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Advisory Committee on Immunization Practices (ACIP)








GRADE: Higher Dose and Adjuvanted Influenza Vaccines for Persons Aged ≥65 Years						Print
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										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 yearsIntervention
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 RIV3/4Outcomes
Benefits†:
Influenza illness
Influenza-associated outpatient/ER visits
Influenza-associated hospitalizations
Influenza-associated deathsHarms:
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 profileInfluenza illness
Critical
YesInfluenza-associated outpatient/ER visits
Critical
YesInfluenza-associated hospitalizations
Critical
YesInfluenza-associated deaths
Critical
YesAny solicited systemic adverse events Grade ≥3
Critical
YesGuillain-Barré syndrome
Critical
YesAny solicited injection site adverse event Grade ≥3
Important
YesAny 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 makingTable 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 studiesDiazGranados 2014 (7)
≥65 years
15,990
15,993
SD-IIV3
RR: 0.76 (0.64, 0.90)
LowaIIV3 vs SD-IIV3—Randomized studiesFrey 2014 (10)
≥65 years
3,479
3,482
SD-IIV3
RR: 1.03 (0.89, 1.19)†
LowRIV3 vs SD-IIV3–Randomized studiesKeitel 2010 (11)
≥65 years
436
433
SD-IIV3
RR: 0.50 (0.05, 5.46)†
UnclearRIV4 vs SD-IIV4–Randomized studiesDunkle 2017 (8)
≥65 years
1,732
1,710
SD-IIV4
RR: 0.83 (0.58, 1.19)
LowHD-IIV3 vs aIIV3–Randomized studiesBelongia 2020 (12)
65-74 years
29
30
aIIV3
RR: 0.34 (0.04, 3.13)†
HighHD-IIV3 vs RIV4–Randomized studiesBelongia 2020 (12)
65-74 years
29
30
RIV4
RR: 0.26 (0.03, 2.18)†
HighaIIV3 vs RIV4–Randomized studiesBelongia 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 studiesBalasubramani 2020 (13)†
≥65 years
1,573
1,420
SD-IIV3/4
OR: 0.91 (73, 1.12)
ModerateIzurieta 2015 (14)
≥65 years
929,730
1,615,545
SD-IIV3
Rate ratio:
0.78 (0.71, 0.86)
SeriousIzurieta 2019 (15)
≥65 years
8,488,136
1,822,862
SD-IIV4 (egg-based)
Rate ratio:
0.99 (0.97, 1.02)
SeriousShay 2017 (16)
≥65 years
2,547,821
3,560,591
SD-IIV3
Rate ratio:
0.85 (0.80, 0.90)
SeriousYoung-Xu 2018 (17)
≥65 years
24,682
49,091
SD-IIV3
Rate ratio:
0.86 (0.68, 1.08)
SeriousaIIV3 vs SD-IIV—Observational studiesIob 2005 (18)
≥65 years
1,487
1,478
SD-IIV3
OR: 0.66 (0.53, 0.82)
SeriousIzurieta 2019 (15)
≥65 years
1,466,918
1,822,862
SD-IIV4 (egg-based)
Rate ratio:
1.07 (1.04, 1.10)
SeriousPelton 2020 (19)
≥65 years
234,313
212,287
SD-IIV4
Rate ratio:
0.64 (0.59, 0.69)
SeriousVan Buynder 2013 (9)
≥65 years
165
62
SD-IIV3
OR: 0.37 (0.14, 0.98)
SeriousHD-IIV3 vs aIIV3—Observational studiesIzurieta 2019 (15)
≥65 years
1,466,918
8,488,136
HD-IIV3 vs aIIV3
Rate ratio:
0.93 (0.91, 0.95)
SeriousPelton 2020 (20)
≥65 years
1,269,855
234,313
HD-IIV3 vs aIIV3
Rate ratio:
1.20 (1.12, 1.28)
SeriousPelton 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 studiesDiazGranados 2015a (22)
≥65 years
15,990
15,993
HD-IIV3 vs SD-IIV3
Rate Ratio:
0.67 (0.19, 2.36)
UnclearVardeny 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)
UnclearHD-IIV3 vs SD-IIV—Cluster Randomized studiesGravenstein 2017 (24)
≥65 years
19,127
19,129
HD-IIV3 vs SD-IIV3
RR: 0.79 (0.66, 0.95)
UnclearHD-IIV3 vs SD-IIV—Observational studiesDoyle 2021 (25)
≥65 years
622
485
HD-IIV3 vs SD-IIV
OR: 0.74 (0.53, 1.02)
SeriousIzurieta 2019 (15)
≥65 years
8,488,136
1,822,862
HD-IIV3 vs SD-IIV4
Rate ratio:
0.90 (0.88, 0.92)
SeriousIzurieta 2020 (20)
≥65 years
7,905,252
1,454,340
HD-IIV3 vs SD-IIV4
Rate ratio:
0.95 (0.91, 0.99)
SeriousIzurieta 2021(21)
≥65 years
7,173,433
1,584,451
HD-IIV3 vs SD-IIV4
Rate ratio:
0.93 (0.89, 0.98)
SeriousLu 2019 (26)
≥65 years
13,770,207
6,151,913
HD-IIV3 vs SD-IIV
Rate ratio:
0.88 (0.28, 0.94)
SeriousPaudel 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)
SeriousRichardson 2015 (28)
≥65 years
25714
139511
HD-IIV3 vs SD-IIV
Rate ratio:
0.98 (0.69, 1.40)
SeriousRobison 2018 (29)
≥65 years
23712
23712
HD-IIV3 vs SD-IIV
Rate ratio:
0.69 (0.52, 0.92)
SeriousYoung-Xu 2018 (17)
≥65 years
24862
49091
HD-IIV3 vs SD-IIV
Rate ratio:
0.75 (0.57, 0.99)
SeriousYoung-Xu 2019 (30)
≥65 years
158636 person-seasons
3480288 person-seasons
HD-IIV3 vs SD-IIV
Rate ratio: 0.87 (0.81, 0.94)
SeriousaIIV3 vs SD-IIV—Cluster Randomized studiesMcConeghy 2020 (31)
≥65 years
24926
25086
aIIV3 vs SD-IIV
HR: 0.79 (0.65, 0.96)
UnclearaIIV3 vs SD-IIV—Observational studiesCocchio 2020 (32)
≥65 years
68660
410737
SD-IIV3/4
OR: 0.37 (0.59, 0.75)
SeriousIzurieta 2019
≥65 years
1466918
1822862
aIIV3 vs SD-IIV
Rate Ratio:
