About
CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Background
Estimated 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.
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
Policy question:
Do the relative benefits and harms of HD-IIV, aIIV, and RIV (referred to collectively as Higher Dose and Adjuvanted Influenza Vaccines) as compared with one another and with standard-dose unadjuvanted inactivated influenza vaccines (SD-IIVs) favor the use of any one or more of these vaccines over other age-appropriate influenza vaccines for persons ≥65 years of age?
Population
Persons aged ≥65 years
Intervention
Trivalent or quadrivalent formulations of:
- High-dose inactivated influenza vaccine (HD-IIV3/4)*
- MF-59 adjuvanted inactivated influenza vaccine (aIIV3/4)*
- Recombinant influenza vaccine (RIV3/4)*
Comparison
Age-appropriate trivalent or quadrivalent influenza vaccines.* Relevant comparisons are:
- HD-IIV3/4 vs standard-dose unadjuvanted inactivated influenza vaccines (SD-IIV3/4)
- aIIV3/4 vs SD-IIV3/4
- RIV3/4 vs SD-IIV3/4
- HD-IIV3/4 vs aIIV3/4
- HD-IIV3/4 vs RIV3/4
- aIIV3/4 vs RIV3/4
Outcomes
Benefits†:
- Influenza illness
- Influenza-associated outpatient/ER visits
- Influenza-associated hospitalizations
- Influenza-associated deaths
- 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
| Outcome | Importance | Included in evidence profile |
|---|---|---|
| Influenza illness | Critical | Yes |
| Influenza-associated outpatient/ER visits | Critical | Yes |
| Influenza-associated hospitalizations | Critical | Yes |
| Influenza-associated deaths | Critical | Yes |
| Any solicited systemic adverse events Grade ≥3 | Critical | Yes |
| Guillain-Barré syndrome | Critical | Yes |
| Any solicited injection site adverse event Grade ≥3 | Important | Yes |
| Any Serious Adverse Event (SAE) | Important | Yes |
* Three options: 1. Critical for decision making; 2. Important but not critical for decision making; 3. Not important for decision making
Table 3a: Summary of Studies Reporting Outcome: Influenza illnesses (Critical)
References in this table: 78101112
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV3—Randomized studies | ||||||
| DiazGranados 2014 (7) | ≥65 years | 15,990 | 15,993 | SD-IIV3 | RR: 0.76 (0.64, 0.90) | Low |
| aIIV3 vs SD-IIV3—Randomized studies | ||||||
| Frey 2014 (10) | ≥65 years | 3,479 | 3,482 | SD-IIV3 | RR: 1.03 (0.89, 1.19)† | Low |
| RIV3 vs SD-IIV3–Randomized studies | ||||||
| Keitel 2010 (11) | ≥65 years | 436 | 433 | SD-IIV3 | RR: 0.50 (0.05, 5.46)† | Unclear |
| RIV4 vs SD-IIV4–Randomized studies | ||||||
| Dunkle 2017 (8) | ≥65 years | 1,732 | 1,710 | SD-IIV4 | RR: 0.83 (0.58, 1.19) | Low |
| HD-IIV3 vs aIIV3–Randomized studies | ||||||
| Belongia 2020 (12) | 65-74 years | 29 | 30 | aIIV3 | RR: 0.34 (0.04, 3.13)† | High |
| HD-IIV3 vs RIV4–Randomized studies | ||||||
| Belongia 2020 (12) | 65-74 years | 29 | 30 | RIV4 | RR: 0.26 (0.03, 2.18)† | High |
| aIIV3 vs RIV4–Randomized studies | ||||||
| Belongia 2020 (12) | 65-74 years | 30 | 30 | RIV4 | RR: 0.75 (0.18, 3.07)† | High |
Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
†No risk estimate reported. RR is calculated from reported counts.
