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Share sensitive information only on official, secure websites.Advisory Committee on Immunization Practices (ACIP)Explore TopicsSearchSearchClear InputFor Everyone* General Committee-Related Information* ACIP Work Groups* ACIP Meeting Information* ACIP Recommendations* Apply for ACIP Membership* ACIP Committee Members* Evidence-Based Recommendations for ACIP* GRADE Evidence Tables – Recommendations in MMWR* Evidence to Recommendations Frameworks* View allRelated Topics:ACIP GRADE Handbook | Vaccine-Specific Recommendations | Vaccines & ImmunizationsView Allsearch close searchsearchACIP Menu CloseACIP MenusearchFor Everyone* General Committee-Related Information* ACIP Work Groups* ACIP Meeting Information* ACIP Recommendations* Apply for ACIP Membership* ACIP Committee Members* Evidence-Based Recommendations for ACIP* GRADE Evidence Tables – Recommendations in MMWR* View All HomeRelated Topics* ACIP GRADE Handbook* Vaccine-Specific Recommendations* Vaccines & ImmunizationsView All ACIPGeneral Committee-Related Information ACIP Work Groups ACIP Meeting Information ACIP Recommendations Apply for ACIP Membership ACIP Committee Members Evidence-Based Recommendations for ACIP GRADE Evidence Tables – Recommendations in MMWR View AllSeptember 9, 2024GRADE: Higher Dose and Adjuvanted Influenza Vaccines for Persons Aged ≥65 YearsAboutCDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.BackgroundEstimated rates of influenza-associated hospitalization and death are generally highest among individuals 65 years of age and older,1234 an age group for whom influenza vaccine effectiveness is often lower relative to younger populations.56 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.789 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.MethodsA 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 PICOPolicy 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?PopulationPersons aged ≥65 yearsInterventionTrivalent 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)*Trivalent or quadrivalent formulations of:ComparisonAge-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 RIV3/4Age-appropriate trivalent or quadrivalent influenza vaccines.* Relevant comparisons are:OutcomesBenefits†:* Influenza illness* Influenza-associated outpatient/ER visits* Influenza-associated hospitalizations* Influenza-associated deathsHarms:Benefits†: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 RankingsOutcome 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)References in this table: 78101112Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-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)† HighAbbreviations: 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 visitsReferences in this table:9131415161718192021Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-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: Serious0.78 (0.71, 0.86)Izurieta 2019 (15) ≥65 years 8,488,136 1,822,862 SD-IIV4 (egg-based) Rate ratio: Serious0.99 (0.97, 1.02)Shay 2017 (16) ≥65 years 2,547,821 3,560,591 SD-IIV3 Rate ratio: Serious0.85 (0.80, 0.90)Young-Xu 2018 (17) ≥65 years 24,682 49,091 SD-IIV3 Rate ratio: Serious0.86 (0.68, 1.08)aIIV3 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: Serious1.07 (1.04, 1.10)Pelton 2020 (19) ≥65 years 234,313 212,287 SD-IIV4 Rate ratio: Serious0.64 (0.59, 0.69)Van 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: Serious0.93 (0.91, 0.95)Pelton 2020 (20) ≥65 years 1,269,855 234,313 HD-IIV3 vs aIIV3 Rate ratio: Serious1.20 (1.12, 1.28)Pelton 2021 (21) ≥65 years 1,672,797 561,243 HD-IIV3 vs aIIV3 Rate ratio: Serious1.07 (1.03, 1.13)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 hospitalizationsReferences in this table:15172021222324252627282930313233343536Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-IIV3 vs SD-IIV–Randomized studiesDiazGranados 2015a (22) ≥65 years 15,990 15,993 HD-IIV3 vs SD-IIV3 Rate Ratio: Unclear0.67 (0.19, 2.36)Vardeny 2021 (23) Mean age 65.5, SD 12.6/12.5 yrs 2,606 2,604 HD-IIV3 vs SD-IIV4 Rate Ratio: Unclear1.25 (0.49, 3.16)HD-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: Serious0.90 (0.88, 0.92)Izurieta 2020 (20) ≥65 years 7,905,252 1,454,340 HD-IIV3 vs SD-IIV4 Rate ratio: Serious0.95 (0.91, 0.99)Izurieta 2021(21) ≥65 years 7,173,433 1,584,451 HD-IIV3 vs