0.98 (0.94, 1.01)
SeriousIzurieta 2020 (33)
≥65 years
2100592
1454340
aIIV3 vs SD-IIV
Rate Ratio:
0.93 (0.89, 0.99)
SeriousIzurieta 2021 (21)
≥65 years
2545513
1584451
aIIV3 vs SD-IIV
Rate Ratio:
0.93 (0.88, 0.99)
SeriousMannino 2012 (34)
≥65 years
64665 person- seasons
79589 person-seasons
aIIV3 vs SD-IIV
OR: 0.75 (0.57, 0.98)
SeriousPebody 2020 (35)
≥65 years
818
17
aIIV3 vs SD-IIV
OR: 0.70 (0.27, 1.83)
ModerateRIV vs SD-IIV—Observational studiesIzurieta 2021 (21)
≥65 years
608433
1584451
RIV vs SD-IIV4
Rate ratio:
0.83 (0.76, 0.91)
SeriousHD-IIV3 vs aIIV3—Observational studiesIzurieta 2019 (15)
≥65 years
8488136
1466918
HD-IIV3 vs aIIV3
Rate ratio:
0.92 (0.90, 0.95)
SeriousIzurieta 2020 (20)
≥65 years
7905252
2100592
HD-IIV3 vs aIIV3
Rate ratio:
1.01 (0.98, 1.05)
SeriousIzurieta 2021 (21)
≥65 years
7173433
2565513
HD-IIV3 vs aIIV3
Rate ratio:
1.0 (0.96, 1.04)
SeriousVan Aalst 2020 (36)
≥65 years
1900920
223793
HD-IIV3 vs aIIV3
Rate ratio:
0.88 (0.80, 0.97)
SeriousHD-IIV3 vs RIV4—Observational studiesIzurieta 2021 (21)
≥65 years
7173433
608433
HD-IIV3 vs RIV4
Rate ratio:
1.12 (1.03, 1.21)
SeriousaIIV3 vs RIV4—Observational studiesIzurieta 2021 (21)
≥65 years
2565513
608433
aIIV3 vs RIV4
Rate ratio:
1.12 (1.03, 1.22)
SeriousTable 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—ObservationalShay 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)
SeriousYoung-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 studiesCouch 2007 (57)
≥65 years
206
208
HD-IIV3 vs SD-IIV3
RR: 3.03 (0.12, 73.93)
UnclearCowling 2020 (37)
65 through 82 years
510
508
HD-IIV3 vs SD-IIV4
RR: 0.66 (0.11, 3.96)
LowKeitel 2006 (11)
≥65 years
50
51
HD-IIV3 vs SD-IIV3
RR: not estimable
UnclearaIIV3 vs SD-IIV–Randomized studiesCowling 2020 (37)
65 through 82 years
3/508
3/508
aIIV3 vs SD-IIV4
RR: 1.00 (0.20, 4.93)
LowMenegon 1999 (38)
≥65 years
96
98
aIIV3 vs SD-IIV3
RR: not estimable
UnclearScheifele 2013 (39)
≥65 years
301
307
aIIV3 vs SD-IIV3
RR: 0.61 (0.23, 1.66)
LowSeo 2014 (40)
≥65 years
111
113
aIIV3 vs SD-IIV3
RR: 3.05 (0.13, 74.16)
UnclearRIV3 vs SD-IIV–Randomized studiesKeitel 2010 (41)
≥65 years
436
433
RIV3 vs SD-IIV3
RR: 0.33 (0.03, 3.17)
UnclearRIV4 vs SD-IIV–Randomized studiesCowling 2020 (37)
65 through 82 years
335
508
RIV4 vs SD-IIV4
RR: 0.22 (0.01, 4.18)
LowHD-IIV3 vs aIIV3–Randomized studiesCowling 2020 (37)
65 through 82 years
510
508
HD-IIV3 vs aIIV3
RR: 0.66 (0.11, 3.96)
LowSchmader 2021 (42)
≥65 years
377
378
HD-IIV3 vs aIIV3
RR: 0.75 (0.26, 2.15)
LowHD-IIV3 vs RIV4–Randomized studiesCowling 2020 (37)
65 through 82 years
510
335
HD-IIV3 vs RIV4
RR: 3.29 (0.16, 68.27)
LowShinde 2019 (43)
≥65 years
153
151
HD-IIV3 vs RIV4
RR: 0.49 (0.09, 2.65)
LowaIIV3 vs RIV4–Randomized studiesCowling 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 studiesVardeny 2021 (23)
Mean age 65.5, SD 12.6/12.5 yrs
2,606
2,604
SD-IIV4
Not estimable
LowaIIV3 vs SD-IIV3–Randomized studiesFrey 2014 (10)
≥65 years
3,479
3,481
SD-IIV3
Not estimable
LowaIIV3 vs SD-IIV3—Observational studiesVilla 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)
SeriousRIV3 vs SD-IIV3—Observational studiesHansen 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)
ModerateHD-IIV3 vs aIIV3–Randomized studiesSchmader 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 studiesCowling 2020 (37)
65 through 82 years
510
508
HD-IIV3 vs SD-IIV4
RR: 0.77 (0.34, 1.73)
LowDiazGranados 2014
≥65 years
15,992
15,991
HD-IIV3 vs SD-IIV3
RR: 0.92 (0.85, 0.99)
LowFalsey 2009 (46)
≥65 years
2,541
1,240
HD-IIV3 vs SD-IIV3
RR: 0.83 (0.65, 1.07)
UnclearKeitel 2006 (11)
≥65 years
50
51
HD-IIV3 vs SD-IIV3
RR: 1.02 (0.22, 4.82)
UnclearNace 2015 (47)
≥65 years
89
98
HD-IIV3 vs SD-IIV3
RR: 0.92 (0.29, 2.90)
HighTsang 2014 (48)
≥65 years
320
319
HD-IIV3 vs SD-IIV3
RR: 0.76 (0.40, 1.43)
UnclearVardeny 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)
LowaIIV3 vs SD-IIV–Randomized studiesCowling 2020 (37)
65 through 82 years
508
508
aIIV3 vs SD-IIV4
RR: 0.65 (0.38, 1.87)
LowDe Bruijn 2007 (49)
≥65 years
130
129
aIIV3 vs SD-IIV3
RR: 2.98 (0.12, 72.41)
HighDe Donato 1999 (50)
≥65 years
248
233
aIIV3 vs SD-IIV3
RR: 0.78 (0.24, 2.53)
HighDella Cioppa 2012 (50)
≥65 years
47
44
aIIV3 vs SD-IIV3
RR: 0.31 (0.01, 7.47)
HighFrey 2014 (10)
≥65 years
3,545
3,537
aIIV3 vs SD-IIV3
RR: 1.08 (0.92, 1.28)
LowLi 2008 (51)
≥65 years
391
198
aIIV3 vs SD-IIV3
RR: 2.03 (0.23, 18.00)
HighScheifele 2013 (39)
≥65 years
301
307
aIIV3 vs SD-IIV3
RR: 1.18 (0.57, 2.43)
LowSindoni 2009 (52)
≥65 years
96
99
aIIV3 vs SD-IIV3
RR: Not estimable
UnclearRIV vs SD-IIV–Randomized studiesCowling 2020 (37)
