vaccine and other vaccines.2

    The US Food and Drug Administration first expanded COVID-19 vaccine emergency use authorizations to include booster doses for adults aged 65 years or older and other high-risk populations (September 22, 2021, for Pfizer-BioNTech and October 20, 2021, for Moderna and Janssen); on November 19, 2021, emergency use authorizations were expanded to include all adults aged 18 years or older at least 6 months after completing a Pfizer-BioNTech or Moderna 2-dose primary series and at least 2 months after a single dose of Janssen vaccine.3-5 On December 9, 2021, the Pfizer-BioNTech emergency use authorization was expanded to include homologous booster doses for persons aged 16 years or older; on January 3, 2022, it was expanded to include children aged 12 years or older, and shorten the time to booster vaccination to 5 months.3-5

    Authorization of COVID-19 vaccine booster doses coincided with the recommended period for seasonal influenza vaccination, increasing the likelihood of simultaneous administration of COVID-19 and influenza vaccines.6 To better characterize the safety of simultaneously administered COVID-19 booster and influenza vaccines in the US population, we evaluated adverse events and health impacts reported to v-safe, a smartphone-based safety surveillance system, during days 0 to 7 following vaccination during September 22, 2021, to May 1, 2022.

    Methods

    The v-safe platform is a smartphone-based active safety surveillance system7 established by the CDC to collect information on health status among US residents after COVID-19 vaccination. This cohort study was reviewed by the CDC consistent with applicable federal law and CDC policy and was deemed not to be human participant research as defined in 45 CFR 46.102(l)(2); institutional review board review was not required. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.

    The v-safe platform is a voluntary surveillance system, and registered participants opt in to receive health surveys; no further consent was required. Following COVID-19 vaccination, persons may register with v-safe, indicate COVID-19 vaccine dose and any simultaneously administered vaccines (received during the same visit), and receive regularly scheduled text message reminders about completing online health surveys. During registration, persons indicate their age, race, and ethnicity; demographic variables were collected to evaluate how well the surveillance population represents the general US population. Health surveys sent in the first week postvaccination include questions about local injection site (pain, redness, swelling, or itching) and systemic reactions (chills, headache, joint pain, myalgia, fatigue, nausea, vomiting, diarrhea, abdominal pain, or rash) self-identified as mild, moderate, or severe and health impacts (whether the vaccine recipient was unable to perform normal daily activities, missed work or school, or received care from a medical professional [telehealth, outpatient, emergency department, or hospitalization]) (eMethods in the Supplement). Registrants may provide more information via free text about reactions or health impacts. A report indicating a medically attended event prompts contact by the CDC v-safe call center; completion of a vaccine adverse event reporting system report, if indicated, is encouraged.

    The v-safe data collected during September 22, 2021, to May 1, 2022, were analyzed and described for v-safe respondents who simultaneously received COVID-19 mRNA booster and seasonal influenza vaccines or a COVID-19 mRNA booster vaccine alone and who completed at least 1 health survey during days 0 to 7 following vaccination. A booster dose was defined as a third dose of COVID-19 mRNA vaccine administered at least 5 months after dose 2, on or after the day on which booster doses were authorized for each manufacturer and age group. Excluded from the analysis were persons who (1) reported simultaneous administration of COVID-19 mRNA booster dose, influenza vaccine, and additional vaccine(s) (n = 2647); (2) reported a booster dose prior to its authorization (n = 26 960); or (3) reported a Moderna COVID-19 vaccine and were aged less than 18 years or Pfizer-BioNTech COVID-19 vaccine and were aged less than 12 years (n = 18). The odds of reporting any injection site or systemic reactions or health impacts following simultaneous administration of COVID-19 mRNA booster dose and influenza vaccines were compared with those following administration of the COVID-19 mRNA booster alone using a logistic regression model, adjusting for sex, age at vaccination, and week of vaccination. Statistical significance was set at α = .05 and 95% CIs were estimated. SAS software, version 9.4 (SAS Institute Inc) was used to conduct all analyses.

    Results

    From September 22, 2021, to May 1, 2022, a total of 92 023 v-safe respondents reported simultaneous receipt of COVID-19 mRNA booster and seasonal influenza vaccines; 889 076 v-safe respondents reported receipt of a COVID-19 mRNA booster alone. Of respondents who simultaneously received COVID-19 mRNA booster and seasonal influenza vaccines, 54 926 (59.7%) were female, 36 234 (39.4%) were male, and sex was unknown for 863 (0.9%); 37 359 (40.6%) were aged 12 to 49 years, 23 760 (25.8%) were aged 50 to 64 years, 24 855 (27.0%) were aged 65 to 74 years, and 6049 (6.6%) were aged 75 years or older (Table 1).