Table 3b: Summary of Studies Reporting Outcome: Influenza outpatient/ER visits
References in this table:9131415161718192021
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV—Observational studies | ||||||
| Balasubramani 2020 (13)† | ≥65 years | 1,573 | 1,420 | SD-IIV3/4 | OR: 0.91 (73, 1.12) | Moderate |
| Izurieta 2015 (14) | ≥65 years | 929,730 | 1,615,545 | SD-IIV3 | Rate ratio: 0.78 (0.71, 0.86) |
Serious |
| Izurieta 2019 (15) | ≥65 years | 8,488,136 | 1,822,862 | SD-IIV4 (egg-based) | Rate ratio: 0.99 (0.97, 1.02) |
Serious |
| Shay 2017 (16) | ≥65 years | 2,547,821 | 3,560,591 | SD-IIV3 | Rate ratio: 0.85 (0.80, 0.90) |
Serious |
| Young-Xu 2018 (17) | ≥65 years | 24,682 | 49,091 | SD-IIV3 | Rate ratio: 0.86 (0.68, 1.08) |
Serious |
| aIIV3 vs SD-IIV—Observational studies | ||||||
| Iob 2005 (18) | ≥65 years | 1,487 | 1,478 | SD-IIV3 | OR: 0.66 (0.53, 0.82) | Serious |
| Izurieta 2019 (15) | ≥65 years | 1,466,918 | 1,822,862 | SD-IIV4 (egg-based) | Rate ratio: 1.07 (1.04, 1.10) |
Serious |
| Pelton 2020 (19) | ≥65 years | 234,313 | 212,287 | SD-IIV4 | Rate ratio: 0.64 (0.59, 0.69) |
Serious |
| Van Buynder 2013 (9) | ≥65 years | 165 | 62 | SD-IIV3 | OR: 0.37 (0.14, 0.98) | Serious |
| HD-IIV3 vs aIIV3—Observational studies | ||||||
| Izurieta 2019 (15) | ≥65 years | 1,466,918 | 8,488,136 | HD-IIV3 vs aIIV3 | Rate ratio: 0.93 (0.91, 0.95) |
Serious |
| Pelton 2020 (20) | ≥65 years | 1,269,855 | 234,313 | HD-IIV3 vs aIIV3 | Rate ratio: 1.20 (1.12, 1.28) |
Serious |
| Pelton 2021 (21) | ≥65 years | 1,672,797 | 561,243 | HD-IIV3 vs aIIV3 | Rate ratio: 1.07 (1.03, 1.13) |
Serious |
Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; OR = odds ratio; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
†Analyses included cases associated with influenza A viruses only.
Table 3c: Summary of Studies Reporting Outcome: Influenza hospitalizations
References in this table:15172021222324252627282930313233343536
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV–Randomized studies | ||||||
| DiazGranados 2015a (22) | ≥65 years | 15,990 | 15,993 | HD-IIV3 vs SD-IIV3 | Rate Ratio: 0.67 (0.19, 2.36) |
Unclear |
| Vardeny 2021 (23) | Mean age 65.5, SD 12.6/12.5 yrs | 2,606 | 2,604 | HD-IIV3 vs SD-IIV4 | Rate Ratio: 1.25 (0.49, 3.16) |
Unclear |
| HD-IIV3 vs SD-IIV—Cluster Randomized studies | ||||||
| Gravenstein 2017 (24) | ≥65 years | 19,127 | 19,129 | HD-IIV3 vs SD-IIV3 | RR: 0.79 (0.66, 0.95) | Unclear |
| HD-IIV3 vs SD-IIV—Observational studies | ||||||
| Doyle 2021 (25) | ≥65 years | 622 | 485 | HD-IIV3 vs SD-IIV | OR: 0.74 (0.53, 1.02) | Serious |
| Izurieta 2019 (15) | ≥65 years | 8,488,136 | 1,822,862 | HD-IIV3 vs SD-IIV4 | Rate ratio: 0.90 (0.88, 0.92) |
Serious |
| Izurieta 2020 (20) | ≥65 years | 7,905,252 | 1,454,340 | HD-IIV3 vs SD-IIV4 | Rate ratio: 0.95 (0.91, 0.99) |
Serious |
| Izurieta 2021(21) | ≥65 years | 7,173,433 | 1,584,451 | HD-IIV3 vs SD-IIV4 | Rate ratio: 0.93 (0.89, 0.98) |
