GRADE: Higher Dose and Adjuvanted Influenza Vaccines for Persons Aged ≥65 Years

Background

Estimated rates of influenza-associated hospitalization and death are generally highest among individuals 65 years of age and older (1-4), an age group for whom influenza vaccine effectiveness is often lower relative to younger populations (5, 6). Two inactivated influenza vaccines approved in the U.S. for persons aged ≥65 years have features intended to promote a better immune response for this age group. These include a high-dose inactivated influenza vaccine containing four times the antigen dosage per virus compared with standard dose inactivated vaccines (approved as a trivalent formulation [HD-IIV3] in 2009 and a quadrivalent formulation [HD-IIV4] in 2019), and an inactivated vaccine containing the adjuvant agent MF59 (approved as a trivalent formulation [aIIV3] in 2015 and a quadrivalent formulation [aIIV4] in 2020). These two vaccines, as well as a recombinant influenza vaccine containing three times the antigen dosage per virus compared with SD-IIVs (initially licensed as a trivalent formulation [RIV3] in 2013 and as a quadrivalent [RIV4] in 2016 and approved for ages ≥18 years), have been evaluated for relative efficacy and effectiveness compared with standard dose unadjuvanted inactivated influenza vaccines (SD-IIVs) among older adults (7-9). This assessment sought to review the available published evidence for relative efficacy, effectiveness, and safety of HD-IIV, aIIV, and RIV to support ACIP discussion of whether any one or more of these three vaccines should be preferentially recommended over other age-appropriate influenza vaccines (unadjuvanted SD-IIVs) for persons ages 65 years and older.

Methods

A systematic literature search was conducted to identify and review published literature relevant to the efficacy, effectiveness and safety of HD-IIV, aIIV, and RIV compared with unadjuvanted SD-IIVs and with one another. Literature search strategies are summarized in Appendix 2. Outcomes of interest were identified by the ACIP Influenza Work Group.  Randomized and observational studies (traditional and test-negative case-control, retrospective and prospective cohort designs) were included. Immunogenicity data were excluded.  Studies reporting estimates of relative efficacy/effectiveness or reporting safety outcomes of relevant intervention and comparator vaccines were included in GRADE. For efficacy and effectiveness outcomes, data from influenza pandemic periods were excluded.  For multi-season studies, efficacy and effectiveness data were examined by season where season-specific estimates were provided. Estimates from observational studies of absolute effectiveness separately reported for HD-IIV, aIIV, RIV, and SD-IIVs compared with placebo, no vaccination, or non-influenza control vaccines were not included in GRADE. For observational studies reporting only influenza event counts but no relative effect estimate, crude estimates were not calculated.

Table 1: Policy Question and PICO

Table 1: Policy Question and PICO
Policy question: Do the relative benefits and harms of HD-IIV, aIIV, and RIV (referred to collectively as Higher Dose and Adjuvanted Influenza Vaccines) as compared with one another and with standard-dose unadjuvanted inactivated influenza vaccines (SD-IIVs) favor the use of any one or more of these vaccines over other age-appropriate influenza vaccines for persons ≥65 years of age?
Population Persons aged ≥65 years
Intervention Trivalent or quadrivalent formulations of:
  • High-dose inactivated influenza vaccine (HD-IIV3/4)*
  • MF-59 adjuvanted inactivated influenza vaccine (aIIV3/4)*
  • Recombinant influenza vaccine (RIV3/4)*
Comparison Age-appropriate trivalent or quadrivalent influenza vaccines.*  Relevant comparisons are:
  • HD-IIV3/4 vs standard-dose unadjuvanted inactivated influenza vaccines (SD-IIV3/4)
  • aIIV3/4 vs SD-IIV3/4
  • RIV3/4 vs SD-IIV3/4
  • HD-IIV3/4 vs aIIV3/4
  • HD-IIV3/4 vs RIV3/4
  • aIIV3/4 vs RIV3/4
Outcomes Benefits†:
  • Influenza illness
  • Influenza-associated outpatient/ER visits
  • Influenza-associated hospitalizations
  • Influenza-associated deaths

Harms:

  • Solicited injection site adverse events Grade ≥3
  • Solicited injection site adverse events Grade ≥3
  • Any Serious Adverse Event (SAE)
  • Guillain-Barré syndrome

* Licensed and available for us in the United States for persons ages 65 years and older, or similar in manufacturing, formulation, and route of administration to such vaccines.

† Defined through laboratory confirmation (other than serologic methods), diagnostic codes, or clinical definitions.

Table 2: Outcomes and Rankings

Table 2: Outcomes and Rankings
Outcome Importance Included in evidence profile
Influenza illness Critical Yes
Influenza-associated outpatient/ER visits Critical Yes
Influenza-associated hospitalizations Critical Yes
Influenza-associated deaths Critical Yes
Any solicited systemic adverse events Grade ≥3 Critical Yes
Guillain-Barré syndrome Critical Yes
Any solicited injection site adverse event Grade ≥3 Important Yes
Any Serious Adverse Event (SAE) Important Yes

* Three options: 1. Critical for decision making; 2.  Important but not critical for decision making; 3. Not important for decision making

Table 3a: Summary of Studies Reporting Outcome: Influenza illnesses (Critical)

Table 3a: Summary of Studies Reporting Outcome: Influenza illnesses (Critical)
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV3—Randomized studies
DiazGranados 2014 (7) ≥65 years 15,990 15,993 SD-IIV3 RR: 0.76 (0.64, 0.90) Low
aIIV3 vs SD-IIV3—Randomized studies
Frey 2014 (10) ≥65 years 3,479 3,482 SD-IIV3 RR: 1.03 (0.89, 1.19)† Low
RIV3 vs SD-IIV3–Randomized studies
Keitel 2010 (11) ≥65 years 436 433 SD-IIV3 RR: 0.50 (0.05, 5.46)† Unclear
RIV4 vs SD-IIV4–Randomized studies
Dunkle 2017 (8) ≥65 years 1,732 1,710 SD-IIV4 RR: 0.83 (0.58, 1.19) Low
HD-IIV3 vs aIIV3–Randomized studies
Belongia 2020 (12) 65-74 years 29 30 aIIV3 RR: 0.34 (0.04, 3.13)† High
HD-IIV3 vs RIV4–Randomized studies
Belongia 2020 (12) 65-74 years 29 30 RIV4 RR: 0.26 (0.03, 2.18)† High
aIIV3 vs RIV4–Randomized studies
Belongia 2020 (12) 65-74 years 30 30 RIV4 RR: 0.75 (0.18, 3.07)† High

Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

†No risk estimate reported. RR is calculated from reported counts.