65 through 82 years
335
508
RIV4 vs SD-IIV4
RR: 0.47 (0.15, 1.42)
LowDunkle 2017 (8)
≥50 years
4,328
4,344
RIV4 vs SD-IIV4
RR: 1.10 (0.87, 1.39)
LowIzikson 2015 (53)
≥50 years
1,314
1,313
RIV3 vs SD-IIV3
RR: 0.50 (0.17, 1.46)
UnclearKeitel 2010 (41)
≥65 years
436
433
RIV3 vs SD-IIV3
RR: 1.05 (0.67, 1.65)
UnclearTreanor 2006 (54)
≥65 years
100
199
RIV3 vs SD-IIV3
RR: 0.99 (0.06, 15.61)
UnclearHD-IIV3 vs aIIV3–Randomized studiesCowling 2020 (37)
65 through 82 years
510
508
HD-IIV3 vs aIIV3
RR: 0.91 (0.39, 2.11)
LowSchmader 2021 (42)
≥65 years
377
378
HD-IIV3 vs aIIV3
RR: 0.33 (0.09, 1.22)
LowHD-IIV3 vs RIV4–Randomized studiesCowling 2020 (37)
65 through 82 years
510
335
HD-IIV3 vs RIV4
RR: 1.64 (0.52, 5.19)
LowShinde 2019 (43)
≥65 years
153
151
HD-IIV3 vs RIV4
RR: 1.97 (0.50, 7.75)
LowaIIV3 vs RIV4–Randomized studiesCowling 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 studiesCowling 2020 (37)
65 through 82 years
510
508
HD-IIV3 vs SD-IIV4
RR: 3.98 (0.45, 35.52)
LowKeitel 2006 (11)
≥65 years
50
51
HD-IIV3 vs SD-IIV3
RR: 7.14 (0.38, 134.72)
UnclearaIIV3 vs SD-IIV–Randomized studiesCowling 2020 (37)
65 through 82 years
508
508
aIIV3 vs SD-IIV4
RR: 3.00 (0.31, 28.74)
LowDella Cioppa 2012
≥65 years
47
44
aIIV3 vs SD-IIV3
RR: 2.81 (0.12, 67.27)
HighMenegon 1999 (38)
≥65 years
96
98
aIIV3 vs SD-IIV3
RR: not estimable
UnclearScheifele 2013 (39)
≥65 years
301
307
aIIV3 vs SD-IIV3
RR: 3.57 (1.19, 10.72)
LowRIV vs SD-IIV–Randomized studiesCowling 2020 (37)
65 through 82 years
335
508
RIV4 vs SD-IIV4
RR: 0.50 (0.02, 12.36)
LowKeitel 2010 (41)
≥65 years
436
433
RIV3 vs SD-IIV3
RR: 0.70 (0.27, 1.81)
UnclearHD-IIV3 vs aIIV3–Randomized studiesCowling 2020 (37)
65 through 82 years
510
508
HD-IIV3 vs aIIV3
RR: 1.33 (0.30, 5.90)
LowSchmader 2021 (42)
≥65 years
377
378
HD-IIV3 vs aIIV3
RR: 0.79 (0.36, 1.71)
LowHD-IIV3 vs RIV4–Randomized studiesCowling 2020 (37)
65 through 82 years
508
335
HD-IIV3 vs RIV4
RR: 5.92 (0.32, 109.56)
LowShinde 2019 (43)
≥65 years
153
151
HD-IIV3 vs RIV4
RR: not estimable
LowaIIV3 vs RIV4–Randomized studiesCowling 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
No of patients
Effect
Certainty
ImportanceNo 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 Illness1
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
CRITICALObservational studies (person-time denominator): influenza-associated outpatient/ER visits4
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
CRITICALObservational studies (person denominator): influenza-associated outpatient/ER visits1
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
CRITICALRandomized studies: Influenza-associated hospitalizations2
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
CRITICALRandomized studies (cluster design): Influenza-associated hospitalizations1
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
CRITICALObservational studies (person-time denominator): influenza-associated hospitalizations8
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
CRITICALObservational studies (person denominator): influenza-associated hospitalizations2
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
CRITICALObservational studies (person-time denominator): Influenza-associated deaths2
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
CRITICALRandomized 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
IMPORTANTRandomized studies: Solicited injection site events Grade 3 or higher2
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
IMPORTANTRandomized studies: Solicited systemic events Grade 3 or higher2
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
CRITICALRandomized studies: Guillain-Barre syndrome1
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**
Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.
Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed.
Observational study.
Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.
Outcome either not laboratory-confirmed or defined by laboratory confirmation of unknown type not performed within the context of the study.
Cluster randomized study, with ICD code-based outcome definition. Not blinded; randomization sequence generation and timing of recruitment of participants unclear.
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.
Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
Not estimableTable 4b: Grade Summary of Findings Table: aIIV3 vs. SD-IIV
Table 4b: Grade Summary of Findings Table: aIIV3 vs. SD-IIV
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo 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 Illness1