Serious |
| Lu 2019 (26) | ≥65 years | 13,770,207 | 6,151,913 | HD-IIV3 vs SD-IIV | Rate ratio: 0.88 (0.28, 0.94) |
Serious |
| Paudel 2020 (27) | ≥65 years | Outpatient cohort: 2796994 Pharmacy cohort: 2760882 |
Outpatient cohort: 2996994 Pharmacy cohort: 2760882 |
HD-IIV3 vs SD-IIV | Outpatient cohort: Rate ratio 0.96 (0.94, 0.99) Pharmacy cohort Rate ratio 0.93 (0.90, 0.97) |
Serious |
| Richardson 2015 (28) | ≥65 years | 25714 | 139511 | HD-IIV3 vs SD-IIV | Rate ratio: 0.98 (0.69, 1.40) |
Serious |
| Robison 2018 (29) | ≥65 years | 23712 | 23712 | HD-IIV3 vs SD-IIV | Rate ratio: 0.69 (0.52, 0.92) |
Serious |
| Young-Xu 2018 (17) | ≥65 years | 24862 | 49091 | HD-IIV3 vs SD-IIV | Rate ratio: 0.75 (0.57, 0.99) |
Serious |
| Young-Xu 2019 (30) | ≥65 years | 158636 person-seasons | 3480288 person-seasons | HD-IIV3 vs SD-IIV | Rate ratio: 0.87 (0.81, 0.94) | Serious |
| aIIV3 vs SD-IIV—Cluster Randomized studies | ||||||
| McConeghy 2020 (31) | ≥65 years | 24926 | 25086 | aIIV3 vs SD-IIV | HR: 0.79 (0.65, 0.96) | Unclear |
| aIIV3 vs SD-IIV—Observational studies | ||||||
| Cocchio 2020 (32) | ≥65 years | 68660 | 410737 | SD-IIV3/4 | OR: 0.37 (0.59, 0.75) | Serious |
| Izurieta 2019 | ≥65 years | 1466918 | 1822862 | aIIV3 vs SD-IIV | Rate Ratio: 0.98 (0.94, 1.01) |
Serious |
| Izurieta 2020 (33) | ≥65 years | 2100592 | 1454340 | aIIV3 vs SD-IIV | Rate Ratio: 0.93 (0.89, 0.99) |
Serious |
| Izurieta 2021 (21) | ≥65 years | 2545513 | 1584451 | aIIV3 vs SD-IIV | Rate Ratio: 0.93 (0.88, 0.99) |
Serious |
| Mannino 2012 (34) | ≥65 years | 64665 person- seasons | 79589 person-seasons | aIIV3 vs SD-IIV | OR: 0.75 (0.57, 0.98) | Serious |
| Pebody 2020 (35) | ≥65 years | 818 | 17 | aIIV3 vs SD-IIV | OR: 0.70 (0.27, 1.83) | Moderate |
| RIV vs SD-IIV—Observational studies | ||||||
| Izurieta 2021 (21) | ≥65 years | 608433 | 1584451 | RIV vs SD-IIV4 | Rate ratio: 0.83 (0.76, 0.91) |
Serious |
| HD-IIV3 vs aIIV3—Observational studies | ||||||
| Izurieta 2019 (15) | ≥65 years | 8488136 | 1466918 | HD-IIV3 vs aIIV3 | Rate ratio: 0.92 (0.90, 0.95) |
Serious |
| Izurieta 2020 (20) | ≥65 years | 7905252 | 2100592 | HD-IIV3 vs aIIV3 | Rate ratio: 1.01 (0.98, 1.05) |
Serious |
| Izurieta 2021 (21) | ≥65 years | 7173433 | 2565513 | HD-IIV3 vs aIIV3 | Rate ratio: 1.0 (0.96, 1.04) |
Serious |
| Van Aalst 2020 (36) | ≥65 years | 1900920 | 223793 | HD-IIV3 vs aIIV3 | Rate ratio: 0.88 (0.80, 0.97) |
Serious |
| HD-IIV3 vs RIV4—Observational studies | ||||||
| Izurieta 2021 (21) | ≥65 years | 7173433 | 608433 | HD-IIV3 vs RIV4 | Rate ratio: 1.12 (1.03, 1.21) |
Serious |
| aIIV3 vs RIV4—Observational studies | ||||||
| Izurieta 2021 (21) | ≥65 years | 2565513 | 608433 | aIIV3 vs RIV4 | Rate ratio: 1.12 (1.03, 1.22) |
Serious |
Table 3d: Summary of Studies Reporting Outcome: Influenza deaths