Table 3b: Summary of Studies Reporting Outcome: Influenza outpatient/ER visits

Table 3b: Summary of Studies Reporting Outcome: Influenza outpatient/ER visits
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV—Observational studies
Balasubramani 2020 (13)† ≥65 years 1,573 1,420 SD-IIV3/4 OR: 0.91 (73, 1.12) Moderate
Izurieta 2015 (14) ≥65 years 929,730 1,615,545 SD-IIV3 Rate ratio:
0.78 (0.71, 0.86)
Serious
Izurieta 2019 (15) ≥65 years 8,488,136 1,822,862 SD-IIV4 (egg-based) Rate ratio:
0.99 (0.97, 1.02)
Serious
Shay 2017 (16) ≥65 years 2,547,821 3,560,591 SD-IIV3 Rate ratio:
0.85 (0.80, 0.90)
Serious
Young-Xu 2018 (17) ≥65 years 24,682 49,091 SD-IIV3 Rate ratio:
0.86 (0.68, 1.08)
Serious
aIIV3 vs SD-IIV—Observational studies
Iob 2005 (18) ≥65 years 1,487 1,478 SD-IIV3 OR: 0.66 (0.53, 0.82) Serious
Izurieta 2019 (15) ≥65 years 1,466,918 1,822,862 SD-IIV4 (egg-based) Rate ratio:
1.07 (1.04, 1.10)
Serious
Pelton 2020 (19) ≥65 years 234,313 212,287 SD-IIV4 Rate ratio:
0.64 (0.59, 0.69)
Serious
Van Buynder 2013 (9) ≥65 years 165 62 SD-IIV3 OR: 0.37 (0.14, 0.98) Serious
HD-IIV3 vs aIIV3—Observational studies
Izurieta 2019 (15) ≥65 years 1,466,918 8,488,136 HD-IIV3 vs aIIV3 Rate ratio:
0.93 (0.91, 0.95)
Serious
Pelton 2020 (20) ≥65 years 1,269,855 234,313 HD-IIV3 vs aIIV3 Rate ratio:
1.20 (1.12, 1.28)
Serious
Pelton 2021 (21) ≥65 years 1,672,797 561,243 HD-IIV3 vs aIIV3 Rate ratio:
1.07 (1.03, 1.13)
Serious

Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; OR = odds ratio; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

†Analyses included cases associated with influenza A viruses only.

Table 3c: Summary of Studies Reporting Outcome: Influenza hospitalizations

Table 3c: Summary of Studies Reporting Outcome: Influenza hospitalizations
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV–Randomized studies
DiazGranados 2015a (22) ≥65 years 15,990 15,993 HD-IIV3 vs SD-IIV3 Rate Ratio:
0.67 (0.19, 2.36)
Unclear
Vardeny 2021 (23) Mean age 65.5, SD 12.6/12.5 yrs 2,606 2,604 HD-IIV3 vs SD-IIV4 Rate Ratio:
1.25 (0.49, 3.16)
Unclear
HD-IIV3 vs SD-IIV—Cluster Randomized studies
Gravenstein 2017 (24) ≥65 years 19,127 19,129 HD-IIV3 vs SD-IIV3 RR: 0.79 (0.66, 0.95) Unclear
HD-IIV3 vs SD-IIV—Observational studies
Doyle 2021 (25) ≥65 years 622 485 HD-IIV3 vs SD-IIV OR: 0.74 (0.53, 1.02) Serious
Izurieta 2019 (15) ≥65 years 8,488,136 1,822,862 HD-IIV3 vs SD-IIV4 Rate ratio:
0.90 (0.88, 0.92)
Serious
Izurieta 2020 (20) ≥65 years 7,905,252 1,454,340 HD-IIV3 vs SD-IIV4 Rate ratio:
0.95 (0.91, 0.99)
Serious
Izurieta 2021(21) ≥65 years 7,173,433 1,584,451 HD-IIV3 vs SD-IIV4 Rate ratio:
0.93 (0.89, 0.98)
Serious
Lu 2019 (26) ≥65 years 13,770,207 6,151,913 HD-IIV3 vs SD-IIV Rate ratio:
0.88 (0.28, 0.94)
Serious
Paudel 2020 (27) ≥65 years Outpatient cohort:
2796994
Pharmacy cohort:
2760882
Outpatient cohort:
2996994
Pharmacy cohort:
2760882
HD-IIV3 vs SD-IIV Outpatient cohort:
Rate ratio
0.96 (0.94, 0.99)
Pharmacy cohort
Rate ratio
0.93 (0.90, 0.97)
Serious
Richardson 2015 (28) ≥65 years 25714 139511 HD-IIV3 vs SD-IIV Rate ratio:
0.98 (0.69, 1.40)
Serious
Robison 2018 (29) ≥65 years 23712 23712 HD-IIV3 vs SD-IIV Rate ratio:
0.69 (0.52, 0.92)
Serious
Young-Xu 2018 (17) ≥65 years 24862 49091 HD-IIV3 vs SD-IIV Rate ratio:
0.75 (0.57, 0.99)
Serious
Young-Xu 2019 (30) ≥65 years 158636 person-seasons 3480288 person-seasons HD-IIV3 vs SD-IIV Rate ratio: 0.87 (0.81, 0.94) Serious
aIIV3 vs SD-IIV—Cluster Randomized studies
McConeghy 2020 (31) ≥65 years 24926 25086 aIIV3 vs SD-IIV HR: 0.79 (0.65, 0.96) Unclear
aIIV3 vs SD-IIV—Observational studies
Cocchio 2020 (32) ≥65 years 68660 410737 SD-IIV3/4 OR: 0.37 (0.59, 0.75) Serious
Izurieta 2019 ≥65 years 1466918 1822862 aIIV3 vs SD-IIV Rate Ratio:
0.98 (0.94, 1.01)
Serious
Izurieta 2020 (33) ≥65 years 2100592 1454340 aIIV3 vs SD-IIV Rate Ratio:
0.93 (0.89, 0.99)
Serious
Izurieta 2021 (21) ≥65 years 2545513 1584451 aIIV3 vs SD-IIV Rate Ratio:
0.93 (0.88, 0.99)
Serious
Mannino 2012 (34) ≥65 years 64665 person- seasons 79589 person-seasons aIIV3 vs SD-IIV OR: 0.75 (0.57, 0.98) Serious
Pebody 2020 (35) ≥65 years 818 17 aIIV3 vs SD-IIV OR: 0.70 (0.27, 1.83) Moderate
RIV vs SD-IIV—Observational studies
Izurieta 2021 (21) ≥65 years 608433 1584451 RIV vs SD-IIV4 Rate ratio:
0.83 (0.76, 0.91)
Serious
HD-IIV3 vs aIIV3—Observational studies
Izurieta 2019 (15) ≥65 years 8488136 1466918 HD-IIV3 vs aIIV3 Rate ratio:
0.92 (0.90, 0.95)
Serious
Izurieta 2020 (20) ≥65 years 7905252 2100592 HD-IIV3 vs aIIV3 Rate ratio:
1.01 (0.98, 1.05)
Serious
Izurieta 2021 (21) ≥65 years 7173433 2565513 HD-IIV3 vs aIIV3 Rate ratio:
1.0 (0.96, 1.04)
Serious
Van Aalst 2020 (36) ≥65 years 1900920 223793 HD-IIV3 vs aIIV3 Rate ratio:
0.88 (0.80, 0.97)
Serious
HD-IIV3 vs RIV4—Observational studies
Izurieta 2021 (21) ≥65 years 7173433 608433 HD-IIV3 vs RIV4 Rate ratio:
1.12 (1.03, 1.21)
Serious
aIIV3 vs RIV4—Observational studies
Izurieta 2021 (21) ≥65 years 2565513 608433 aIIV3 vs RIV4 Rate ratio:
1.12 (1.03, 1.22)
Serious

Table 3d: Summary of Studies Reporting Outcome: Influenza deaths

Table 3d: Summary of Studies Reporting Outcome: Influenza deaths
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV—Observational
Shay 2017 (16) ≥65 years 2,547,821
(30,079,255 person-weeks)
3,560,591
42,696,182 person-weeks)
SD-IIV3 RR: 0.77 (0.58, 1.00) Serious
Young-Xu 2020 (33) ≥65 years 207,574 361,978 SD-IIV3 RR: 0.62 (0.46, 0.82) Moderate

Abbreviations: HD-IIV3 = high dose inactivated influenza vaccine, trivalent; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