SD-IIV4 Rate ratio: Serious0.93 (0.89, 0.98)Lu 2019 (26) ≥65 years 13,770,207 6,151,913 HD-IIV3 vs SD-IIV Rate ratio: Serious0.88 (0.28, 0.94)Outpatient cohort:Outpatient cohort: Outpatient cohort: Rate ratioPaudel 2020 (27) ≥65 years 2796994 2996994 HD-IIV3 vs SD-IIV 0.96 (0.94, 0.99) SeriousPharmacy cohort: Pharmacy cohort: Pharmacy cohort2760882 2760882 Rate ratio0.93 (0.90, 0.97)Richardson 2015 (28) ≥65 years 25714 139511 HD-IIV3 vs SD-IIV Rate ratio: Serious0.98 (0.69, 1.40)Robison 2018 (29) ≥65 years 23712 23712 HD-IIV3 vs SD-IIV Rate ratio: Serious0.69 (0.52, 0.92)Young-Xu 2018 (17) ≥65 years 24862 49091 HD-IIV3 vs SD-IIV Rate ratio: Serious0.75 (0.57, 0.99)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) 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: Serious0.98 (0.94, 1.01)Izurieta 2020 (33) ≥65 years 2100592 1454340 aIIV3 vs SD-IIV Rate Ratio: Serious0.93 (0.89, 0.99)Izurieta 2021 (21) ≥65 years 2545513 1584451 aIIV3 vs SD-IIV Rate Ratio: Serious0.93 (0.88, 0.99)Mannino 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: Serious0.83 (0.76, 0.91)HD-IIV3 vs aIIV3—Observational studiesIzurieta 2019 (15) ≥65 years 8488136 1466918 HD-IIV3 vs aIIV3 Rate ratio: Serious0.92 (0.90, 0.95)Izurieta 2020 (20) ≥65 years 7905252 2100592 HD-IIV3 vs aIIV3 Rate ratio: Serious1.01 (0.98, 1.05)Izurieta 2021 (21) ≥65 years 7173433 2565513 HD-IIV3 vs aIIV3 Rate ratio: Serious1.0 (0.96, 1.04)Van Aalst 2020 (36) ≥65 years 1900920 223793 HD-IIV3 vs aIIV3 Rate ratio: Serious0.88 (0.80, 0.97)HD-IIV3 vs RIV4—Observational studiesIzurieta 2021 (21) ≥65 years 7173433 608433 HD-IIV3 vs RIV4 Rate ratio: Serious1.12 (1.03, 1.21)aIIV3 vs RIV4—Observational studiesIzurieta 2021 (21) ≥65 years 2565513 608433 aIIV3 vs RIV4 Rate ratio: Serious1.12 (1.03, 1.22)Table 3d: Summary of Studies Reporting Outcome: Influenza deathsReferences in this table:1633Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-IIV3 vs SD-IIV—ObservationalShay 2017 (16) ≥65 years 2,547,821 3,560,591 SD-IIV3 RR: 0.77 (0.58, 1.00) Serious(30,079,255 person-weeks) 42,696,182 person-weeks)Young-Xu 2020 (33) ≥65 years 207,574 361,978 SD-IIV3 RR: 0.62 (0.46, 0.82) ModerateAbbreviations: 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)>References in this table:1137383940414243Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-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) LowAbbreviations: 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)References in this table:1023424445Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-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 studiesRD: 088,449 vaccine doses over 3 seasons 82,539 Risk with aIIV3:Villa 2013 (44) ≥65 years (6-week window) vaccine doses over 3 seasons SD-IIV3 (0, 4.47) Serious(6-week window) Risk with aIIV3:(0, 4.17)RIV3 vs SD-IIV3—Observational studiesOutpatient, 0-41 days:Hansen 2020 (45) ≥18 years 21,976 28,3683 SD-IIV3 OR: 0 (0, 16.066 ModerateInpatient/ER, 0-41 days:OR: 0 (0, 112.6)HD-IIV3 vs aIIV3–Randomized studiesSchmader 2021 (42) ≥65 years 377 378 aIIV4 Not estimable LowAbbreviations: 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)References in this table: 81011233237414243464748495051525354Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-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) LowAbbreviations: 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)References in this table:11373839414243Author Age/other characteristics N intervention N comparison Comparison vaccine Effect estimate* Study limitations (Risk of Bias)Publication yearHD-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) LowAbbreviations: 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-IIVCertainty assessment № of patients Effect Certainty Importance№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HD-IIV3 SD-IIV Relative Absolute(95% CI) (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 45 fewer per 10,000 Level 1 CRITICAL(0.64 to 0.90) (from 65 fewer to 19 fewer) HighObservational 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 — per 10,000 Level 3 CRITICAL(0.76 to 0.99) (from — to –) LowObservational 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 0.91 184 fewer per 10,000 Level 4 CRITICAL(0.73 to 1.12) (from 551 fewer to 245 more) Very lowRandomized 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 fewer per 