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
CRITICALObservational studies (person-time denominator): influenza-associated outpatient/ER visits2
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
CRITICALObservational studies (person denominator): influenza-associated outpatient/ER visits2
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
CRITICALRandomized studies (cluster design): Influenza-associated hospitalizations1
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
CRITICALObservational studies (person-time denominator): influenza-associated hospitalizations4
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
CRITICALObservational Studies (person denominator): Influenza-associated hospitalizations2
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
CRITICALRandomized studies: Solicited systemic events Grade 3 or higher4
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
CRITICALRandomized Studies: Guillain-Barre syndrome1
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
CRITICALObservational studies: Guillain-Barre syndrome1
observational studies
seriousg
not serious
not serious
very seriousk
none
0/88449 (0.0%)
0/82539 (0.0%)
not estimable

Level 4
Very low
CRITICALRandomized 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
IMPORTANTRandomized studies: Solicited injection site events Grade 3 or higher4
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**
Symptom-based outcome definition.
Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.
Disparate results for two studies conducted in the United States during the same season.
Pooled estimate is derived from two estimates that are each relatively precise but sit on either side of the null with no CI overlap
Majority of data come from studies in which outcome definition is not laboratory-confirmed.
Cluster randomized study with ICD-code based outcome definitions. Not blinded; randomization sequence generation and timing of recruitment of participants unclear.
Observational study/studies; outcome is ICD code defined rather than laboratory confirmed for all or larger studies.
Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.
Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
CI ranges from slightly to substantially favoring comparator vaccine.
Not estimableTable 4c: Grade Summary of Findings Table: RIV3 vs. SD-IIV
Table 4c: Grade Summary of Findings Table: RIV3 vs. SD-IIV
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo 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 Illness2
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
CRITICALObservational studies (person-time denominator): influenza-associated hospitalizations1
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
CRITICALRCTs: Systemic events Grade 3 or higher2
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
CRITICALGuillain-Barre syndrome1
observational studies
seriousb
not serious
not serious
very seriouse
none
0/21976 (0.0%)
4/283683 (0.0%)
not estimable

Level 4
Very low
CRITICALRandomized 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
IMPORTANTRCTs: Injection site events Grade 3 or higher2
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**
Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed.
Population in this analysis includes persons ages 50 and older; slightly over half ages 50 through 64 years.
Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.
Not estimableTable 4d: Grade Summary of Findings Table: HD-IIV3 vs. aIIV3
Table 4d: Grade Summary of Findings Table: HD-IIV3 vs. aIIV3
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo 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 Illness1
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
CRITICALObservational studies (person-time denominator): influenza-associated outpatient/ER visits3
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
CRITICALObservational studies (person-time denominator): influenza-associated hospitalizations4
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
CRITICALRandomized studies: Solicited systemic events Grade 3 or higher2
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
CRITICALRandomized studies: Guillain-Barre syndrome1
randomized trials
not serious
not serious
not serious
very serioush
none
0/377 (0.0%)
0/378 (0.0%)
not estimable

Level 3
Low
CRITICALRandomized 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
IMPORTANTRandomized studies: Solicited injection site events Grade 3 or higher2
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**
Open-label study.
Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.
Disparate estimates from two different studies conducted over the same influenza season.
Width of confidence interval derives from inconsistency of estimates that are each on their own precise but which lie on opposite sides of null.
Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code-defined rather than laboratory-confirmed.
Confidence interval includes null and indicates potential for either meaningful effect or no difference.
Not estimableTable 4e: Grade Summary of Findings Table: HD-IIV3 vs. RIV4
Table 4e: Grade Summary of Findings Table: HD-IIV3 vs. RIV4
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo 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 Illness1
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
CRITICALObservational studies (person-time denominator): influenza-associated hospitalizations1
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
CRITICALRandomized studies: Solicited systemic events Grade 3 or higher2
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
CRITICALRandomized 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
IMPORTANTRandomized studies: Solicited injection site events Grade 3 or higher2
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**
Open-label study.
Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
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
No of patients
Effect
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
aIIV3
RIV4
Relative
(95% CI)
Absolute
(95% CI)Randomized studies: Influenza-associated Illness1
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
CRITICALObservational studies (person-time denominator): influenza-associated hospitalizations1
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
CRITICALRandomized studies: Solicited systemic events Grade 3 or higher1
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
CRITICALRandomized 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
IMPORTANTRandomized studies: Solicited injection site events Grade 3 or higher1
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**
Open-label study.
Small sample size and low event rate; sensitive to small changes in distribution of events between groups.
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 comparisonVaccines of interest vs SD-IIVs
EIVs vs one anotherOutcome
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
RIV4BENEFITSInfluenza illnesses
Critical
Yes
Level 1
High
Level 2
Moderate
Level 2
Moderate
Level 4
Very low
Level 4
Very low
Level 4
Very lowInfluenza outpatient/ER visits
Critical
Yes
Level 3
Low
Level 3
Low

Level 4
Very LowInfluenza hospitalizations
Critical
Yes
Level 2
Moderate
Level 2
Moderate
Level 3
low
Level 4
Very Low
Level 3
Low
Level 3
LowInfluenza deaths
Critical
Yes
Level 3
LowHARMSAny Serious Adverse Event (SAE)
Important
Yes
Level 1
High
Level 2
Moderate
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
LowSolicited 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
LowSolicited systemic
adverse events Grade ≥3
Critical
Yes
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
Low
Level 3
LowGuillain-Barré syndrome
Critical
Yes
Level 3
Low
Level 3
Low
Level 4
Very low
Level 3
LowOVERALL:
Level 3
Low
Level 3
Low
Level 4
Very low
Level 4
Very low
Level 4
Very low
Level 4
Very lowTop of PageAppendix 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 sourceBalasubramani 2020 (13)
TNCC
US
(US Flu VE Network)
≥65 years
2,993
1,573 HD-IIV3
1,420 SD-IIV3/4
Outpatient/ER
US governmentBelongia 2020 (12)
Randomized
US
65 through 74 years
99
29  HD-IIV3
30 aIIV3
30 RIV4

Illnesses
US governmentCocchio 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 governmentCowling 2020 (37)
Randomized
Hong Kong
65 through 82 years
1,861
510 HD-IIV3
508 aIIV3
335 RIV4
508 SD-IIV4
SAEs
Reactogenicity
US governmentDiazGranados 2014 (7)
Randomized
US/Canada
≥65 years
31,983
15,993
HD-IIV3
15,990 SD-IIV3
Illnesses
SAEs
Sanofi PasteurDiazGranados 2015 (22)
Randomized
US
Canada
≥65 years
31,983
15,993
HD-IIV3
15,990 SD-IIV3
Hospitalizations
Sanofi PasteurDe 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
NovartisDoyle 2021 (25)
TNCC
US
(HAIVEN)
≥65 years
1,107
622 HD-IIV3
485 SD-IIV
Hospitalization
US governmentDunkle 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 authorsFalsey 2009 (46)
Randomized
US
≥65 years
3,781
2,541 HD-IIV3
1,240 SD-IIV3
SAEs
Sanofi PasteurFrey 2014 (10)
Randomized
US, Colombia,
Panama
Philippines
≥65 years
6,961
3,479 HD-IIV3
3,482 SD-IIV3
Illnesses
SAEs
Reactogenicity
GBS
NovartisGravenstein 2017 (24)
Cluster Randomized
US
≥65 years
53,008
26,639 HD-IIV3
26,369 SD-IIV3
Hospitalization
Sanofi PasteurIob 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 statedIzikson 2015 (53)
Randomized
US
≥50 years
2,627
1,314 RIV3
1,313 SD-IIV3
SAEs
BARDA; Protein Sciences authorsIzurieta 2015 (14)
Retro. cohort
US
(Medicare)
≥65 years
2,545,275
929,730 HD-IIV3
1,615,545
SD-IIV3
Outpatient/ER
US governmentIzurieta 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 governmentIzurieta 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 governmentIzurieta 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 governmentHansen 2020 (45)
Retro. cohort
US
≥65 years
305,659
