Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults: A Randomized Clinical Trial

JAMA Netw Open. 2021 Jan 4;4(1):e2031266. doi: 10.1001/jamanetworkopen.2020.31266.


Importance: Trivalent adjuvanted inactivated influenza vaccine (aIIV3) and trivalent high-dose inactivated influenza vaccine (HD-IIV3) are US-licensed for adults aged 65 years and older. Data are needed on the comparative safety, reactogenicity, and health-related quality of life (HRQOL) effects of these vaccines.

Objective: To compare safety, reactogenicity, and changes in HRQOL scores after aIIV3 vs HD-IIV3.

Design, setting, and participants: This randomized blinded clinical trial was a multicenter US study conducted during the 2017 to 2018 and 2018 to 2019 influenza seasons. Among 778 community-dwelling adults aged at least 65 years and assessed for eligibility, 13 were ineligible and 8 withdrew before randomization. Statistical analysis was performed from August 2019 to August 2020.

Interventions: Intramuscular administration of aIIV3 or HD-IIV3 after age-stratification (65-79 years; ≥80 years) and randomization.

Main outcomes and measures: Proportions of participants with moderate-to-severe injection-site pain and 14 other solicited reactions during days 1 to 8, using a noninferiority test (5% noninferiority margin), and serious adverse events (SAE) and adverse events of clinical interest (AECI), including new-onset immune-mediated conditions, during days 1 to 43. Changes in HRQOL scores before and after vaccination (days 1, 3) were also compared between study groups.

Results: A total of 757 adults were randomized, 378 to receive aIIV3 and 379 to receive HD-IIV3. Of these participants, there were 420 women (55%) and 589 White individuals (78%) with a median (range) age of 72 (65-97) years. The proportion reporting moderate-to-severe injection-site pain, limiting or preventing activity, after aIIV3 (12 participants [3.2%]) (primary outcome) was noninferior compared with HD-IIV3 (22 participants [5.8%]) (difference -2.7%; 95% CI, -5.8 to 0.4). Ten reactions met noninferiority criteria for aIIV3; 4 (moderate-to-severe injection-site tenderness, arthralgia, fatigue, malaise) did not. It was inconclusive whether these 4 reactions occurred in higher proportions of participants after aIIV3. No participant sought medical care for a vaccine reaction. No AECI was observed. Nine participants had at least SAE after aIIV3 (2.4%; 95% CI,1.1% to 4.5%); 3 had at least 1 SAE after HD-IIV3 (0.8%; 95% CI, 0.2% to 2.2%). No SAE was associated with vaccination. Changes in prevaccination and postvaccination HRQOL scores were not clinically meaningful and not different between the groups.

Conclusions and relevance: Overall safety and HRQOL findings were similar after aIIV3 and HD-IIV3, and consistent with prelicensure data. From a safety standpoint, this study's results support using either vaccine to prevent influenza in older adults.

Trial registration: Identifier: NCT03183908.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic* / administration & dosage
  • Adjuvants, Immunologic* / adverse effects
  • Aged
  • Aged, 80 and over
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Female
  • Humans
  • Influenza Vaccines* / administration & dosage
  • Influenza Vaccines* / adverse effects
  • Influenza Vaccines* / immunology
  • Influenza, Human / prevention & control*
  • Injections, Intramuscular
  • Male
  • Quality of Life*
  • Vaccines, Inactivated* / administration & dosage
  • Vaccines, Inactivated* / adverse effects
  • Vaccines, Inactivated* / immunology


  • Adjuvants, Immunologic
  • Influenza Vaccines
  • Vaccines, Inactivated

Associated data