100,000 Level 2 CRITICAL(0.48 to 2.09) (from 4 fewer to 8 more) ModerateRandomized 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 — per 10,000 Level 2 CRITICAL(0.66 to 0.95) (from — to –) ModerateObservational studies (person-time denominator): influenza-associated hospitalizations8 observational studies very seriousb not serious not serious not serious none -/43519865* -/20193377* Rate ratio 0.92 — per 10,000 Level 3 CRITICAL(0.90 to 0.94) (from — to –) LowObservational 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 24 fewer per 1,000 Level 3 CRITICAL(0.57 to 0.88) (from 36 fewer to 10 fewer) LowObservational studies (person-time denominator): Influenza-associated deaths2 observational studies very seriousb not serious not serious not serious none -/2755395* -/3922569* Rate ratio 0.69 — per 10,000 Level 3 CRITICAL(0.57 to 0.84) (from — to –) LowRandomized 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 68 fewer per 10,000 Level 1 IMPORTANT(0.85 to 0.97) (from 114 fewer to 23 fewer) HighRandomized 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 72 more per 10,000 Level 3 IMPORTANT(0.88 to 28.74) (from 2 fewer to 496 more) LowRandomized 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 2 fewer per 10,000 Level 3 CRITICAL(0.20 to 4.53) (from 31 fewer to 138 more) LowRandomized 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 CRITICALLow*Counts not provided for all studies.CI: confidence interval; RR: risk ratioExplanationsa Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.b Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed.c Observational study.d Confidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.e Outcome either not laboratory-confirmed or defined by laboratory confirmation of unknown type not performed within the context of the study.f Cluster randomized study, with ICD code-based outcome definition. Not blinded; randomization sequence generation and timing of recruitment of participants unclear.g 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.h Small sample size and low event rate; sensitive to small changes in distribution of events between groups.i Not estimableTable 4b: Grade Summary of Findings Table: aIIV3 vs. SD-IIVCertainty assessment № of patients Effect Certainty Importance№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations aIIV3 SD-IIV Relative Absolute(95% CI) (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 27 more per 10,000 Level 2 CRITICAL(0.89 to 1.19) (from 99 fewer to 171 more) ModerateObservational 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 — per 10,000 Level 4 CRITICAL(0.97 to 1.03) (from — to –) Very lowObservational studies (person denominator): influenza-associated outpatient/ER visits2 observational studies very seriouse not serious not serious not serious none 344/1333 197/988 RR 0.64 718 fewer per 10,000 Level 3 CRITICAL(0.52 to 0.79) (from 957 fewer to 419 fewer) LowRandomized studies (cluster design): Influenza-associated hospitalizations1 randomized trials seriousf not serious not serious not serious none 242/24926 309/25806 Rate ratio 0.79 25 per 10,000 patient(s) per years Level 2 CRITICAL(0.65 to 0.96) (from 42 fewer to 5 fewer) ModerateObservational studies (person-time denominator): influenza-associated hospitalizations4 observational studies very seriousg not serious not serious not serious none /6133023* -/4861653* Rate ratio 0.88 — per 10,000 Level 3 CRITICAL(0.80 to 0.97) (from — to –) LowObservational Studies (person denominator): Influenza-associated hospitalizations2 observational studies very seriousg not serious not serious not serious none 230/85483 35/79610 0.75 1 fewer per 10,000 Level 3 CRITICAL(0.58 to 0.97) (from 2 fewer to 0 fewer) LowRandomized 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 29 fewer per 10,000 Level 3 CRITICAL(0.34 to 1.76) (from 84 fewer to 96 more) LowRandomized 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 2 fewer per 10,000 Level 3 CRITICAL(0.01 to 8.16) (from 3 fewer to 20 more) LowObservational 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 CRITICALVery lowRandomized 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 38 more per 10,000 Level 2 IMPORTANT(0.92 to 1.26) (from 44 fewer to 142 more) ModerateRandomized 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 3.39 125 more per 10,000 Level 3 