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV—Observational | ||||||
| Shay 2017 (16) | ≥65 years | 2,547,821 (30,079,255 person-weeks) |
3,560,591 42,696,182 person-weeks) |
SD-IIV3 | RR: 0.77 (0.58, 1.00) | Serious |
| Young-Xu 2020 (33) | ≥65 years | 207,574 | 361,978 | SD-IIV3 | RR: 0.62 (0.46, 0.82) | Moderate |
Abbreviations: HD-IIV3 = high dose inactivated influenza vaccine, trivalent; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
Table 3e: Summary of Studies Reporting Outcome: Any Solicited Systemic AE Grade ≥3 (Critical)>
References in this table:1137383940414243
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV–Randomized studies | ||||||
| Couch 2007 (57) | ≥65 years | 206 | 208 | HD-IIV3 vs SD-IIV3 | RR: 3.03 (0.12, 73.93) | Unclear |
| Cowling 2020 (37) | 65 through 82 years | 510 | 508 | HD-IIV3 vs SD-IIV4 | RR: 0.66 (0.11, 3.96) | Low |
| Keitel 2006 (11) | ≥65 years | 50 | 51 | HD-IIV3 vs SD-IIV3 | RR: not estimable | Unclear |
| aIIV3 vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 3/508 | 3/508 | aIIV3 vs SD-IIV4 | RR: 1.00 (0.20, 4.93) | Low |
| Menegon 1999 (38) | ≥65 years | 96 | 98 | aIIV3 vs SD-IIV3 | RR: not estimable | Unclear |
| Scheifele 2013 (39) | ≥65 years | 301 | 307 | aIIV3 vs SD-IIV3 | RR: 0.61 (0.23, 1.66) | Low |
| Seo 2014 (40) | ≥65 years | 111 | 113 | aIIV3 vs SD-IIV3 | RR: 3.05 (0.13, 74.16) | Unclear |
| RIV3 vs SD-IIV–Randomized studies | ||||||
| Keitel 2010 (41) | ≥65 years | 436 | 433 | RIV3 vs SD-IIV3 | RR: 0.33 (0.03, 3.17) | Unclear |
| RIV4 vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 335 | 508 | RIV4 vs SD-IIV4 | RR: 0.22 (0.01, 4.18) | Low |
| HD-IIV3 vs aIIV3–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 508 | HD-IIV3 vs aIIV3 | RR: 0.66 (0.11, 3.96) | Low |
| Schmader 2021 (42) | ≥65 years | 377 | 378 | HD-IIV3 vs aIIV3 | RR: 0.75 (0.26, 2.15) | Low |
| HD-IIV3 vs RIV4–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 335 | HD-IIV3 vs RIV4 | RR: 3.29 (0.16, 68.27) | Low |
| Shinde 2019 (43) | ≥65 years | 153 | 151 | HD-IIV3 vs RIV4 | RR: 0.49 (0.09, 2.65) | Low |
| aIIV3 vs RIV4–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 508 | 335 | aIIV3 vs RIV4 | RR: 4.62 (0.24, 89.17) | Low |
Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
Table 3f: Summary of Studies Reporting Outcome: Guillain-Barré syndrome (Critical)
References in this table:1023424445
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV4–Randomized studies | ||||||
| Vardeny 2021 (23) | Mean age 65.5, SD 12.6/12.5 yrs | 2,606 | 2,604 | SD-IIV4 | Not estimable | Low |
| aIIV3 vs SD-IIV3–Randomized studies | ||||||
| Frey 2014 (10) | ≥65 years | 3,479 | 3,481 | SD-IIV3 | Not estimable | Low |
| aIIV3 vs SD-IIV3—Observational studies | ||||||
| Villa 2013 (44) | ≥65 years | 88,449 vaccine doses over 3 seasons (6-week window) |
82,539 vaccine doses over 3 seasons (6-week window) |
