[Skip to Content]
[Skip to Content Landing]

Association of Influenza Vaccination With SARS-CoV-2 Infection and Associated Hospitalization and Mortality Among Patients Aged 66 Years or Older

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is influenza vaccination associated with SARS-CoV-2 infection and related outcomes, such as hospitalization and mortality in individuals aged 66 years or older?

Findings  In this cohort study of 2 279 805 patients, influenza vaccination was found to be associated with a 22% to 24% lower risk of SARS-CoV-2 infection; however, undertaking a periodic health examination (PHE) was also associated with a 15% lower risk of SARS-CoV-2 infection. The negative association between influenza vaccination and SARS-CoV-2–related outcomes differed considerably when the analysis was stratified by the history of PHE in the preceding year.

Meaning  The findings of this study suggest that a PHE may at least partially modify the association between influenza vaccination and SARS-CoV-2–associated outcomes in individuals aged 66 years or older owing to the healthy vaccinee bias.


Importance  Vaccine effectiveness studies have rarely implemented strategies to reduce the healthy vaccinee bias arising from differences in health care–seeking behavior between vaccinated and unvaccinated individuals. Although previous observational studies suggest that influenza vaccination is associated with a reduced risk of SARS-CoV-2–associated outcomes, the healthy vaccinee bias may have led to overestimating the vaccination effect.

Objective  To estimate the association between influenza vaccination and SARS-CoV-2–associated outcomes.

Design, Setting, and Participants  This cohort study was conducted over 2 consecutive influenza vaccination campaigns (2019-2020 and 2020-2021), owing to the substantial COVID-19 burden and the greater validity of influenza vaccination data in the studied age group. The study population included community-dwelling adults aged 66 years or older in Ontario, Canada.

Exposure  Influenza vaccination for a given season.

Main Outcomes and Measures  The outcomes of interest included SARS-CoV-2 infection, SARS-CoV-2–associated hospitalization, SARS-CoV-2–associated death, and a composite of SARS-CoV-2–associated hospitalization or death. Cox proportional hazards models were used to measure the association between influenza vaccination and SARS-CoV-2–associated outcomes, censoring individuals who moved into long-term care, received COVID-19 vaccines, or died before the observation period end date. Primary care periodic health examinations (PHEs) were explored as a negative tracer exposure (ie, no association expected with SARS-CoV-2 outcomes) and as an effect modifier of the association between influenza vaccination and SARS-CoV-2 outcomes.

Results  Of 2 922 449 individuals aged 66 years or older (54.2% female) living in Ontario, 2 279 805 were included in the study. Among these, 1 234 647 (54.2%) were female and 1 045 158 (45.8%) were male; their mean (SD) age was 75.08 (7.21) years. Those who had received influenza vaccination exhibited a lower incidence of SARS-CoV-2 infection than unvaccinated individuals for the 2019-2020 cohort (adjusted hazards ratio [aHR], 0.78; 95% CI, 0.73-0.84) and the 2020-2021 cohort (aHR, 0.76; 95% CI, 0.74-0.78). This association was also observed for SARS-CoV-2–associated hospitalization or death (2019-2020: aHR, 0.83; 95% CI, 0.74-0.92; 2020-2021: aHR, 0.66; 95% CI, 0.63-0.70). Similarly, undergoing a PHE was also associated with a lower incidence of SARS-CoV-2 infection (aHR, 0.85; 95% CI, 0.78-0.91) and SARS-CoV-2–associated hospitalization or death (aHR, 0.80; 95% CI, 0.70-0.90), and modified the association between influenza vaccination and SARS-CoV-2 infection for vaccinated individuals who underwent PHE (aHR, 0.62; 95% CI, 0.52-0.74) and for vaccinated individuals who did not undergo PHE (aHR, 0.81; 95% CI, 0.76-0.87), and also SARS-CoV-2–associated hospitalization or death in vaccinated individuals who underwent PHE (aHR, 0.66; 95% CI, 0.49-0.88) and vaccinated individuals who did not undergo PHE (aHR, 0.85, 95% CI, 0.76-0.95).

Conclusions and Relevance  The findings of this cohort study suggest that undergoing a PHE may at least partially modify the association between influenza vaccination and SARS-CoV-2–associated outcomes in individuals aged 66 years or older, providing evidence of the healthy vaccinee bias that may affect vaccine effectiveness studies.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: August 11, 2022.

Published: September 28, 2022. doi:10.1001/jamanetworkopen.2022.33730

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

Corresponding Author: Seyed M. Hosseini-Moghaddam, MD, MSc, MPH, University Health Network, University of Toronto, 585 University Ave, 9 MaRS-9078, Toronto, ON M5G 2N2, Canada (sasan.hosseini@uhn.ca).