IMPORTANT(1.32 to 8.72) (from 17 more to 403 more) Low*Counts not provided for all studies.CI: confidence interval; RR: risk ratioExplanationsa Symptom-based outcome definitionb Observational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmed.cDisparate results for two studies conducted in the United States during the same season.dPooled estimate is derived from two estimates that are each relatively precise but sit on either side of the null with no CI overlapeMajority of data come from studies in which outcome definition is not laboratory-confirmed.fCluster randomized study with ICD-code based outcome definitions. Not blinded; randomization sequence generation and timing of recruitment of participants unclear.gObservational study/studies; outcome is ICD code defined rather than laboratory confirmed for all or larger studies.hConfidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.iSmall sample size and low event rate; sensitive to small changes in distribution of events between groups.j CI ranges from slightly to substantially favoring comparator vaccine.k Not estimableTable 4c: Grade Summary of Findings Table: RIV3 vs. SD-IIVCertainty assessment № of patients Effect Certainty Importance№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations RIV SD-IIV Relative Absolute(95% CI) (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 54 fewer per 10,000 Level 2 CRITICAL(0.57 to 1.17) (from 128 fewer to 51 more) ModerateObservational 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 — per 10,000 Level 3 CRITICAL(0.76 to 0.91) (from — to –) LowRCTs: 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 5 fewer per 1,000 Level 3 CRITICAL(0.05 to 1.67) (from 6 fewer to 4 more) LowGuillain-Barre syndrome1 observational studies seriousb not serious not serious very seriouse none 0/21976 (0.0%) 4/283683 (0.0%) not estimable Level 4 CRITICALVery lowRandomized 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 9 more per 10,000 Level 3 IMPORTANT(0.84 to 1.26) (from 45 fewer to 74 more) LowRCTs: 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 39 fewer per 10,000 Level 3 IMPORTANT(0.27 to 1.69) (from 85 fewer to 81 more) LowCI: confidence interval; OR: odds ratio; RR: risk ratioExplanationsa Small sample size and low event rate; sensitive to small changes in distribution of events between groups.b Observational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code defined rather than laboratory-confirmed.c Population in this analysis includes persons ages 50 and older; slightly over half ages 50 through 64 years.dConfidence interval crosses null and incudes potential for meaningful effect favoring either vaccine.e Not estimableTable 4d: Grade Summary of Findings Table: HD-IIV3 vs. aIIV3Certainty assessment № of patients Effect Certainty Importance№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HD-IIV3 aIIV3 Relative Absolute(95% CI) (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 0.34 660 fewer per 10,000 Level 4 CRITICAL(0.04 to 3.13) (from 960 fewer to 2130 more) Very lowObservational 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 — per 10,000 Level 4 CRITICAL(0.92 to 1.23) (from — to –) Very lowObservational studies (person-time denominator): influenza-associated hospitalizations4 observational studies very seriousf not serious not serious seriousg none -/25467741* -/6356816* Rate ratio 0.96 — per 10,000 Level 4 CRITICAL(0.90 to 1.01) (from — to –) Very lowRandomized 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 34 fewer per 10,000 Level 3 CRITICAL(0.29 to 1.80) (from 88 fewer to 99 more) LowRandomized 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 CRITICALLowRandomized 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 79 fewer per 10,000 Level 3 IMPORTANT(0.32 to 1.30) (from 153 fewer to 68 more) LowRandomized 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 23 fewer per 10,000 Level 3 IMPORTANT(0.45 to 1.75) (from 106 fewer to 144 more) Low*Event counts not provided for all studies.CI: confidence interval; RR: risk ratioExplanationsa Open-label study.bSmall sample size and low event rate; sensitive to small changes in distribution of events between groups.cObservational study with outcome defined by CPT code for influenza rapid test and record of prescription for oseltamivir; not laboratory-confirmeddDisparate estimates