Table 3e: Summary of Studies Reporting Outcome: Any Solicited Systemic AE Grade ≥3 (Critical)>

Table 3e: Summary of Studies Reporting Outcome: Any Solicited Systemic AE Grade ≥3 (Critical)
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV–Randomized studies
Couch 2007 (57) ≥65 years 206 208 HD-IIV3 vs SD-IIV3 RR: 3.03 (0.12, 73.93) Unclear
Cowling 2020 (37) 65 through 82 years 510 508 HD-IIV3 vs SD-IIV4 RR: 0.66 (0.11, 3.96) Low
Keitel 2006 (11) ≥65 years 50 51 HD-IIV3 vs SD-IIV3 RR: not estimable Unclear
aIIV3 vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 3/508 3/508 aIIV3 vs SD-IIV4 RR: 1.00 (0.20, 4.93) Low
Menegon 1999 (38) ≥65 years 96 98 aIIV3 vs SD-IIV3 RR: not estimable Unclear
Scheifele 2013 (39) ≥65 years 301 307 aIIV3 vs SD-IIV3 RR: 0.61 (0.23, 1.66) Low
Seo 2014 (40) ≥65 years 111 113 aIIV3 vs SD-IIV3 RR: 3.05 (0.13, 74.16) Unclear
RIV3 vs SD-IIV–Randomized studies
Keitel 2010 (41) ≥65 years 436 433 RIV3 vs SD-IIV3 RR: 0.33 (0.03, 3.17) Unclear
RIV4 vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 335 508 RIV4 vs SD-IIV4 RR: 0.22 (0.01, 4.18) Low
HD-IIV3 vs aIIV3–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 508 HD-IIV3 vs aIIV3 RR: 0.66 (0.11, 3.96) Low
Schmader 2021 (42) ≥65 years 377 378 HD-IIV3 vs aIIV3 RR: 0.75 (0.26, 2.15) Low
HD-IIV3 vs RIV4–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 335 HD-IIV3 vs RIV4 RR: 3.29 (0.16, 68.27) Low
Shinde 2019 (43) ≥65 years 153 151 HD-IIV3 vs RIV4 RR: 0.49 (0.09, 2.65) Low
aIIV3 vs RIV4–Randomized studies
Cowling 2020 (37) 65 through 82 years 508 335 aIIV3 vs RIV4 RR: 4.62 (0.24, 89.17) Low

Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3  = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

Table 3f: Summary of Studies Reporting Outcome: Guillain-Barré syndrome (Critical)

Table 3f: Summary of Studies Reporting Outcome: Guillain-Barré syndrome (Critical)
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV4–Randomized studies
Vardeny 2021 (23) Mean age 65.5, SD 12.6/12.5 yrs 2,606 2,604 SD-IIV4 Not estimable Low
aIIV3 vs SD-IIV3–Randomized studies
Frey 2014 (10) ≥65 years 3,479 3,481 SD-IIV3 Not estimable Low
aIIV3 vs SD-IIV3—Observational studies
Villa 2013 (44) ≥65 years 88,449 vaccine doses over 3 seasons
(6-week window)
82,539
vaccine doses over 3 seasons
(6-week window)
SD-IIV3 RD: 0
Risk with aIIV3:
(0, 4.47)
Risk with aIIV3:
(0, 4.17)
Serious
RIV3 vs SD-IIV3—Observational studies
Hansen 2020 (45) ≥18 years 21,976 28,3683 SD-IIV3 Outpatient, 0-41 days:
OR: 0 (0, 16.066
Inpatient/ER, 0-41 days:
OR: 0 (0, 112.6)
Moderate
HD-IIV3 vs aIIV3–Randomized studies
Schmader 2021 (42) ≥65 years 377 378 aIIV4 Not estimable Low

Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; OR = odds ratio; RD = risk difference; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

Table 3g: Summary of Studies Reporting Outcome: Any Serious Adverse Event (SAE) (Important)

Table 3g: Summary of Studies Reporting Outcome: Any Serious Adverse Event (SAE) (Important)
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 508 HD-IIV3 vs SD-IIV4 RR: 0.77 (0.34, 1.73) Low
DiazGranados 2014 ≥65 years 15,992 15,991 HD-IIV3 vs SD-IIV3 RR: 0.92 (0.85, 0.99) Low
Falsey 2009 (46) ≥65 years 2,541 1,240 HD-IIV3 vs SD-IIV3 RR: 0.83 (0.65, 1.07) Unclear
Keitel 2006 (11) ≥65 years 50 51 HD-IIV3 vs SD-IIV3 RR: 1.02 (0.22, 4.82) Unclear
Nace 2015 (47) ≥65 years 89 98 HD-IIV3 vs SD-IIV3 RR: 0.92 (0.29, 2.90) High
Tsang 2014 (48) ≥65 years 320 319 HD-IIV3 vs SD-IIV3 RR: 0.76 (0.40, 1.43) Unclear
Vardeny 2021 (23) Mean age 65.5, SD 12.6/12.5 yrs 2,606 2,604 HD-IIV3 vs SD-IIV4 RR: 0.50 (0.09, 2.73) Low
aIIV3 vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 508 508 aIIV3 vs SD-IIV4 RR: 0.65 (0.38, 1.87) Low
De Bruijn 2007 (49) ≥65 years 130 129 aIIV3 vs SD-IIV3 RR: 2.98 (0.12, 72.41) High
De Donato 1999 (50) ≥65 years 248 233 aIIV3 vs SD-IIV3 RR: 0.78 (0.24, 2.53) High
Della Cioppa 2012 (50) ≥65 years 47 44 aIIV3 vs SD-IIV3 RR: 0.31 (0.01, 7.47) High
Frey 2014 (10) ≥65 years 3,545 3,537 aIIV3 vs SD-IIV3 RR: 1.08 (0.92, 1.28) Low
Li 2008 (51) ≥65 years 391 198 aIIV3 vs SD-IIV3 RR: 2.03 (0.23, 18.00) High
Scheifele 2013 (39) ≥65 years 301 307 aIIV3 vs SD-IIV3 RR: 1.18 (0.57, 2.43) Low
Sindoni 2009 (52) ≥65 years 96 99 aIIV3 vs SD-IIV3 RR: Not estimable Unclear
RIV vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 335 508 RIV4 vs SD-IIV4 RR: 0.47 (0.15, 1.42) Low
Dunkle 2017 (8) ≥50 years 4,328 4,344 RIV4 vs SD-IIV4 RR: 1.10 (0.87, 1.39) Low
Izikson 2015 (53) ≥50 years 1,314 1,313 RIV3 vs SD-IIV3 RR: 0.50 (0.17, 1.46) Unclear
Keitel 2010 (41) ≥65 years 436 433 RIV3 vs SD-IIV3 RR: 1.05 (0.67, 1.65) Unclear
Treanor 2006 (54) ≥65 years 100 199 RIV3 vs SD-IIV3 RR: 0.99 (0.06, 15.61) Unclear
HD-IIV3 vs aIIV3–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 508 HD-IIV3 vs aIIV3 RR: 0.91 (0.39, 2.11) Low
Schmader 2021 (42) ≥65 years 377 378 HD-IIV3 vs aIIV3 RR: 0.33 (0.09, 1.22) Low
HD-IIV3 vs RIV4–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 335 HD-IIV3 vs RIV4 RR: 1.64 (0.52, 5.19) Low
Shinde 2019 (43) ≥65 years 153 151 HD-IIV3 vs RIV4 RR: 1.97 (0.50, 7.75) Low
aIIV3 vs RIV4–Randomized studies
Cowling 2020 (37) 65 through 82 years 508 335 aIIV3 vs RIV4 RR: 1.81 (0.58, 5.65) Low

Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3  = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

Table 3h: Summary of Studies Reporting Outcome: Any Solicited injection site AE Grade ≥3 (Important)

Table 3h: Summary of Studies Reporting Outcome: Any Solicited injection site AE Grade ≥3 (Important)
Author
Publication year
Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)
HD-IIV3 vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 508 HD-IIV3 vs SD-IIV4 RR: 3.98 (0.45, 35.52) Low
Keitel 2006 (11) ≥65 years 50 51 HD-IIV3 vs SD-IIV3 RR: 7.14 (0.38, 134.72) Unclear
aIIV3 vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 508 508 aIIV3 vs SD-IIV4 RR: 3.00 (0.31, 28.74) Low
Della Cioppa 2012 ≥65 years 47 44 aIIV3 vs SD-IIV3 RR: 2.81 (0.12, 67.27) High
Menegon 1999 (38) ≥65 years 96 98 aIIV3 vs SD-IIV3 RR: not estimable Unclear
Scheifele 2013 (39) ≥65 years 301 307 aIIV3 vs SD-IIV3 RR: 3.57 (1.19, 10.72) Low
RIV vs SD-IIV–Randomized studies
Cowling 2020 (37) 65 through 82 years 335 508 RIV4 vs SD-IIV4 RR: 0.50 (0.02, 12.36) Low
Keitel 2010 (41) ≥65 years 436 433 RIV3 vs SD-IIV3 RR: 0.70 (0.27, 1.81) Unclear
HD-IIV3 vs aIIV3–Randomized studies
Cowling 2020 (37) 65 through 82 years 510 508 HD-IIV3 vs aIIV3 RR: 1.33 (0.30, 5.90) Low
Schmader 2021 (42) ≥65 years 377 378 HD-IIV3 vs aIIV3 RR: 0.79 (0.36, 1.71) Low
HD-IIV3 vs RIV4–Randomized studies
Cowling 2020 (37) 65 through 82 years 508 335 HD-IIV3 vs RIV4 RR: 5.92 (0.32, 109.56) Low
Shinde 2019 (43) ≥65 years 153 151 HD-IIV3 vs RIV4 RR: not estimable Low
aIIV3 vs RIV4–Randomized studies
Cowling 2020 (37) 65 through 82 years 508 335 aIIV3 vs RIV4 RR: 4.62 (0.24, 89.17) Low

Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV3 = recombinant influenza vaccine, trivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.

*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.

Table 4a: Grade Summary of Findings Table: HD-IIV3 vs. SD-IIV

Table 4a: Grade Summary of Findings Table: HD-IIV3 vs. SD-IIV
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HD-IIV3 SD-IIV Relative
(95% CI)
Absolute
(95% CI)
Randomized studies: Influenza-associated Illness
1 randomized trials not serious not serious not serious not serious none 228/15990 (1.4%) 301/15993 (1.9%) RR 0.76
(0.64 to 0.90)
45 fewer per 10,000
(from 65 fewer to 19 fewer)
Level 1
High
CRITICAL
Observational studies (person-time denominator): influenza-associated outpatient/ER visits
4 observational studies very seriousa,b not serious not serious not serious none -/11001581* -/5658869* Rate ratio 0.87
(0.76 to 0.99)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
Observational studies (person denominator): influenza-associated outpatient/ER visits
1 observational studies very seriousc not serious not serious seriousd none 593/3141 (18.9%) 580/2840 (20.4%) RR 0.91
(0.73 to 1.12)
184 fewer per 10,000
(from 551 fewer to 245 more)
Level 4
Very low
CRITICAL
Randomized studies: Influenza-associated hospitalizations
2 randomized trials seriouse not serious not serious not serious none 14/18596 (0.1%) 14/18597 (0.1%) RR 1.00
(0.48 to 2.09)
0 fewer per 100,000
(from 4 fewer to 8 more)
Level 2
Moderate
CRITICAL
Randomized studies (cluster design): Influenza-associated hospitalizations
1 Cluster randomized trial seriousf not serious not serious not serious none 247/19127 309/19129 Rate ratio 0.79
(0.66 to 0.95)
— per 10,000
(from — to –)
Level 2
Moderate
CRITICAL
Observational studies (person-time denominator): influenza-associated hospitalizations
8 observational studies very seriousb not serious not serious not serious none -/43519865* -/20193377* Rate ratio 0.92
(0.90 to 0.94)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
Observational studies (person denominator): influenza-associated hospitalizations
2 observational studies very seriousg not serious not serious not serious none 177/24334 (0.7%) 201/24197 (0.8%) RR 0.71
(0.57 to 0.88)
24 fewer per 1,000
(from 36 fewer to 10 fewer)
Level 3
Low
CRITICAL
Observational studies (person-time denominator): Influenza-associated deaths
2 observational studies very seriousb not serious not serious not serious none -/2755395* -/3922569* Rate ratio 0.69
(0.57 to 0.84)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
Randomized studies: Any Serious Adverse Event (SAE)
7 randomized trials not serious not serious not serious not serious none 1518/22109 (6.7%) 1582/20811 (7.5%) RR 0.91
(0.85 to 0.97)
68 fewer per 10,000
(from 114 fewer to 23 fewer)
Level 1
High
IMPORTANT
Randomized studies: Solicited injection site events Grade 3 or higher
2 randomized trials not serious not serious not serious very serioush none 7/560 (1.3%) 1/559 (0.2%) RR 5.03
(0.88 to 28.74)
72 more per 10,000
(from 2 fewer to 496 more)
Level 3
Low
IMPORTANT
Randomized studies: Solicited systemic events Grade 3 or higher
2 randomized trials not serious not serious not serious very serioush none 3/766 (0.4%) 3/767 (0.4%) RR 0.95
(0.20 to 4.53)
2 fewer per 10,000
(from 31 fewer to 138 more)
Level 3
Low
CRITICAL
Randomized studies: Guillain-Barre syndrome
1 randomized trials not serious not serious not serious very seriousi none 0/2606 (0.0%) 0/2604 (0.0%) not estimable Level 3
Low
CRITICAL

*Counts not provided for all studies.

CI: confidence interval; RR: risk ratio

Explanations

  1. Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.
  2. Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed.
  3. Observational study.
  4. Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.
  5. Outcome either not laboratory-confirmed or defined by laboratory confirmation of unknown type not performed within the context of the study.
  6. Cluster randomized study, with ICD code-based outcome definition. Not blinded; randomization sequence generation and timing of recruitment of participants unclear.
  7. Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed for the larger of the studies.
  8. Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
  9. Not estimable