Author Contributions: Dr Hosseini-Moghaddam and Mr Calzavara had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hosseini-Moghaddam.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: He, Calzavara, Campitelli.

Obtained funding: Hosseini-Moghaddam.

Administrative, technical, or material support: Hosseini-Moghaddam.

Supervision: Hosseini-Moghaddam, Kwong.

Conflict of Interest Disclosures: Dr Hosseini-Moghaddam reported receiving grants from the Ontario Health Data Platform (OHDP) during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-term Care (MLTC). This work is also supported by the OHDP, a Province of Ontario initiative to support Ontario’s ongoing response to COVID-19 and its related impact.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: Parts of this material are based on data and information provided by the Canadian Institute for Health Information (CIHI) and Ontario Health (OH). The opinions, results, views, and conclusions reported in this article are those of the authors and do not necessarily reflect those of CIHI or OH; no endorsement by CIHI or OH is intended or should be inferred. No endorsement by the OHDP, its partners, or the Province of Ontario is intended or should be inferred.

Additional Contributions: We thank IQVIA Solutions Canada Inc, for use of their Drug Information File.

Walsh  EE , Frenck  RW  Jr , Falsey  AR ,  et al.  Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates.   N Engl J Med. 2020;383(25):2439-2450. doi:10.1056/NEJMoa2027906 PubMedGoogle ScholarCrossref
Wang  R , Liu  M , Liu  J .  The association between influenza vaccination and COVID-19 and its outcomes: a systematic review and meta-analysis of observational studies.   Vaccines (Basel). 2021;9(5):529. doi:10.3390/vaccines9050529 PubMedGoogle ScholarCrossref
Fink  G , Orlova-Fink  N , Schindler  T ,  et al.  Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil.   BMJ Evid Based Med. 2020;26(4):192-193. doi:10.1136/bmjebm-2020-111549 PubMedGoogle ScholarCrossref
Marín-Hernández  D , Schwartz  RE , Nixon  DF .  Epidemiological evidence for association between higher influenza vaccine uptake in the elderly and lower COVID-19 deaths in Italy.   J Med Virol. 2021;93(1):64-65. doi:10.1002/jmv.26120 PubMedGoogle ScholarCrossref
Zanettini  C , Omar  M , Dinalankara  W ,  et al.  Influenza vaccination and COVID19 mortality in the USA.   Vaccines. 2021;9(5):427. doi:10.1101/2020.06.24.20129817Google Scholar
Lee  S , Ryu  J-H .  Influenza viruses: innate immunity and mRNA vaccines.   Front Immunol. 2021;12:710647. doi:10.3389/fimmu.2021.710647 PubMedGoogle ScholarCrossref
Pawlowski  C , Puranik  A , Bandi  H ,  et al.  Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations.   Sci Rep. 2021;11(1):4741. doi:10.1038/s41598-021-83641-y PubMedGoogle ScholarCrossref
Rijkers  GT , van Overveld  FJ .  The “original antigenic sin” and its relevance for SARS-CoV-2 (COVID-19) vaccination.   Clin Immunol Commun. 2021;1:13-16. doi:10.1016/j.clicom.2021.10.001 Google ScholarCrossref
Conlon  A , Ashur  C , Washer  L , Eagle  KA , Hofmann Bowman  MA .  Impact of the influenza vaccine on COVID-19 infection rates and severity.   Am J Infect Control. 2021;49(6):694-700. doi:10.1016/j.ajic.2021.02.012 PubMedGoogle ScholarCrossref
Mosaddeghi  P , Shahabinezhad  F , Dorvash  M , Goodarzi  M , Negahdaripour  M .  Harnessing the non-specific immunogenic effects of available vaccines to combat COVID-19.   Hum Vaccin Immunother. 2021;17(6):1650-1661. doi:10.1080/21645515.2020.1833577 PubMedGoogle ScholarCrossref
Prompetchara  E , Ketloy  C , Palaga  T .  Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic.   Asian Pac J Allergy Immunol. 2020;38(1):1-9. PubMedGoogle Scholar
Remschmidt  C , Wichmann  O , Harder  T .  Frequency and impact of confounding by indication and healthy vaccinee bias in observational studies assessing influenza vaccine effectiveness: a systematic review.   BMC Infect Dis. 2015;15(1):429. doi:10.1186/s12879-015-1154-y PubMedGoogle ScholarCrossref