from two different studies conducted over the same influenza season.eWidth of confidence interval derives from inconsistency of estimates that are each on their own precise but which lie on opposite sides of null.fObservational study/studies with incomplete adjustment for all potential confounders of interest. Outcome is ICD code-defined rather than laboratory-confirmed.gConfidence interval includes null and indicates potential for either meaningful effect or no difference.hNot estimableTable 4e: Grade Summary of Findings Table: HD-IIV3 vs. RIV4Certainty assessment № of patients Effect Certainty Importance№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HD-IIV3 RIV4 Relative Absolute(95% CI) (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 0.26 987 fewer per 10,000 Level 4 CRITICAL(0.03 to 2.18) (from 1,293 fewer to 1,573 more) Very lowObservational 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 — per 10,000 Level 3 CRITICAL(1.03 to 1.21) (from — to –) LowRandomized 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 12 fewer per 10,000 Level 3 CRITICAL(0.22 to 3.32) (from 64 fewer to 191 more) LowRandomized 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 1.77 111 more per 10,000 Level 3 IMPORTANT(0.73 to 4.27) (from 39 fewer to 471 more) LowRandomized 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 fewer per 100,000 Level 3 IMPORTANT(0.32 to 109.56) (from 0 fewer to 0 fewer) LowCI: confidence interval; RR: risk ratioExplanationsaOpen-label study.bSmall sample size and low event rate; sensitive to small changes in distribution of events between groups.cObservational 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. RIV4Certainty assessment № of patients Effect Certainty Importance№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations aIIV3 RIV4 Relative Absolute(95% CI) (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 0.75 333 fewer per 10,000 Level 4 CRITICAL(0.18 to 3.07) (from 1,093 fewer to 2,760 more) Very lowObservational 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 — per 10,000 Level 3 CRITICAL(1.03 to 1.22) (from — to –) LowRandomized 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 fewer per 10,000 Level 3 CRITICAL(0.24 to 89.17) (from 0 fewer to 0 fewer) LowRandomized 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 97 more per 10,000 Level 3 IMPORTANT(0.58 to 5.65) (from 50 fewer to 555 more) LowRandomized 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 fewer per 100,000 Level 3 IMPORTANT(0.24 to 89.17) (from 0 fewer to 0 fewer) LowCI: confidence interval; RR: risk ratioExplanationsaOpen-label study.bSmall sample size and low event rate; sensitive to small changes in distribution of events between groups.cObservational 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 InterestCertainty, by comparisonVaccines of interest vs SD-IIVs EIVs vs one anotherOutcome Importance Included in profile? HD-IIV3 vs aIIV3 vs RIV vs HD-IIV3 vs HD-IIV3 vs aIIV3 vsSD-IIV SD-IIV SD-IIV aIIV3 RIV4 RIV4BENEFITSInfluenza illnesses Critical Yes Level 1 Level 2 Level 2 Level 4 Level 4 Level 4High Moderate Moderate Very low Very low Very lowInfluenza outpatient/ER visits Critical Yes Level 3 Level 3 Level 4Low Low Very LowInfluenza hospitalizations Critical Yes Level 2 Level 2 Level 3 Level 4 Level 3 Level 3Moderate Moderate low Very Low Low LowInfluenza deaths Critical Yes Level 3LowHARMSAny Serious Adverse Event (SAE) Important Yes Level 1 Level 2 Level 3 Level 3 Level 3 Level 3High Moderate Low Low Low LowSolicited injection site adverse events Grade ≥3 Important Yes Level 3 Level 3 Level 3 Level 3 Level 3 Level 3Low Low Low Low Low LowSolicited systemic Critical Yes Level 3 Level 3 Level 3 Level 3 Level 3 Level 3adverse events Grade ≥3 Low Low Low Low Low LowGuillain-Barré syndrome Critical Yes Level 3 Level 3 Level 4 Level 3Low Low Very low LowOVERALL: Level 3 Level 3 Level 4 Level 4 Level 4 Level 4Low Low Very low Very low Very low Very lowAppendix 1: Studies Included in the Review of EvidenceLast name first author, Study design Country Age Total population N N Outcomes Funding sourcePublication year Intervention comparisonBalasubramani 2020 (13) TNCC US ≥65 years 2,993 1,573 HD-IIV3 1,420 SD-IIV3/4 Outpatient/ER US government(US Flu VE Network)29 HD-IIV3Belongia 2020 (12) Randomized US 65 through 74 years 99 30 aIIV3 