SD-IIV3 | RD: 0 Risk with aIIV3: (0, 4.47) Risk with aIIV3: (0, 4.17) |
Serious |
| RIV3 vs SD-IIV3—Observational studies | ||||||
| Hansen 2020 (45) | ≥18 years | 21,976 | 28,3683 | SD-IIV3 | Outpatient, 0-41 days: OR: 0 (0, 16.066 Inpatient/ER, 0-41 days: OR: 0 (0, 112.6) |
Moderate |
| HD-IIV3 vs aIIV3–Randomized studies | ||||||
| Schmader 2021 (42) | ≥65 years | 377 | 378 | aIIV4 | Not estimable | Low |
Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; OR = odds ratio; RD = risk difference; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
Table 3g: Summary of Studies Reporting Outcome: Any Serious Adverse Event (SAE) (Important)
References in this table: 81011233237414243464748495051525354
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 508 | HD-IIV3 vs SD-IIV4 | RR: 0.77 (0.34, 1.73) | Low |
| DiazGranados 2014 | ≥65 years | 15,992 | 15,991 | HD-IIV3 vs SD-IIV3 | RR: 0.92 (0.85, 0.99) | Low |
| Falsey 2009 (46) | ≥65 years | 2,541 | 1,240 | HD-IIV3 vs SD-IIV3 | RR: 0.83 (0.65, 1.07) | Unclear |
| Keitel 2006 (11) | ≥65 years | 50 | 51 | HD-IIV3 vs SD-IIV3 | RR: 1.02 (0.22, 4.82) | Unclear |
| Nace 2015 (47) | ≥65 years | 89 | 98 | HD-IIV3 vs SD-IIV3 | RR: 0.92 (0.29, 2.90) | High |
| Tsang 2014 (48) | ≥65 years | 320 | 319 | HD-IIV3 vs SD-IIV3 | RR: 0.76 (0.40, 1.43) | Unclear |
| Vardeny 2021 (23) | Mean age 65.5, SD 12.6/12.5 yrs | 2,606 | 2,604 | HD-IIV3 vs SD-IIV4 | RR: 0.50 (0.09, 2.73) | Low |
| aIIV3 vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 508 | 508 | aIIV3 vs SD-IIV4 | RR: 0.65 (0.38, 1.87) | Low |
| De Bruijn 2007 (49) | ≥65 years | 130 | 129 | aIIV3 vs SD-IIV3 | RR: 2.98 (0.12, 72.41) | High |
| De Donato 1999 (50) | ≥65 years | 248 | 233 | aIIV3 vs SD-IIV3 | RR: 0.78 (0.24, 2.53) | High |
| Della Cioppa 2012 (50) | ≥65 years | 47 | 44 | aIIV3 vs SD-IIV3 | RR: 0.31 (0.01, 7.47) | High |
| Frey 2014 (10) | ≥65 years | 3,545 | 3,537 | aIIV3 vs SD-IIV3 | RR: 1.08 (0.92, 1.28) | Low |
| Li 2008 (51) | ≥65 years | 391 | 198 | aIIV3 vs SD-IIV3 | RR: 2.03 (0.23, 18.00) | High |
| Scheifele 2013 (39) | ≥65 years | 301 | 307 | aIIV3 vs SD-IIV3 | RR: 1.18 (0.57, 2.43) | Low |
| Sindoni 2009 (52) | ≥65 years | 96 | 99 | aIIV3 vs SD-IIV3 | RR: Not estimable | Unclear |
| RIV vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 335 | 508 | RIV4 vs SD-IIV4 | RR: 0.47 (0.15, 1.42) | Low |
| Dunkle 2017 (8) | ≥50 years | 4,328 | 4,344 | RIV4 vs SD-IIV4 | RR: 1.10 (0.87, 1.39) | Low |
| Izikson 2015 (53) | ≥50 years | 1,314 | 1,313 | RIV3 vs SD-IIV3 | RR: 0.50 (0.17, 1.46) | Unclear |
| Keitel 2010 (41) | ≥65 years | 436 | 433 | RIV3 vs SD-IIV3 | RR: 1.05 (0.67, 1.65) | Unclear |
| Treanor 2006 (54) | ≥65 years | 100 | 199 | RIV3 vs SD-IIV3 | RR: 0.99 (0.06, 15.61) | Unclear |
| HD-IIV3 vs aIIV3–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 508 | HD-IIV3 vs aIIV3 | RR: 0.91 (0.39, 2.11) | Low |
| Schmader 2021 (42) | ≥65 years | 377 | 378 | HD-IIV3 vs aIIV3 | RR: 0.33 (0.09, 1.22) | Low |