Wise  J .  COVID-19: Pfizer BioNTech vaccine reduced cases by 94% in Israel, shows peer reviewed study.   BMJ. 2021;372:n567. doi:10.1136/bmj.n567 PubMedGoogle ScholarCrossref
Nelson  JC , Jackson  ML , Weiss  NS , Jackson  LA .  New strategies are needed to improve the accuracy of influenza vaccine effectiveness estimates among seniors.   J Clin Epidemiol. 2009;62(7):687-694. doi:10.1016/j.jclinepi.2008.06.014 PubMedGoogle ScholarCrossref
Kwong  JC , Campitelli  MA , Gubbay  JB ,  et al.  Vaccine effectiveness against laboratory-confirmed influenza hospitalizations among elderly adults during the 2010-2011 season.   Clin Infect Dis. 2013;57(6):820-827. doi:10.1093/cid/cit404 PubMedGoogle ScholarCrossref
Public Health Ontario. Coronavirus disease 2019 (COVID-19)—PCR. 2021. Accessed November 6, 2020. https://www.publichealthontario.ca/en/laboratory-services/test-information-index/covid-19
Huang  K , Lin  SW , Sheng  WH , Wang  CC .  Influenza vaccination and the risk of COVID-19 infection and severe illness in older adults in the United States.   Sci Rep. 2021;11(1):11025. doi:10.1038/s41598-021-90068-y PubMedGoogle ScholarCrossref
Debisarun  PA , Struycken  P , Domínguez-Andrés  J ,  et al.  The effect of influenza vaccination on trained immunity: impact on COVID-19.   medRxiv. Preprint posted online October 16, 2020. doi:10.1101/2020.10.14.20212498 Google Scholar
Ainslie  KEC , Haber  M , Orenstein  WA .  Bias of influenza vaccine effectiveness estimates from test-negative studies conducted during an influenza pandemic.   Vaccine. 2019;37(14):1987-1993. doi:10.1016/j.vaccine.2019.02.036 PubMedGoogle ScholarCrossref
Debisarun  PA , Gössling  KL , Bulut  O ,  et al.  Induction of trained immunity by influenza vaccination—impact on COVID-19.   PLoS Pathog. 2021;17(10):e1009928. doi:10.1371/journal.ppat.1009928 PubMedGoogle ScholarCrossref
Sánchez-Ramón  S , Conejero  L , Netea  MG , Sancho  D , Palomares  Ó , Subiza  JL .  Trained immunity–based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations.   Front Immunol. 2018;9:2936. doi:10.3389/fimmu.2018.02936 PubMedGoogle ScholarCrossref
Lee  YJ , Lee  JY , Jang  YH , Seo  S-U , Chang  J , Seong  BL .  Non-specific effect of vaccines: immediate protection against respiratory syncytial virus infection by a live attenuated influenza vaccine.   Front Microbiol. 2018;9:83. doi:10.3389/fmicb.2018.00083 PubMedGoogle ScholarCrossref
Piedra  PA , Gaglani  MJ , Kozinetz  CA ,  et al.  Trivalent live attenuated intranasal influenza vaccine administered during the 2003-2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children.   Pediatrics. 2007;120(3):e553-e564. doi:10.1542/peds.2006-2836 PubMedGoogle ScholarCrossref
Cao  RG , Suarez  NM , Obermoser  G ,  et al.  Differences in antibody responses between trivalent inactivated influenza vaccine and live attenuated influenza vaccine correlate with the kinetics and magnitude of interferon signaling in children.   J Infect Dis. 2014;210(2):224-233. doi:10.1093/infdis/jiu079 PubMedGoogle ScholarCrossref
Anestad  G .  Interference between outbreaks of respiratory syncytial virus and influenza virus infection.   Lancet. 1982;1(8270):502. doi:10.1016/S0140-6736(82)91466-0 PubMedGoogle ScholarCrossref
Pusch  E , Renz  H , Skevaki  C .  Respiratory virus–induced heterologous immunity: part of the problem or part of the solution?   Allergo J. 2018;27(3):28-45. doi:10.1007/s15007-018-1580-4 PubMedGoogle ScholarCrossref
Jackson  LA , Nelson  JC , Benson  P ,  et al.  Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors.   Int J Epidemiol. 2006;35(2):345-352. doi:10.1093/ije/dyi275 PubMedGoogle ScholarCrossref
Granger  BB , Swedberg  K , Ekman  I ,  et al; CHARM investigators.  Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial.   Lancet. 2005;366(9502):2005-2011. doi:10.1016/S0140-6736(05)67760-4 PubMedGoogle ScholarCrossref