    In the week after vaccination, systemic reactions were reported by 36 144 respondents (58.9%) who simultaneously received Pfizer-BioNTech COVID-19 booster and influenza vaccines and 21 027 respondents (68.6%) who simultaneously received Moderna COVID-19 booster and influenza vaccines (Table 2). Most reactions were reported as mild or moderate (Table 3) and were reported most frequently on the day following vaccination. The most frequently reported systemic reactions following simultaneous administration were fatigue, headache, and myalgia. Adjusted odds ratios (aORs) were estimated for simultaneous administration compared with booster dose alone, controlling for sex, age, and week of vaccination. Respondents who simultaneously received an influenza vaccine and either the Pfizer-BioNTech COVID-19 booster (aOR, 1.08; 95% CI, 1.06-1.10) or the Moderna COVID-19 booster (aOR, 1.11; 95% CI, 1.08-1.14) were slightly more likely to report any systemic reaction in the week following vaccination than respondents who received a COVID-19 mRNA booster alone (Table 4).

    Health impacts in the week after vaccination were reported by 11 658 respondents (19.0%) who simultaneously received Pfizer-BioNTech COVID-19 booster and influenza vaccines and 8210 respondents (26.8%) who simultaneously received Moderna COVID-19 booster and influenza vaccines. Inability to perform normal daily activities in the week following vaccination was reported by 9519 respondents (15.5%) who simultaneously received Pfizer-BioNTech COVID-19 booster and influenza vaccines and 6811 respondents (22.2%) who simultaneously received Moderna COVID-19 booster and influenza vaccines; fewer than 1% of respondents simultaneously administered vaccines required medical care, including 22 respondents (0.02%) who reportedly received care at a hospital. Information regarding reported hospitalizations (through a linked vaccine adverse event reporting system report, v-safe follow-up call, or v-safe free-text data) was available for 19 (86.4%) of the 22 respondents, including 10 (45.5%) who indicated hospitalization was unrelated or reported in error. Among the remaining respondents, reasons for hospitalization included excessive vomiting, supraventricular tachycardia, cardiac arrhythmia, chest discomfort, autoinflammatory disease flare, kidney infection, hypoxia, and stroke. Respondents who simultaneously received influenza and Pfizer-BioNTech COVID-19 booster vaccines were not more likely to report a health impact in the week following vaccination (aOR, 0.99; 95% CI, 0.97-1.02) than respondents who received a COVID-19 Pfizer-BioNTech COVID-19 booster alone; respondents who simultaneously received influenza and Moderna COVID-19 booster vaccines were slightly more likely to report any health impact in the week following vaccination (aOR, 1.05; 95% CI, 1.02-1.08) than respondents who received a Moderna COVID-19 booster alone.

    Discussion

    The v-safe respondents who simultaneously received Pfizer-BioNTech or Moderna COVID-19 booster and seasonal influenza vaccines reported systemic reactions in the week after vaccination 8% to 11%, respectively, more frequently than did respondents who received a COVID-19 mRNA booster vaccine alone. Reactions after simultaneous vaccination or COVID-19 mRNA booster vaccination alone were usually mild. The phase 4 trial8 that included persons who simultaneously received dose 2 Pfizer-BioNTech COVID-19 and influenza vaccines did not identify any serious safety concerns. Hospitalization following either of these vaccine combinations was uncommonly reported to v-safe. Given the limited data collected by v-safe, it is not possible to determine whether hospitalization was related to vaccination unless specifically noted by the respondent.

    Our findings are generally consistent with results from the phase 3 trial9 of simultaneous administration of an adjuvanted recombinant subunit vaccine for prevention of herpes zoster with substantial reactogenicity and quadrivalent inactivated influenza vaccine. Participants aged 50 years or older who received simultaneous vaccination reported systemic reactions more frequently (60.9%) than participants who received adjuvanted recombinant subunit herpes zoster vaccine (52.1%) or influenza vaccine (33.6%) alone; however, this difference was not considered clinically meaningful by Schwarz et al.9 Although we did not collect information on reactions after influenza vaccine alone, influenza vaccines in general are not particularly reactogenic. However, as reported by Falsey et al,10 some influenza vaccines appear to be more reactogenic for others; for example, among adults aged 65 years or older, local reactions were more frequently reported following high-dose influenza vaccine than standard-dose vaccine.

    Limitations

    This analysis has limitations. The v-safe platform is a voluntary program, and, as a result, data might not be generalizable to the entire population receiving COVID-19 vaccines. The v-safe program relies on self-report of COVID-19 vaccine received; therefore, some misclassification of exposure is possible. The v-safe app collects information of solicited adverse events following COVID-19 vaccination and is not designed to detect rare unsolicited adverse events. Given the short interval between vaccination and submission of v-safe responses, recall bias should be minimal. To minimize the complexity of data collection for respondents, v-safe does not include information regarding influenza vaccine type. Some influenza vaccines are more reactogenic than others, especially those approved for older adults; however, our model controlled for age, and this adjustment may address the differential reactogenicity of influenza vaccines administered to older adults. In addition, it is possible that the small increases in reactogenicity found with simultaneous administration were due to residual confounding between those who received only a COVID-19 booster vs both COVID-19 and influenza vaccines.