Table 4b: Grade Summary of Findings Table: aIIV3 vs. SD-IIV

Table 4b: Grade Summary of Findings Table: aIIV3 vs. SD-IIV
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations aIIV3 SD-IIV Relative
(95% CI)
Absolute
(95% CI)
Randomized studies: Influenza-associated Illness
1 randomized trials seriousa not serious not serious not serious none 322/3479 (9.3%) 314/3482 (9.0%) RR 1.03
(0.89 to 1.19)
27 more per 10,000
(from 99 fewer to 171 more)
Level 2
Moderate
CRITICAL
Observational studies (person-time denominator): influenza-associated outpatient/ER visits
2 observational studies very seriousb seriousc not serious not seriousd none -/1701231* -/2035149* Rate ratio 1.00
(0.97 to 1.03)
— per 10,000
(from — to –)
Level 4
Very low
CRITICAL
Observational studies (person denominator): influenza-associated outpatient/ER visits
2 observational studies very seriouse not serious not serious not serious none 344/1333 197/988 RR 0.64
(0.52 to 0.79)
718 fewer per 10,000
(from 957 fewer to 419 fewer)
Level 3
Low
CRITICAL
Randomized studies (cluster design): Influenza-associated hospitalizations
1 randomized trials seriousf not serious not serious not serious none 242/24926 309/25806 Rate ratio 0.79
(0.65 to 0.96)
25 per 10,000 patient(s) per years
(from 42 fewer to 5 fewer)
Level 2
Moderate
CRITICAL
Observational studies (person-time denominator): influenza-associated hospitalizations
4 observational studies very seriousg not serious not serious not serious none /6133023* -/4861653* Rate ratio 0.88
(0.80 to 0.97)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
Observational Studies (person denominator): Influenza-associated hospitalizations
2 observational studies very seriousg not serious not serious not serious none 230/85483 35/79610 0.75
(0.58 to 0.97)
1 fewer per 10,000
(from 2 fewer to 0 fewer)
Level 3
Low
CRITICAL
Randomized studies: Solicited systemic events Grade 3 or higher
4 randomized trials not serious not serious not serious very seriousi none 10/1016 (1.0%) 13/1026 (1.3%) RR 0.77
(0.34 to 1.76)
29 fewer per 10,000
(from 84 fewer to 96 more)
Level 3
Low
CRITICAL
Randomized Studies: Guillain-Barre syndrome
1 randomized trials not serious not serious not serious very seriousk none 0/3545 (0.0%) 1/3537 (0.0%) RR 0.33
(0.01 to 8.16)
2 fewer per 10,000
(from 3 fewer to 20 more)
Level 3
Low
CRITICAL
Observational studies: Guillain-Barre syndrome
1 observational studies seriousg not serious not serious very seriousk none 0/88449 (0.0%) 0/82539 (0.0%) not estimable Level 4
Very low
CRITICAL
Randomized studies: Any Serious Adverse Event (SAE)
8 randomized trials not serious not serious not serious serioush none 300/5266 (5.7%) 277/5055 (5.5%) RR 1.07
(0.92 to 1.26)
38 more per 10,000
(from 44 fewer to 142 more)
Level 2
Moderate
IMPORTANT
Randomized studies: Solicited injection site events Grade 3 or higher
4 randomized trials not serious not serious not serious very seriousi,j none 18/952 (1.9%) 5/957 (0.5%) RR 3.39
(1.32 to 8.72)
125 more per 10,000
(from 17 more to 403 more)
Level 3
Low
IMPORTANT

*Counts not provided for all studies.

CI: confidence interval; RR: risk ratio

Explanations

  1. Symptom-based outcome definition.
  2. Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.
  3. Disparate results for two studies conducted in the United States during the same season.
  4. Pooled estimate is derived from two estimates that are each relatively precise but sit on either side of the null with no CI overlap
  5. Majority of data come from studies in which outcome definition is not laboratory-confirmed.
  6. Cluster randomized study with ICD-code based outcome definitions. Not blinded; randomization sequence generation and timing of recruitment of participants unclear.
  7. Observational study/studies; outcome is ICD code defined rather than laboratory confirmed for all or larger studies.
  8. Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.
  9. Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
  10. CI ranges from slightly to substantially favoring comparator vaccine.
  11. Not estimable

Table 4c: Grade Summary of Findings Table: RIV3 vs. SD-IIV

Table 4c: Grade Summary of Findings Table: RIV3 vs. SD-IIV
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations RIV SD-IIV Relative
(95% CI)
Absolute
(95% CI)
Randomized studies: Influenza-associated Illness
2 randomized trials not serious not serious not serious seriousa none 53/2168 (2.4%) 64/2143 (3.0%) RR 0.82
(0.57 to 1.17)
54 fewer per 10,000
(from 128 fewer to 51 more)
Level 2
Moderate
CRITICAL
Observational studies (person-time denominator): influenza-associated hospitalizations
1 observational studies very seriousb not serious not serious not serious none 640/608433 2309/1584451 Rate ratio 0.83
(0.76 to 0.91)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
RCTs: Systemic events Grade 3 or higher
2 randomized trials not serious not serious not serious very seriousa none 1/771 (0.1%) 6/941 (0.6%) RR 0.28
(0.05 to 1.67)
5 fewer per 1,000
(from 6 fewer to 4 more)
Level 3
Low
CRITICAL
Guillain-Barre syndrome
1 observational studies seriousb not serious not serious very seriouse none 0/21976 (0.0%) 4/283683 (0.0%) not estimable Level 4
Very low
CRITICAL
Randomized studies: Any Serious Adverse Event (SAE)
5 randomized trials not serious not serious seriousc seriousd none 191/6513 (2.9%) 190/6697 (2.8%) RR 1.03
(0.84 to 1.26)
9 more per 10,000
(from 45 fewer to 74 more)
Level 3
Low
IMPORTANT
RCTs: Injection site events Grade 3 or higher
2 randomized trials not serious not serious not serious very seriousa none 7/771 (0.9%) 11/941 (1.2%) RR 0.67
(0.27 to 1.69)
39 fewer per 10,000
(from 85 fewer to 81 more)
Level 3
Low
IMPORTANT

CI: confidence interval; OR: odds ratio; RR: risk ratio

Explanations

  1. Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
  2. Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed.
  3. Population in this analysis includes persons ages 50 and older; slightly over half ages 50 through 64 years.
  4. Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.
  5. Not estimable

Table 4d: Grade Summary of Findings Table: HD-IIV3 vs. aIIV3

Table 4d: Grade Summary of Findings Table: HD-IIV3 vs. aIIV3
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HD-IIV3 aIIV3 Relative
(95% CI)
Absolute
(95% CI)
Randomized studies: Influenza-associated Illness
1 randomized trials seriousa not serious not serious very seriousb none 1/29 (3.4%) 3/30 (10.0%) RR 0.34
(0.04 to 3.13)
660 fewer per 10,000
(from 960 fewer to 2130 more)
Level 4
Very low
CRITICAL
Observational studies (person-time denominator): influenza-associated outpatient/ER visits
3 observational studies very seriousc seriousd not serious not seriouse none -/11430788* -/2262474* Rate ratio 1.06
(0.92 to 1.23)
— per 10,000
(from — to –)
Level 4
Very low
CRITICAL
Observational studies (person-time denominator): influenza-associated hospitalizations
4 observational studies very seriousf not serious not serious seriousg none -/25467741* -/6356816* Rate ratio 0.96
(0.90 to 1.01)
— per 10,000
(from — to –)
Level 4
Very low
CRITICAL
Randomized studies: Solicited systemic events Grade 3 or higher
2 randomized trials not serious not serious not serious very seriousb none 8/887 (0.9%) 11/886 (1.2%) RR 0.73
(0.29 to 1.80)
34 fewer per 10,000
(from 88 fewer to 99 more)
Level 3
Low
CRITICAL
Randomized studies: Guillain-Barre syndrome
1 randomized trials not serious not serious not serious very serioush none 0/377 (0.0%) 0/378 (0.0%) not estimable Level 3
Low
CRITICAL
Randomized studies: Any Serious Adverse Event (SAE)
2 randomized trials not serious not serious not serious very seriousb none 13/887 (1.5%) 20/886 (2.3%) RR 0.65
(0.32 to 1.30)
79 fewer per 10,000
(from 153 fewer to 68 more)
Level 3
Low
IMPORTANT
Randomized studies: Solicited injection site events Grade 3 or higher
2 randomized trials not serious not serious not serious very seriousb none 15/887 (1.7%) 17/886 (1.9%) RR 0.88
(0.45 to 1.75)
23 fewer per 10,000
(from 106 fewer to 144 more)
Level 3
Low
IMPORTANT

*Event counts not provided for all studies.