21,976 RIV3
283,683 SD-IIV3
GBS
Protein SciencesKeitel 2006 (11)
Randomized
US
≥65 years
101
50 HD-IIV3
51 SD-IIV3
SAEs
Reactogenicity
US governmentKeitel 2010 (41)
Randomized
US
≥65 years
869
436 RIV3
433 SD-IIV3
SAEs
Reactogenicity
Unclear; Protein Sciences authorLi 2008 (51)
Randomized
China
≥60 years
589
391 aIIV3
198 SD-IIV3
SAEs
NovartisLu 2019 (26)
Retro. cohort
US
≥65 years
19,922,120
13,770,207
HD-IIV3
6,151,913
SD-IIV
Hospitalizations
US governmentMannino 2012 (34)
Prospective cohort
Italy
≥65 years
164,254 person-seasons
84,665 person-seasons
79,589
person-seasons
Hospitalizations
NovartisMcConeghy 2020 (31)
Cluster Randomized
US
≥65 years
50,012
24,926 aIIV3
25,086 SD-IIV3
Hospitalization
SeqirusMenegon 1999 (38)
Randomized
Italy
Mean 68.6 years, range 23-97
194
96 aIIV3
98 HD-IIV3
Reactogenicity
Ministry grantNace 2015 (47)
Randomized
US
≥65 years
187
89 HD-IIV3
98 SD-IIV3
SAEs
Sanofi PasteurPaudel 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 PasteurPebody (35)
TNCC
UK
≥65 years
835
818
17
Hospitalizations
UK GovernmentPelton 2020 (19)
Retro. cohort
US
≥65 years
446,600
1,269,855 HD-IIV3
234,313
aIIV3
212,287
SD-IIV
Outpatient/ER
SeqirusPelton 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 governmentRobison 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 governmentScheifele 2013 (39)
Randomized
Canada
≥65 years
608
301 aIIV3
307 SD-IIV3
SAEs
Reactogenicity
Canadian governmentSchmader 2021 (42)
Randomized
US
≥65 years
755
378 aIIV3
377 HD-IIV3

SAEs
Reactogenicity
GBS
US governmentSeo 2014 (40)
Randomized
S. Korea
≥65 years
224
113 aIIV3
111 SD-IIV3
Reactogenicity
S. Korean governmentSindoni 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
NovavaxTreanor 2006 (54)
Randomized
US
≥65 years
199
100 RIV3
99 SD-IIV3
SAEs
US government; Protein Sciences authorTsang 2014 (48)
Randomized
US
≥65 years
639
320 HD-IIV3
319 SD-IIV3
SAEs
Sanofi PasteurVan Aalst 2020 (36)
Retro. cohort
US
≥65 years
2,124,713
1,900,920
HD-IIV3
223,793
aIIV3

Hospitalizations
Sanofi PasteurVan Buynder 2013 (9)
TNCC
Canada
≥65 years
227
165 aIIV3
62 SD-IIV3
Outpatient/ER
Unrestricted grant, Novartis; Fraser Health AuthorityVardeny 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 PasteurVilla 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 authorsYoung-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 authorsYoung-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 AdministrationAppendix 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 = ReviewReferences
Mullooly JP, Bridges CB, Thompson WW, Chen J, Weintraub E, Jackson LA, et al. Influenza- and RSV-associated hospitalizations among adults. Vaccine. 2007 Jan 15;25(5):846-55.
Reed C, Chaves SS, Daily Kirley P, Emerson R, Aragon D, Hancock EB, et al. Estimating influenza disease burden from population-based surveillance data in the United States. PLoS One. 2015;10(3):e0118369.
Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8;289(2):179-86.
Rolfes MA, Foppa IM, Garg S, Flannery B, Brammer L, Singleton JA, et al. Annual estimates of the burden of seasonal influenza in the United States: A tool for strengthening influenza surveillance and preparedness. Influenza Other Respir Viruses. 2018 Jan;12(1):132-7.
Reber AJ, Chirkova T, Kim JH, Cao W, Biber R, Shay DK, et al. Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population. Aging Dis. 2011;3(1):68-90.
CDC. Past seasons vaccine effectiveness estimates. www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html#2021. .
DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, et al. Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults. 2014;371(7):635-45.
Dunkle LM, Izikson R, Patriarca P, Goldenthal KL, Muse D, Callahan J, et al. Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. 2017;376(25):2427-36.
Van Buynder PG, Konrad S, Van Buynder JL, Brodkin E, Krajden M, Ramler G, et al. The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly. Vaccine. 2013 2013/12/09/;31(51):6122-8.
Frey SE, Reyes MR, Reynales H, Bermal NN, Nicolay U, Narasimhan V, et al. Comparison of the safety and immunogenicity of an MF59(R)-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine. 2014 Sep 3;32(39):5027-34.
Keitel WA, Atmar RL, Cate TR, Petersen NJ, Greenberg SB, Ruben F, et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med. 2006 May 22;166(10):1121-7.
Belongia EA, Levine MZ, Olaiya O, Gross FL, King JP, Flannery B, et al. Clinical trial to assess immunogenicity of high-dose, adjuvanted, and recombinant influenza vaccines against cell-grown A(H3N2) viruses in adults 65 to 74 years, 2017-2018. Vaccine. 2020 Mar 30;38(15):3121-8.
Balasubramani GK, Choi WS, Nowalk MP, Zimmerman RK, Monto AS, Martin ET, et al. Relative effectiveness of high dose versus standard dose influenza vaccines in older adult outpatients over four seasons, 2015-16 to 2018-19. Vaccine. 2020 Sep 29;38(42):6562-9.
Izurieta HS, Thadani N, Shay DK, Lu Y, Maurer A, Foppa IM, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet Infect Dis. 2015 Mar;15(3):293-300.
Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, et al. Relative Effectiveness of Cell-Cultured and Egg-Based Influenza Vaccines Among Elderly Persons in the United States, 2017-2018. J Infect Dis. 2019 Sep 13;220(8):1255-64.