    Conclusions

    In this cohort analysis, initial safety findings from v-safe for simultaneously administered COVID-19 mRNA booster dose and seasonal influenza vaccines indicate that respondents who received simultaneous administration were slightly more likely to report systemic reactions in the week following vaccination than respondents who received COVID-19 mRNA booster alone. In both groups, most reactions reported in the week following vaccination were generally mild. These results may help better characterize the outcomes associated with simultaneously administered COVID-19 mRNA booster and influenza vaccines in the US population.

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    Article Information

    Accepted for Publication: May 8, 2022.

    Published: July 15, 2022. doi:10.1001/jamanetworkopen.2022.22241

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Hause AM et al. JAMA Network Open.

    Corresponding Author: Anne M. Hause, PhD, MSPH, Centers for Disease Control and Prevention, 1825 Century Center Blvd, Atlanta, GA 30345 (voe5@cdc.gov).

    Author Contributions: Dr Hause and Mr Zhang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Hause, Gee, Shimabukuro, Shay.

    Acquisition, analysis, or interpretation of data: Hause, Zhang, Yue, Marquez, Myers, Parker, Su, Shimabukuro, Shay.

    Drafting of the manuscript: Hause, Zhang, Yue, Marquez, Parker, Shay.

    Critical revision of the manuscript for important intellectual content: Hause, Myers, Gee, Su, Shimabukuro, Shay.

    Statistical analysis: Hause, Zhang, Yue, Marquez.

    Administrative, technical, or material support: Myers, Parker, Gee, Su, Shay.

    Supervision: Hause, Myers, Shimabukuro, Shay.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This work was internally funded by the Centers for Disease Control and Prevention (CDC).

    Role of the Funder/Sponsor: The authors affiliated with the CDC along with the other coauthors conducted the investigations; performed collection, management, analysis, and interpretation of the data; were involved in the preparation, review, and approval of the manuscript; and made the decision to submit the manuscript for publication.

    Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the CDC. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC.

    References
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    Woodworth  KR, Moulia  D, Collins  JP,  et al.  The Advisory Committee on Immunization Practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine in children aged 5-11 years - United States, November 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(45):1579-1583. doi:10.15585/mmwr.mm7045e1 PubMedGoogle ScholarCrossref
    2.
    Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. US Department of Health and Human Services, CDC; 2021. Accessed November 23, 2021. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html
    3.
    US Food and Drug Administration. Pfizer-BioNTech COVID-19 vaccine letter of authorization. US Food and Drug Administration; 2021. Accessed November 23, 2021. https://www.fda.gov/media/150386/download
    4.
    US Food and Drug Administration. Moderna COVID-19 vaccine letter of authorization. US Food and Drug Administration; 2021. Accessed November 23, 2021. https://www.fda.gov/media/144636/download
    5.
    US Food and Drug Administration. Janssen COVID-19 vaccine letter of authorization. US Food and Drug Administration; 2021. Accessed November 23, 2021. https://www.fda.gov/media/146303/download
    6.
    Grohskopf  LA, Alyanak  E, Ferdinands  JM,  et al.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 influenza season.   MMWR Recomm Rep. 2021;70(5):1-28. doi:10.15585/mmwr.rr7005a1 PubMedGoogle ScholarCrossref
    7.
    Centers for Disease Control and Prevention. v-safe after vaccination health checker. Accessed Jun 13, 2022. https://vsafe.cdc.gov/en/
    8.
    Lazarus  R, Baos  S, Cappel-Porter  H,  et al; ComfluCOV Trial Group.  Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial.   Lancet. 2021;398(10318):2277-2287. doi:10.1016/S0140-6736(21)02329-1 PubMedGoogle ScholarCrossref
    9.
    Schwarz  TF, Aggarwal  N, Moeckesch  B,  et al.  Immunogenicity and safety of an adjuvanted herpes zoster subunit vaccine coadministered with seasonal influenza vaccine in adults aged 50 years or older.   J Infect Dis. 2017;216(11):1352-1361. doi:10.1093/infdis/jix481 PubMedGoogle ScholarCrossref
    10.
    Falsey  AR, Treanor  JJ, Tornieporth  N, Capellan  J, Gorse  GJ.  Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older.   J Infect Dis. 2009;200(2):172-180. doi:10.1086/599790 PubMedGoogle ScholarCrossref
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