CI: confidence interval; RR: risk ratio

Explanations

  1. Open-label study.
  2. Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
  3. Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.
  4. Disparate estimates from two different studies conducted over the same influenza season.
  5. Width of confidence interval derives from inconsistency of estimates that are each on their own precise but which lie on opposite sides of null.
  6. Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code-defined rather than laboratory-confirmed.
  7. Confidence interval includes null and indicates potential for either meaningful effect or no difference.
  8. Not estimable

Table 4e: Grade Summary of Findings Table: HD-IIV3 vs. RIV4

Table 4e: Grade Summary of Findings Table: HD-IIV3 vs. RIV4
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HD-IIV3 RIV4 Relative
(95% CI)
Absolute
(95% CI)
Randomized studies: Influenza-associated Illness
1 randomized trials seriousa not serious not serious very seriousb none 1/29 (3.4%) 4/30 (13.3%) RR 0.26
(0.03 to 2.18)
987 fewer per 10,000
(from 1,293 fewer to 1,573 more)
Level 4
Very low
CRITICAL
Observational studies (person-time denominator): influenza-associated hospitalizations
1 observational studies very seriousc not serious not serious not serious none 81492/7173433 640/608433 Rate ratio 1.12
(1.03 to 1.21)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
Randomized studies: Solicited systemic events Grade 3 or higher
2 randomized trials not serious not serious not serious very seriousb none 4/663 (0.6%) 4/486 (0.8%) RR 0.86
(0.22 to 3.32)
12 fewer per 10,000
(from 64 fewer to 191 more)
Level 3
Low
CRITICAL
Randomized studies: Any Serious Adverse Event (SAE)
2 randomized trials not serious not serious not serious very seriousb none 16/663 (2.4%) 7/486 (1.4%) RR 1.77
(0.73 to 4.27)
111 more per 10,000
(from 39 fewer to 471 more)
Level 3
Low
IMPORTANT
Randomized studies: Solicited injection site events Grade 3 or higher
2 randomized trials not serious not serious not serious very seriousb none 4/663 (0.6%) 0/486 (0.0%) RR 5.92
(0.32 to 109.56)
0 fewer per 100,000
(from 0 fewer to 0 fewer)
Level 3
Low
IMPORTANT

CI: confidence interval; RR: risk ratio

Explanations

  1. Open-label study.
  2. Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
  3. Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code-defined rather than laboratory-confirmed.

Table 4f: Grade Summary of Findings Table: aIIV vs. RIV4

Table 4f: Grade Summary of Findings Table: aIIV vs. RIV4
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations aIIV3 RIV4 Relative
(95% CI)
Absolute
(95% CI)
Randomized studies: Influenza-associated Illness
1 randomized trials seriousa not serious not serious very seriousb none 3/30 (10.0%) 4/30 (13.3%) RR 0.75
(0.18 to 3.07)
333 fewer per 10,000
(from 1,093 fewer to 2,760 more)
Level 4
Very low
CRITICAL
Observational studies (person-time denominator): influenza-associated hospitalizations
1 observational studies very seriousc not serious not serious not serious none 2783/2565513 640/608433 Rate ratio 1.12
(1.03 to 1.22)
— per 10,000
(from — to –)
Level 3
Low
CRITICAL
Randomized studies: Solicited systemic events Grade 3 or higher
1 randomized trials not serious not serious not serious very seriousb none 3/508 (0.6%) 0/335 (0.0%) RR 4.62
(0.24 to 89.17)
0 fewer per 10,000
(from 0 fewer to 0 fewer)
Level 3
Low
CRITICAL
Randomized studies: Any Serious Adverse Event (SAE)
1 randomized trials not serious not serious not serious very seriousb none 11/508 (2.2%) 4/335 (1.2%) RR 1.81
(0.58 to 5.65)
97 more per 10,000
(from 50 fewer to 555 more)
Level 3
Low
IMPORTANT
Randomized studies: Solicited injection site events Grade 3 or higher
1 randomized trials not serious not serious not serious very seriousb none 3/508 (0.6%) 0/335 (0.0%) RR 4.62
(0.24 to 89.17)
0 fewer per 100,000
(from 0 fewer to 0 fewer)
Level 3
Low
IMPORTANT

CI: confidence interval; RR: risk ratio

Explanations

  1. Open-label study.
  2. Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
  3. Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code-defined rather than laboratory-confirmed.

Table 5: Summary of Evidence for Outcomes of Interest

Table 5: Summary of Evidence for Outcomes of Interest
Certainty, by comparison
Vaccines of interest vs SD-IIVs EIVs vs one another
Outcome Importance Included in profile? HD-IIV3 vs
SD-IIV
aIIV3 vs
SD-IIV
RIV vs
SD-IIV
HD-IIV3 vs
aIIV3
HD-IIV3 vs
RIV4
aIIV3 vs
RIV4
BENEFITS
Influenza illnesses Critical Yes Level 1
High
Level 2
Moderate
Level 2
Moderate
Level 4
Very low
Level 4
Very low
Level 4
Very low
Influenza outpatient/ER visits Critical Yes Level 3
Low
Level 3
Low
Level 4
Very Low
Influenza hospitalizations Critical Yes Level 2
Moderate
Level 2
Moderate
Level 3
low
Level 4
Very Low
Level 3
Low
Level 3
Low
Influenza deaths Critical Yes Level 3
Low
HARMS
Any Serious Adverse Event (SAE) Important Yes Level 1
High
Level 2
Moderate
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Solicited injection site adverse events Grade ≥3 Important Yes Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Solicited systemic
adverse events Grade ≥3
Critical Yes Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Guillain-Barré syndrome Critical Yes Level 3
Low
Level 3
Low
Level 4
Very low
Level 3
Low
OVERALL: Level 3
Low
Level 3
Low
Level 4
Very low
Level 4
Very low
Level 4
Very low
Level 4
Very low