Shay DK, Chillarige Y, Kelman J, Forshee RA, Foppa IM, Wernecke M, et al. Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries in Preventing Postinfluenza Deaths During 2012-2013 and 2013-2014. J Infect Dis. 2017 Feb 15;215(4):510-7.
Young-Xu Y, Van Aalst R, Mahmud SM, Rothman KJ, Snider JT, Westreich D, et al. Relative Vaccine Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among Veterans Health Administration Patients. J Infect Dis. 2018 May 5;217(11):1718-27.
Iob A, Brianti G, Zamparo E, Gallo T. Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy. Epidemiol Infect. 2005 Aug;133(4):687-93.
Pelton SI, Divino V, Shah D, Mould-Quevedo J, DeKoven M, Krishnarajah G, et al. Evaluating the Relative Vaccine Effectiveness of Adjuvanted Trivalent Influenza Vaccine Compared to High-Dose Trivalent and Other Egg-Based Influenza Vaccines among Older Adults in the US during the 2017-2018 Influenza Season. Vaccines (Basel). 2020 Aug 7;8(3).
Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, et al. Relative Effectiveness of Influenza Vaccines Among the United States Elderly, 2018-2019. J Infect Dis. 2020 Jun 29;222(2):278-87.
Izurieta HS, Lu M, Kelman J, Lu Y, Lindaas A, Loc J, et al. Comparative Effectiveness of Influenza Vaccines Among US Medicare Beneficiaries Ages 65 Years and Older During the 2019-2020 Season. Clin Infect Dis. 2021 Dec 6;73(11):e4251-e9.
DiazGranados CA, Robertson CA, Talbot HK, Landolfi V, Dunning AJ, Greenberg DP. Prevention of serious events in adults 65 years of age or older: A comparison between high-dose and standard-dose inactivated influenza vaccines. Vaccine. 2015 Sep 11;33(38):4988-93.
Vardeny O, Kim K, Udell JA, Joseph J, Desai AS, Farkouh ME, et al. Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-risk Cardiovascular Disease: A Randomized Clinical Trial. JAMA. 2021 Jan 5;325(1):39-49.
Gravenstein S, Davidson HE, Taljaard M, Ogarek J, Gozalo P, Han L, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: a cluster-randomised trial. Lancet Respir Med. 2017 Sep;5(9):738-46.
Doyle JD, Beacham L, Martin ET, Talbot HK, Monto A, Gaglani M, et al. Relative and Absolute Effectiveness of High-Dose and Standard-Dose Influenza Vaccine Against Influenza-Related Hospitalization Among Older Adults-United States, 2015-2017. Clin Infect Dis. 2021 Mar 15;72(6):995-1003.
Lu Y, Chillarige Y, Izurieta HS, Wei Y, Xu W, Lu M, et al. Effect of Age on Relative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries Aged >/=65 Years. J Infect Dis. 2019 Sep 26;220(9):1511-20.
Paudel M, Mahmud S, Buikema A, Korrer S, Van Voorhis D, Brekke L, et al. Relative vaccine efficacy of high-dose versus standard-dose influenza vaccines in preventing probable influenza in a Medicare Fee-for-Service population. Vaccine. 2020 Jun 15;38(29):4548-56.
Richardson DM, Medvedeva EL, Roberts CB, Linkin DR, Centers for Disease C, Prevention Epicenter P. Comparative effectiveness of high-dose versus standard-dose influenza vaccination in community-dwelling veterans. Clin Infect Dis. 2015 Jul 15;61(2):171-6.
Robison SG, Thomas AR. Assessing the effectiveness of high-dose influenza vaccine in preventing hospitalization among seniors, and observations on the limitations of effectiveness study design. Vaccine. 2018 Oct 29;36(45):6683-7.
Young-Xu Y, Snider JT, van Aalst R, Mahmud SM, Thommes EW, Lee JKH, et al. Analysis of relative effectiveness of high-dose versus standard-dose influenza vaccines using an instrumental variable method. Vaccine. 2019 Mar 7;37(11):1484-90.
McConeghy KW, Huang SS, Miller LG, McKinnell JA, Shireman TI, Mor V, et al. Hospital Influenza Admissions as a Harbinger for Nursing Home Influenza Cases. J Am Med Dir Assoc. 2020 Jan;21(1):121-6.
Cocchio S, Gallo T, Del Zotto S, Clagnan E, Iob A, Furlan P, et al. Preventing the Risk of Hospitalization for Respiratory Complications of Influenza among the Elderly: Is There a Better Influenza Vaccination Strategy? A Retrospective Population Study. Vaccines (Basel). 2020 Jun 28;8(3).
Young-Xu Y, Thornton Snider J, Mahmud SM, Russo EM, Van Aalst R, Thommes EW, et al. High-dose influenza vaccination and mortality among predominantly male, white, senior veterans, United States, 2012/13 to 2014/15. Euro Surveill. 2020 May;25(19).
Mannino S, Villa M, Apolone G, Weiss NS, Groth N, Aquino I, et al. Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy. Am J Epidemiol. 2012 Sep 15;176(6):527-33.
Pebody R, Whitaker H, Zhao H, Andrews N, Ellis J, Donati M, et al. Protection provided by influenza vaccine against influenza-related hospitalisation in >/=65 year olds: Early experience of introduction of a newly licensed adjuvanted vaccine in England in 2018/19. Vaccine. 2020 Jan 10;38(2):173-9.
van Aalst R, Gravenstein S, Mor V, Mahmud SM, Wilschut J, Postma M, et al. Comparative effectiveness of high dose versus adjuvanted influenza vaccine: A retrospective cohort study. Vaccine. 2020 Jan 10;38(2):372-9.