Illnesses US government30 RIV4Cocchio 2020 (18) Retro. cohort Italy ≥65 years 479,397 68660 aIIV3 410,737 Hospitalizations No external funding.Conventional vaccine strategy (classified as use in ≥90% of cases)Couch 2007 (57) Randomized US ≥65 years 214 206 HD-IIV3 208 SD-IIV3 Reactogenicity US government510 HD-IIV3 SAEsCowling 2020 (37) Randomized Hong Kong 65 through 82 years 1,861 508 aIIV3 508 SD-IIV4 Reactogenicity US government335 RIV4DiazGranados 2014 (7) Randomized US/Canada ≥65 years 31,983 15,993 15,990 SD-IIV3 Illnesses Sanofi PasteurHD-IIV3 SAEsDiazGranados 2015 (22) Randomized US ≥65 years 31,983 15,993 15,990 SD-IIV3 Hospitalizations Sanofi PasteurCanada HD-IIV3De 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 ≥65 years 1,107 622 HD-IIV3 485 SD-IIV Hospitalization US government(HAIVEN)9,003 ≥50 yrs 4,498 ≥50 yrs 4,505 ≥50 IllnessesDunkle 2017 (8) Randomized US ≥50 years 3,452 ≥65 yrs 1,743 ≥65 yrs 1,710 ≥65 SAEs BARDA; Protein Sciences authorsRIV4 SD-IIV4Falsey 2009 (46) Randomized US ≥65 years 3,781 2,541 HD-IIV3 1,240 SD-IIV3 SAEs Sanofi PasteurUS, Colombia, IllnessesFrey 2014 (10) Randomized Panama ≥65 years 6,961 3,479 HD-IIV3 3,482 SD-IIV3 SAEs NovartisPhilippines ReactogenicityGBSGravenstein 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 ≥65 years 2,545,275 929,730 HD-IIV3 1,615,545 Outpatient/ER US government(Medicare) SD-IIV38,488,136Izurieta 2019 (15) Retro. Cohort US ≥65 years 11,737,916 HD-IIV3 1,822,862 Outpatient/ER, US government(Medicare) 1,466,918 SD-IIV4 HospitalizationsaIIV37,905,252HD-IIV3Izurieta 2020 (20) Retro. Cohort US ≥65 years 11,717,822 2,100,512 1,454,340 Hospitalizations US government(Medicare) aIIV3 SD-IIV4257,718RIV47,173,433HD-IIV3Izurieta 2021 (21) Retro. cohort US ≥65 years 11,931,830 2,565,513 1,584,451 Hospitalizations US government(Medicare) aIIV3 SD-IIV4608,433RIV4Hansen 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 US governmentReactogenicityKeitel 2010 (41) Randomized US ≥65 years 869 436 RIV3 433 SD-IIV3 SAEs Unclear; Protein Sciences authorReactogenicityLi 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 6,151,913 Hospitalizations US governmentHD-IIV3 SD-IIVMannino 2012 (34) Prospective cohort Italy ≥65 years 164,254 person-seasons 84,665 person-seasons 79,589 Hospitalizations Novartisperson-seasonsMcConeghy 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 Pasteur2,420,450 1210225 1,210,225Paudel 2020 (27) Retro. cohort US ≥65 years Pharmacy cohort Pharmacy cohort Pharmacy cohort Hospitalizations Sanofi Pasteur2,421,758 1,210,879 1,210,879Outpatient cohort Outpatient cohort Outpatient cohortPebody (35) TNCC UK ≥65 years 835 818 17 Hospitalizations UK Government1,269,855 HD-IIV3 212,287Pelton 2020 (19) Retro. cohort US ≥65 years 446,600 234,313 SD-IIV Outpatient/ER SeqirusaIIV31,672,797Pelton 2021 (56) Retro. cohort US ≥65 years 2,234,040 HD-IIV3 Outpatient/ER Funding not stated. Seqirus authors.561,243aIIV3Richardson 2015 (28) Retro. cohort US ≥65 years 165,225 25,714 HD-IIV3 139,511 SD-IIV Hospitalizations US government(VA)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 ≥65 years 9,722,909 1,039,645 1,683,264 Outpatient/ER US government(Medicare) HD-IIV3 SD-IIV3 DeathsScheifele 2013 (39) Randomized Canada ≥65 years 608 301 aIIV3 307 SD-IIV3 SAEs Canadian governmentReactogenicity378 aIIV3 SAEsSchmader 2021 (42) Randomized US ≥65 years 755 377 HD-IIV3 Reactogenicity US governmentGBSSeo 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.153 HD-IIV3 SAEsShinde 2022 (43) Randomized US ≥65 years 304 151 RIV5 Reactogenicity NovavaxGBSTreanor 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 Pasteur1,900,920Van Aalst 2020 (36) Retro. cohort US ≥65 years 2,124,713 HD-IIV3 Hospitalizations Sanofi Pasteur223,793aIIV3Van 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 ≥65 years 73,773 24,682 49,091 Outpatient/ER, Sanofi Pasteur; Sanofi authors(VA) HD-IIV3 SD-IIV3 HospitalizationsYoung-Xu 2019 (30) Retro. Cohort US ≥65 years 3,638,924 158,636 3,480,288 Hospitalizations Unrestricted grant, Sanofi Pasteur; Sanofi authors(VA) HD-IIV3 SD-IIV3Young-Xu 2020 (33) Retro. Cohort US ≥65 years 569,552 person-seasons 207,574 person-seasons 361,978 person-seasons Deaths Unrestricted grant, Sanofi Pasteur; Sanofi authors(VA) HD-IIV3 SD-IIV3References in this appendix: 78910111213141516171819202122242526272829303133343536373839404142434445464748495051525354555657Abbreviations: 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 StrategiesMain search (1990 through September 7, 2021):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.ANDExp 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)ANDAdverse.