Appendix 1: Studies Included in the Review of Evidence

Appendix 1: Studies Included in the Review of Evidence
Last name first author,
Publication year
Study design Country Age Total population N
Intervention
N
comparison
Outcomes Funding source
Balasubramani 2020 (13) TNCC US
(US Flu VE Network)
≥65 years 2,993 1,573 HD-IIV3 1,420 SD-IIV3/4 Outpatient/ER US government
Belongia 2020 (12) Randomized US 65 through 74 years 99 29  HD-IIV3
30 aIIV3
30 RIV4
Illnesses US government
Cocchio 2020 (18) Retro. cohort Italy ≥65 years 479,397 68660 aIIV3 410,737
Conventional vaccine strategy (classified as use in ≥90% of cases)
Hospitalizations No external funding.
Couch 2007 (57) Randomized US ≥65 years 214 206 HD-IIV3 208 SD-IIV3 Reactogenicity US government
Cowling 2020 (37) Randomized Hong Kong 65 through 82 years 1,861 510 HD-IIV3
508 aIIV3
335 RIV4
508 SD-IIV4 SAEs
Reactogenicity
US government
DiazGranados 2014 (7) Randomized US/Canada ≥65 years 31,983 15,993
HD-IIV3
15,990 SD-IIV3 Illnesses
SAEs
Sanofi Pasteur
DiazGranados 2015 (22) Randomized US
Canada
≥65 years 31,983 15,993
HD-IIV3
15,990 SD-IIV3 Hospitalizations Sanofi Pasteur
De Bruijn 2007 (49) Randomized Germany, Sweden, Lithuania, Bulgaria ≥61 years 259 130 aIIV3 129 SD-IIV3 SAEs Unclear; Solvay authors.
De Donato 1999 (50) Randomized Italy ≥65 years 481 248 aIIV3 233 SD-IIV3 SAEs Unclear; Chiron authors.
Della Cioppa 2012 (55) Randomized Poland, Belgium, Germany ≥65 years 91 47 aIIV3 44 SD-IIV3 SAEs Novartis
Doyle 2021 (25) TNCC US
(HAIVEN)
≥65 years 1,107 622 HD-IIV3 485 SD-IIV Hospitalization US government
Dunkle 2017 (8) Randomized US ≥50 years 9,003 ≥50 yrs
3,452 ≥65 yrs
4,498 ≥50 yrs
1,743 ≥65 yrs
RIV4
4,505 ≥50
1,710 ≥65
SD-IIV4
Illnesses
SAEs
BARDA; Protein Sciences authors
Falsey 2009 (46) Randomized US ≥65 years 3,781 2,541 HD-IIV3 1,240 SD-IIV3 SAEs Sanofi Pasteur
Frey 2014 (10) Randomized US, Colombia,
Panama
Philippines
≥65 years 6,961 3,479 HD-IIV3 3,482 SD-IIV3 Illnesses
SAEs
Reactogenicity
GBS
Novartis
Gravenstein 2017 (24) Cluster Randomized US ≥65 years 53,008 26,639 HD-IIV3 26,369 SD-IIV3 Hospitalization Sanofi Pasteur
Iob 2005 (18) Cohort Italy Mean 85 years, range 23-100 (3.65% were <65 years) 2,966 1,487 aIIV3 1,479 SD-IIV3 Illnesses Not stated
Izikson 2015 (53) Randomized US ≥50 years 2,627 1,314 RIV3 1,313 SD-IIV3 SAEs BARDA; Protein Sciences authors
Izurieta 2015 (14) Retro. cohort US
(Medicare)
≥65 years 2,545,275 929,730 HD-IIV3 1,615,545
SD-IIV3
Outpatient/ER US government
Izurieta 2019 (15) Retro. Cohort US
(Medicare)
≥65 years 11,737,916 8,488,136
HD-IIV3
1,466,918
aIIV3
1,822,862
SD-IIV4
Outpatient/ER,
Hospitalizations
US government
Izurieta 2020 (20) Retro. Cohort US
(Medicare)
≥65 years 11,717,822 7,905,252
HD-IIV3
2,100,512
aIIV3
257,718
RIV4
1,454,340
SD-IIV4
Hospitalizations US government
Izurieta 2021 (21) Retro. cohort US
(Medicare)
≥65 years 11,931,830 7,173,433
HD-IIV3
2,565,513
aIIV3
608,433
RIV4
1,584,451
SD-IIV4
Hospitalizations US government
Hansen 2020 (45) Retro. cohort US ≥65 years 305,659 21,976 RIV3 283,683 SD-IIV3 GBS Protein Sciences
Keitel 2006 (11) Randomized US ≥65 years 101 50 HD-IIV3 51 SD-IIV3 SAEs
Reactogenicity
US government
Keitel 2010 (41) Randomized US ≥65 years 869 436 RIV3 433 SD-IIV3 SAEs
Reactogenicity
Unclear; Protein Sciences author
Li 2008 (51) Randomized China ≥60 years 589 391 aIIV3 198 SD-IIV3 SAEs Novartis
Lu 2019 (26) Retro. cohort US ≥65 years 19,922,120 13,770,207
HD-IIV3
6,151,913
SD-IIV
Hospitalizations US government
Mannino 2012 (34) Prospective cohort Italy ≥65 years 164,254 person-seasons 84,665 person-seasons 79,589
person-seasons
Hospitalizations Novartis
McConeghy 2020 (31) Cluster Randomized US ≥65 years 50,012 24,926 aIIV3 25,086 SD-IIV3 Hospitalization Seqirus
Menegon 1999 (38) Randomized Italy Mean 68.6 years, range 23-97 194 96 aIIV3 98 HD-IIV3 Reactogenicity Ministry grant
Nace 2015 (47) Randomized US ≥65 years 187 89 HD-IIV3 98 SD-IIV3 SAEs Sanofi Pasteur
Paudel 2020 (27) Retro. cohort US ≥65 years 2,420,450
Pharmacy cohort
2,421,758
Outpatient cohort
1210225
Pharmacy cohort
1,210,879
Outpatient cohort
1,210,225
Pharmacy cohort
1,210,879
Outpatient cohort
Hospitalizations Sanofi Pasteur
Pebody (35) TNCC UK ≥65 years 835 818 17 Hospitalizations UK Government
Pelton 2020 (19) Retro. cohort US ≥65 years 446,600 1,269,855 HD-IIV3
234,313
aIIV3
212,287
SD-IIV
Outpatient/ER Seqirus
Pelton 2021 (56) Retro. cohort US ≥65 years 2,234,040 1,672,797
HD-IIV3
561,243
aIIV3
Outpatient/ER Funding not stated. Seqirus authors.
Richardson 2015 (28) Retro. cohort US
(VA)
≥65 years 165,225 25,714 HD-IIV3 139,511 SD-IIV Hospitalizations US government
Robison 2018 (29) Matched cohort US ≥65 years 47,424 23,712 HD-IIV3 23,712 SD-IIV Hospitalizations Funding not stated.  No industry authors.
Shay 2017 (16) Retro. cohort US
(Medicare)
≥65 years 9,722,909 1,039,645
HD-IIV3
1,683,264
SD-IIV3
Outpatient/ER
Deaths
US government
Scheifele 2013 (39) Randomized Canada ≥65 years 608 301 aIIV3 307 SD-IIV3 SAEs
Reactogenicity
Canadian government
Schmader 2021 (42) Randomized US ≥65 years 755 378 aIIV3
377 HD-IIV3
SAEs
Reactogenicity
GBS
US government
Seo 2014 (40) Randomized S. Korea ≥65 years 224 113 aIIV3 111 SD-IIV3 Reactogenicity S. Korean government
Sindoni 2009 (52) Randomized Italy ≥65 years 195 96 aIIV3 99 SD-IIV3 SAEs Not stated. No industry authors.
Shinde 2022 (43) Randomized US ≥65 years 304 153 HD-IIV3
151 RIV5
SAEs
Reactogenicity
GBS
Novavax
Treanor 2006 (54) Randomized US ≥65 years 199 100 RIV3 99 SD-IIV3 SAEs US government; Protein Sciences author
Tsang 2014 (48) Randomized US ≥65 years 639 320 HD-IIV3 319 SD-IIV3 SAEs Sanofi Pasteur
Van Aalst 2020 (36) Retro. cohort US ≥65 years 2,124,713 1,900,920
HD-IIV3
223,793
aIIV3
Hospitalizations Sanofi Pasteur
Van Buynder 2013 (9) TNCC Canada ≥65 years 227 165 aIIV3 62 SD-IIV3 Outpatient/ER Unrestricted grant, Novartis; Fraser Health Authority
Vardeny 2021 (30) Randomized US, Canada Mean 65.5 (SD 12) years 5,260 2,630 HD-IIV3 2,630 SD-IIV4 Hospitalization US government, Sanofi Pasteur
Villa 2013 (44) Retro. Cohort Italy ≥65 years 170,988 88,449 aIIV3 82,539 SD-IIV3 GBS Unclear; Novartis authors.
Young-Xu 2018 (17) Retro. Cohort US
(VA)
≥65 years 73,773 24,682
HD-IIV3
49,091
SD-IIV3
Outpatient/ER,
Hospitalizations
Sanofi Pasteur; Sanofi authors
Young-Xu 2019 (30) Retro. Cohort US
(VA)
≥65 years 3,638,924 158,636
HD-IIV3
3,480,288
SD-IIV3
Hospitalizations Unrestricted grant, Sanofi Pasteur; Sanofi authors
Young-Xu 2020 (33) Retro. Cohort US
(VA)
≥65 years 569,552 person-seasons 207,574 person-seasons
HD-IIV3
361,978 person-seasons
SD-IIV3
Deaths Unrestricted grant, Sanofi Pasteur; Sanofi authors
Abbreviations: GBS = Guillain-Barré syndrome, HAIVEN = US Hospitalized Adult Influenza Vaccine Effectiveness Network, Retro. Cohort = retrospective cohort, SAE = Serious Adverse Event, TNCC = test negative case-control, VA = Veterans Administration