Cowling BJ, Thompson MG, Ng TWY, Fang VJ, Perera R, Leung NHL, et al. Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults. J Infect Dis. 2020 Sep 14;222(8):1383-91.
Menegon T, Baldo V, Bonello C, Dalla Costa D, Di Tommaso A, Trivello R. Influenza vaccines: antibody responses to split virus and MF59-adjuvanted subunit virus in an adult population. Eur J Epidemiol. 1999 Jul;15(6):573-6.
Scheifele DW, McNeil SA, Ward BJ, Dionne M, Cooper C, Coleman B, et al. Safety, immunogenicity, and tolerability of three influenza vaccines in older adults: results of a randomized, controlled comparison. Hum Vaccin Immunother. 2013 Nov;9(11):2460-73.
Seo YB, Choi WS, Lee J, Song JY, Cheong HJ, Kim WJ. Comparison of the immunogenicity and safety of the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines in the elderly. Clin Vaccine Immunol. 2014 Jul;21(7):989-96.
Keitel WA, Treanor JJ, El Sahly HM, Gilbert A, Meyer AL, Patriarca PA, et al. Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine (TIV) among persons > or =65 years old. Vaccine. 2009 Dec 11;28(2):379-85.
Schmader KE, Liu CK, Harrington T, Rountree W, Auerbach H, Walter EB, et al. 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.
Shinde V, Cho I, Plested JS, Agrawal S, Fiske J, Cai R, et al. Comparison of the safety and immunogenicity of a novel Matrix-M-adjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in older adults: a phase 3 randomised controlled trial. Lancet Infect Dis. 2022 Jan;22(1):73-84.
Villa M, Black S, Groth N, Rothman KJ, Apolone G, Weiss NS, et al. Safety of MF59-adjuvanted influenza vaccination in the elderly: results of a comparative study of MF59-adjuvanted vaccine versus nonadjuvanted influenza vaccine in northern Italy. Am J Epidemiol. 2013 Oct 1;178(7):1139-45.
Hansen J, Goddard K, Timbol J, Zhang L, Lewis N, Dunkle L, et al. Safety of Recombinant Influenza Vaccine Compared to Inactivated Influenza Vaccine in Adults: An Observational Study. Open Forum Infect Dis. 2020 Jun;7(6):ofaa179.
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 Jul 15;200(2):172-80.
Nace DA, Lin CJ, Ross TM, Saracco S, Churilla RM, Zimmerman RK. Randomized, controlled trial of high-dose influenza vaccine among frail residents of long-term care facilities. J Infect Dis. 2015 Jun 15;211(12):1915-24.
Tsang P, Gorse GJ, Strout CB, Sperling M, Greenberg DP, Ozol-Godfrey A, et al. Immunogenicity and safety of Fluzone((R)) intradermal and high-dose influenza vaccines in older adults >/=65 years of age: a randomized, controlled, phase II trial. Vaccine. 2014 May 1;32(21):2507-17.
de Bruijn I, Meyer I, Gerez L, Nauta J, Giezeman K, Palache B. Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly. Vaccine. 2007 Dec 21;26(1):119-27.
De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine. 1999 Aug 6;17(23-24):3094-101.
Li R, Fang H, Li Y, Liu Y, Pellegrini M, Podda A. Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects. Immun Ageing. 2008 Feb 20;5:2.
Sindoni D, La Fauci V, Squeri R, Cannavo G, Bacilieri S, Panatto D, et al. Comparison between a conventional subunit vaccine and the MF59-adjuvanted subunit influenza vaccine in the elderly: an evaluation of the safety, tolerability and immunogenicity. J Prev Med Hyg. 2009 Jun;50(2):121-6.
Izikson R, Leffell DJ, Bock SA, Patriarca PA, Post P, Dunkle LM, et al. Randomized comparison of the safety of Flublok((R)) versus licensed inactivated influenza vaccine in healthy, medically stable adults >/= 50 years of age. Vaccine. 2015 Nov 27;33(48):6622-8.
Treanor JJ, Schiff GM, Couch RB, Cate TR, Brady RC, Hay CM, et al. Dose-related safety and immunogenicity of a trivalent baculovirus-expressed influenza-virus hemagglutinin vaccine in elderly adults. J Infect Dis. 2006 May 1;193(9):1223-8.
Della Cioppa G, Nicolay U, Lindert K, Leroux-Roels G, Clement F, Castellino F, et al. Superior immunogenicity of seasonal influenza vaccines containing full dose of MF59 ((R)) adjuvant: results from a dose-finding clinical trial in older adults. Hum Vaccin Immunother. 2012 Feb;8(2):216-27.
Pelton SI, Divino V, Postma MJ, Shah D, Mould-Quevedo J, DeKoven M, et al. A retrospective cohort study assessing relative effectiveness of adjuvanted versus high-dose trivalent influenza vaccines among older adults in the United States during the 2018-19 influenza season. Vaccine. 2021 Apr 22;39(17):2396-407.
Couch RB, Winokur P, Brady R, Belshe R, Chen WH, Cate TR, et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 2007;25(44):7656-63.Top of Page
							
					
							Last Reviewed:  August 24, 2022						Source: 	National Center for Immunization and Respiratory Diseases
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