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*).dtEmbase(OVID)1988-Exp influenza vaccine/ OR ((influenza ADJ5 vaccin*) OR (flu ADJ5 vaccin*) OR MF59* OR MF-59*).ti,ab. OR influenza vaccines.rn.ANDExp 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)ANDAdverse.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*).dcCINAHL(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 2021Cochrane Library[mh “Influenza Vaccine”] OR ((influenza NEAR/5 vaccin*) OR (flu NEAR/5 vaccin*) OR MF59* OR MF-59*):ti,abAND[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,abAND(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,abLimit 1990 – ; update December 2019 – February 2021ScopusTITLE-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 2021Clinicaltrials.govvaccine OR vaccination | influenza | Older Adult | First posted from 12/05/2019 to 02/10/2021Supplementary search for review articles (1990 through September 7, 2021):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.ANDAdverse.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).tiLimit 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.ANDAdverse.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).tiLimit 1990 – ; NOT pubmed/medlineCINAHL(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 recordsCochrane Library(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 recordsScopusTITLE-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 = ReviewView the complete list of GRADE evidence tablesList of GRADE evidence tablesOn This Page* Background* Methods* Appendix 1: Studies Included in the Review of Evidence* Appendix 2. Literature Search StrategiesRelated PagesView AllBack to Top* GRADE Evidence Tables – Recommendations in MMWR* ACIP Grading Recommendations for HPV Vaccine for Males* Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Safety of Influenza Vaccines for Persons with Egg Allergy* ACIP Grading for Japanese Encephalitis Vaccine in Children* ACIP Evidence to Recommendations for Japanese Encephalitis VaccineView All ACIPACIP Grading for Japanese Encephalitis Vaccine in ChildrenSeptember 9, 2024Sources Print ShareFacebook LinkedIn Twitter SyndicateContent Source:National Center for Immunization and Respiratory Diseases (NCIRD)References1. 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):846-55.2. 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):e0118369.3. 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):179-86.4. 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):132-7.5. 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):68-90.6. CDC. Past seasons vaccine effectiveness estimates. www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html#2021. .7. 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):635-45.8. 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):2427-36.9. 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):6122-8.10. 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):5027-34.11. 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):1121-7.12. 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):3121-8.13. 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):6562-9.14. 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):293-300.15. Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, et al. 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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):6683-7.30. 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):1484-90.31. 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):121-6.32. 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).33. 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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):1383-91.38. 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):573-6.39. 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):2460-73.40. 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):989-96.41. Keitel WA, Treanor JJ, El Sahly HM, Gilbert A, Meyer AL, Patriarca PA, et al. 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