Appendix 2. Literature Search Strategies

Main search (1990 through September 7, 2021):

Main search (1990 through September 7, 2022):
Database Strategy
Medline
(OVID)
1946-
Exp influenza vaccines/ OR ((influenza ADJ5 vaccin*) OR (flu ADJ5 vaccin*) OR MF59* OR MF-59*).ti,ab. OR influenza vaccines.rn.

AND

Exp Aged/ OR ((65 ADJ5 older) OR (65 ADJ5 over) OR (65 ADJ5 between) OR older adult* OR older people OR older population OR senior* OR elderly)

AND

Adverse.fx OR ae.fs OR dosage.fx OR ad.fs OR (safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR adjuvanted OR recombinant OR HD-IIV3 OR aIIV OR RIV* OR inactivated OR Guillain-Barre OR hypersensitiv* OR anaphylaxis OR harm* OR benefit*)

 

Limit 1990 – ; update (201912* OR 2020* OR 2021*).dt

Embase
(OVID)
1988-
Exp influenza vaccine/ OR ((influenza ADJ5 vaccin*) OR (flu ADJ5 vaccin*) OR MF59* OR MF-59*).ti,ab. OR influenza vaccines.rn.

AND

Exp Aged/ OR ((65 ADJ5 older) OR (65 ADJ5 over) OR (65 ADJ5 between) OR older adult* OR older people OR older population OR senior* OR elderly)

AND

Adverse.fx OR ae.fs OR dosage.fx OR ad.fs OR (safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR adjuvanted OR recombinant OR HD-IIV3 OR aIIV OR RIV* OR inactivated OR Guillain-Barre OR hypersensitiv* OR anaphylaxis OR harm* OR benefit*)

 

Limit 1990 – ; NOT pubmed/medline ; update (201912* OR 2020* OR 2021*).dc

CINAHL
(Ebsco)
(MH “Influenza Vaccine”) OR ((influenza N5 vaccin*) OR (flu N5 vaccin*) OR MF59* OR MF-59*)

AND

(MH “Aged+”) OR ((65 N5 older) OR (65 N5 over) OR (65 N5 between) OR “older adult*” OR “older people” OR “older population” OR senior* OR elderly)

AND

(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR adjuvanted OR recombinant OR HD-IIV3 OR aIIV OR RIV* OR inactivated OR Guillain-Barre OR hypersensitiv* OR anaphylaxis OR harm* OR benefit*)

 

Limit 1990 – ; exclude Medline records; update December 2019 – February 2021

Cochrane Library [mh “Influenza Vaccine”] OR ((influenza NEAR/5 vaccin*) OR (flu NEAR/5 vaccin*) OR MF59* OR MF-59*):ti,ab

AND

[mh ^Aged] OR ((65 NEAR/5 older) OR (65 NEAR/5 over) OR (65 NEAR/5 between) OR “older adult*” OR “older people” OR “older population” OR senior* OR elderly):ti,ab

AND

(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR adjuvanted OR recombinant OR HD-IIV3 OR aIIV OR RIV* OR inactivated OR Guillain-Barre OR hypersensitiv* OR anaphylaxis OR harm* OR benefit*):ti,ab

Limit 1990 – ; update December 2019 – February 2021

Scopus TITLE-ABS-KEY((influenza W/5 vaccin*) OR (flu W/5 vaccin*) OR MF59* OR MF-59*) AND (INDEXTERMS(Aged) OR TITLE-ABS-KEY((65 W/5 older) OR (65 W/5 over) OR (65 W/5 between) OR “older adult*” OR “older people” OR “older population” OR senior* OR elderly)) AND TITLE-ABS-KEY(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR adjuvanted OR recombinant OR HD-IIV3 OR aIIV OR RIV* OR inactivated OR Guillain-Barre OR hypersensitiv* OR anaphylaxis OR harm* OR benefit*) AND NOT INDEX(medline)
Limit 1990 – ; update December 2019 – February 2021
Clinicaltrials.gov vaccine OR vaccination | influenza | Older Adult | First posted from 12/05/2019 to 02/10/2021

 

Supplementary search for review articles (1990 through September 7, 2021):

Supplementary search for review articles (1990 through September 7, 2022):
Database Strategy
Medline
(OVID)
1946-
Exp influenza vaccines/ OR ((influenza ADJ5 vaccin*) OR (flu ADJ5 vaccin*) OR MF59* OR MF-59*).ti,ab. OR influenza vaccines.rn.

AND

Adverse.fx OR ae.fs OR dosage.fx OR ad.fs OR Age Factors/ OR (safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR administration OR harm* OR benefit*)

AND

(systematic OR review OR metaanalysis OR meta analysis).ti

Limit 1990 – ;

Embase
(OVID)
1988-
Exp influenza vaccine/ OR ((influenza ADJ5 vaccin*) OR (flu ADJ5 vaccin*) OR MF59* OR MF-59*).ti,ab. OR influenza vaccines.rn.

AND

Adverse.fx OR ae.fs OR dosage.fx OR ad.fs OR (safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR anaphylaxis OR harm* OR benefit*)

AND

(systematic OR review OR metaanalysis OR meta analysis OR evidence).ti

 

Limit 1990 – ; NOT pubmed/medline

CINAHL
(Ebsco)
(MH “Influenza Vaccine”) OR ((influenza N5 vaccin*) OR (flu N5 vaccin*) OR MF59* OR MF-59*)

AND

(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR anaphylaxis OR harm* OR benefit*)

 

AND

(TI (systematic OR review OR metaanalysis OR “meta analysis” OR evidence))

 

Limit 1990 – ; exclude Medline records

Cochrane Library [mh “Influenza Vaccine”] OR ((influenza NEAR/5 vaccin*) OR (flu NEAR/5 vaccin*) OR MF59* OR MF-59*):ti,ab

AND

(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR anaphylaxis OR harm* OR benefit*):ti,ab

Limit 1990 – ; publication type = review

Scopus TITLE-ABS-KEY((influenza W/5 vaccin*) OR (flu W/5 vaccin*) OR MF59* OR MF-59*) AND TITLE-ABS-KEY(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR anaphylaxis OR harm* OR benefit*) AND TITLE(review* OR systematic OR meta*) AND NOT INDEX(medline)
Limit 1990 – ; publication type = Review

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