| HD-IIV3 vs RIV4–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 335 | HD-IIV3 vs RIV4 | RR: 1.64 (0.52, 5.19) | Low |
| Shinde 2019 (43) | ≥65 years | 153 | 151 | HD-IIV3 vs RIV4 | RR: 1.97 (0.50, 7.75) | Low |
| aIIV3 vs RIV4–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 508 | 335 | aIIV3 vs RIV4 | RR: 1.81 (0.58, 5.65) | Low |
Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
Table 3h: Summary of Studies Reporting Outcome: Any Solicited injection site AE Grade ≥3 (Important)
References in this table:11373839414243
| Author Publication year |
Age/other characteristics | N intervention | N comparison | Comparison vaccine | Effect estimate* | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|
| HD-IIV3 vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 508 | HD-IIV3 vs SD-IIV4 | RR: 3.98 (0.45, 35.52) | Low |
| Keitel 2006 (11) | ≥65 years | 50 | 51 | HD-IIV3 vs SD-IIV3 | RR: 7.14 (0.38, 134.72) | Unclear |
| aIIV3 vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 508 | 508 | aIIV3 vs SD-IIV4 | RR: 3.00 (0.31, 28.74) | Low |
| Della Cioppa 2012 | ≥65 years | 47 | 44 | aIIV3 vs SD-IIV3 | RR: 2.81 (0.12, 67.27) | High |
| Menegon 1999 (38) | ≥65 years | 96 | 98 | aIIV3 vs SD-IIV3 | RR: not estimable | Unclear |
| Scheifele 2013 (39) | ≥65 years | 301 | 307 | aIIV3 vs SD-IIV3 | RR: 3.57 (1.19, 10.72) | Low |
| RIV vs SD-IIV–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 335 | 508 | RIV4 vs SD-IIV4 | RR: 0.50 (0.02, 12.36) | Low |
| Keitel 2010 (41) | ≥65 years | 436 | 433 | RIV3 vs SD-IIV3 | RR: 0.70 (0.27, 1.81) | Unclear |
| HD-IIV3 vs aIIV3–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 510 | 508 | HD-IIV3 vs aIIV3 | RR: 1.33 (0.30, 5.90) | Low |
| Schmader 2021 (42) | ≥65 years | 377 | 378 | HD-IIV3 vs aIIV3 | RR: 0.79 (0.36, 1.71) | Low |
| HD-IIV3 vs RIV4–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 508 | 335 | HD-IIV3 vs RIV4 | RR: 5.92 (0.32, 109.56) | Low |
| Shinde 2019 (43) | ≥65 years | 153 | 151 | HD-IIV3 vs RIV4 | RR: not estimable | Low |
| aIIV3 vs RIV4–Randomized studies | ||||||
| Cowling 2020 (37) | 65 through 82 years | 508 | 335 | aIIV3 vs RIV4 | RR: 4.62 (0.24, 89.17) | Low |
Abbreviations: aIIV3 = adjuvanted inactivated influenza vaccine, trivalent; HD-IIV3 = high dose inactivated influenza vaccine, trivalent; RIV3 = recombinant influenza vaccine, trivalent; SD-IIV = unadjuvanted standard-dose inactivated influenza vaccine, trivalent or quadrivalent unspecified; SD-IIV3 = unadjuvanted standard-dose inactivated influenza vaccine, trivalent; SD-IIV4 = unadjuvanted standard-dose inactivated influenza vaccine, quadrivalent; RIV3 = recombinant influenza vaccine, trivalent; RIV4 = recombinant influenza vaccine, quadrivalent; RR = relative risk.
*For multiseason studies, estimate provided is for all seasons combined unless otherwise specified.