Voysey  M , Clemens  SAC , Madhi  SA ,  et al; Oxford COVID Vaccine Trial Group.  Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.   Lancet. 2021;397(10269):99-111. doi:10.1016/S0140-6736(20)32661-1 PubMedGoogle ScholarCrossref
Chung  H , He  S , Nasreen  S ,  et al; Canadian Immunization Research Network (CIRN) Provincial Collaborative Network (PCN) Investigators.  Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada: test negative design study.   BMJ. 2021;374:n1943. doi:10.1136/bmj.n1943 PubMedGoogle ScholarCrossref
Thompson  MG , Stenehjem  E , Grannis  S ,  et al.  Effectiveness of COVID-19 vaccines in ambulatory and inpatient care settings.   N Engl J Med. 2021;385(15):1355-1371. doi:10.1056/NEJMoa2110362 PubMedGoogle ScholarCrossref
Pilishvili  T , Gierke  R , Fleming-Dutra  KE ,  et al; Vaccine Effectiveness Among Healthcare Personnel Study Team.  Effectiveness of mRNA COVID-19 vaccine among U.S. health care personnel.   N Engl J Med. 2021;385(25):e90. doi:10.1056/NEJMoa2106599 PubMedGoogle ScholarCrossref
Pilishvili  T , Fleming-Dutra  KE , Farrar  JL ,  et al; Vaccine Effectiveness Among Healthcare Personnel Study Team.  Interim estimates of vaccine effectiveness of Pfizer-BioNTech and Moderna COVID-19 accines among health care personnel—33 U.S. sites, January-March 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(20):753-758. doi:10.15585/mmwr.mm7020e2 PubMedGoogle ScholarCrossref
Tenforde  MW , Olson  SM , Self  WH ,  et al; IVY Network; HAIVEN Investigators.  Effectiveness of Pfizer-BioNTech and Moderna vaccines gainst COVID-19 among hospitalized adults aged ≥65 years—United States, January-March 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(18):674-679. doi:10.15585/mmwr.mm7018e1 PubMedGoogle ScholarCrossref
Thompson  MG , Burgess  JL , Naleway  AL ,  et al.  Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers—eight U.S. locations, December 2020-March 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(13):495-500. doi:10.15585/mmwr.mm7013e3 PubMedGoogle ScholarCrossref
Britton  A , Jacobs Slifka  KM , Edens  C ,  et al.  Effectiveness of the Pfizer-BioNTech COVID-19 vaccine among residents of two skilled nursing facilities experiencing COVID-19 outbreaks—Connecticut, December 2020-February 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(11):396-401. doi:10.15585/mmwr.mm7011e3 PubMedGoogle ScholarCrossref
Ozasa  K , Fukushima  W .  Commentary: test-negative design reduces confounding by healthcare-seeking attitude in case-control studies.   J Epidemiol. 2019;29(8):279-281. doi:10.2188/jea.JE20180177 PubMedGoogle ScholarCrossref
Sullivan  SG , Tchetgen Tchetgen  EJ , Cowling  BJ .  Theoretical basis of the test-negative study design for assessment of influenza vaccine effectiveness.   Am J Epidemiol. 2016;184(5):345-353. doi:10.1093/aje/kww064 PubMedGoogle ScholarCrossref
Gilstad-Hayden  K , Durante  A , Earnshaw  VA , Rosenthal  L , Ickovics  JR .  Association of influenza vaccine uptake with health, access to health care, and medical mistreatment among adults from low-income neighborhoods in New Haven, CT: a classification tree analysis.   Prev Med. 2015;74:97-102. doi:10.1016/j.ypmed.2015.02.008 PubMedGoogle ScholarCrossref
Landi  F , Onder  G , Carpenter  I , Garms-Homolova  V , Bernabei  R .  Prevalence and predictors of influenza vaccination among frail, community-living elderly patients: an international observational study.   Vaccine. 2005;23(30):3896-3901. doi:10.1016/j.vaccine.2005.03.008 PubMedGoogle ScholarCrossref
Burns  VE , Ring  C , Carroll  D .  Factors influencing influenza vaccination uptake in an elderly, community-based sample.   Vaccine. 2005;23(27):3604-3608. doi:10.1016/j.vaccine.2004.12.031 PubMedGoogle ScholarCrossref
Schwartz  KL , Jembere  N , Campitelli  MA , Buchan  SA , Chung  H , Kwong  JC . Using physician billing claims from the Ontario Health Insurance Plan to determine individual influenza vaccination status: an updated validation study.  CMAJ Open. 2016;4(3):E463-E470. doi:10.9778/cmajo.20160009PubMedCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.