Table 4a: Grade Summary of Findings Table: HD-IIV3 vs. SD-IIV
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | HD-IIV3 | SD-IIV | Relative (95% CI) |
Absolute (95% CI) |
||
| Randomized studies: Influenza-associated Illness | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | not serious | none | 228/15990 (1.4%) | 301/15993 (1.9%) | RR 0.76 (0.64 to 0.90) |
45 fewer per 10,000 (from 65 fewer to 19 fewer) |
Level 1 High |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated outpatient/ER visits | ||||||||||||
| 4 | observational studies | very seriousa,b | not serious | not serious | not serious | none | -/11001581* | -/5658869* | Rate ratio 0.87 (0.76 to 0.99) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| Observational studies (person denominator): influenza-associated outpatient/ER visits | ||||||||||||
| 1 | observational studies | very seriousc | not serious | not serious | seriousd | none | 593/3141 (18.9%) | 580/2840 (20.4%) | RR 0.91 (0.73 to 1.12) |
184 fewer per 10,000 (from 551 fewer to 245 more) |
Level 4 Very low |
CRITICAL |
| Randomized studies: Influenza-associated hospitalizations | ||||||||||||
| 2 | randomized trials | seriouse | not serious | not serious | not serious | none | 14/18596 (0.1%) | 14/18597 (0.1%) | RR 1.00 (0.48 to 2.09) |
0 fewer per 100,000 (from 4 fewer to 8 more) |
Level 2 Moderate |
CRITICAL |
| Randomized studies (cluster design): Influenza-associated hospitalizations | ||||||||||||
| 1 | Cluster randomized trial | seriousf | not serious | not serious | not serious | none | 247/19127 | 309/19129 | Rate ratio 0.79 (0.66 to 0.95) |
— per 10,000 (from — to –) |
Level 2 Moderate |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated hospitalizations | ||||||||||||
| 8 | observational studies | very seriousb | not serious | not serious | not serious | none | -/43519865* | -/20193377* | Rate ratio 0.92 (0.90 to 0.94) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| Observational studies (person denominator): influenza-associated hospitalizations | ||||||||||||
| 2 | observational studies | very seriousg | not serious | not serious | not serious | none | 177/24334 (0.7%) | 201/24197 (0.8%) | RR 0.71 (0.57 to 0.88) |
24 fewer per 1,000 (from 36 fewer to 10 fewer) |
Level 3 Low |
CRITICAL |
| Observational studies (person-time denominator): Influenza-associated deaths | ||||||||||||
| 2 | observational studies | very seriousb | not serious | not serious | not serious | none | -/2755395* | -/3922569* | Rate ratio 0.69 (0.57 to 0.84) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| Randomized studies: Any Serious Adverse Event (SAE) | ||||||||||||
| 7 | randomized trials | not serious | not serious | not serious | not serious | none | 1518/22109 (6.7%) | 1582/20811 (7.5%) | RR 0.91 (0.85 to 0.97) |
68 fewer per 10,000 (from 114 fewer to 23 fewer) |
Level 1 High |
IMPORTANT |
| Randomized studies: Solicited injection site events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very serioush | none | 7/560 (1.3%) | 1/559 (0.2%) | RR 5.03 (0.88 to 28.74) |
72 more per 10,000 (from 2 fewer to 496 more) |
Level 3 Low |
IMPORTANT |
| Randomized studies: Solicited systemic events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very serioush | none | 3/766 (0.4%) | 3/767 (0.4%) | RR 0.95 (0.20 to 4.53) |
2 fewer per 10,000 (from 31 fewer to 138 more) |
Level 3 Low |
CRITICAL |
| Randomized studies: Guillain-Barre syndrome | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | very seriousi | none | 0/2606 (0.0%) | 0/2604 (0.0%) | not estimable | Level 3 Low |
CRITICAL | |
*Counts not provided for all studies.
CI: confidence interval; RR: risk ratio
Explanations
a 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 estimable
Table 4b: Grade Summary of Findings Table: aIIV3 vs. SD-IIV
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | aIIV3 | SD-IIV | Relative (95% CI) |
Absolute (95% CI) |
||
| Randomized studies: Influenza-associated Illness | ||||||||||||
| 1 | randomized trials | seriousa | not serious | not serious | not serious | none | 322/3479 (9.3%) | 314/3482 (9.0%) | RR 1.03 (0.89 to 1.19) |
27 more per 10,000 (from 99 fewer to 171 more) |
Level 2 Moderate |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated outpatient/ER visits | ||||||||||||
| 2 | observational studies | very seriousb | seriousc | not serious | not seriousd | none | -/1701231* | -/2035149* | Rate ratio 1.00 (0.97 to 1.03) |
— per 10,000 (from — to –) |
Level 4 Very low |
CRITICAL |
| Observational studies (person denominator): influenza-associated outpatient/ER visits | ||||||||||||
| 2 | observational studies | very seriouse | not serious | not serious | not serious | none | 344/1333 | 197/988 | RR 0.64 (0.52 to 0.79) |
718 fewer per 10,000 (from 957 fewer to 419 fewer) |
Level 3 Low |
CRITICAL |
| Randomized studies (cluster design): Influenza-associated hospitalizations | ||||||||||||
| 1 | randomized trials | seriousf | not serious | not serious | not serious | none | 242/24926 | 309/25806 | Rate ratio 0.79 (0.65 to 0.96) |
25 per 10,000 patient(s) per years (from 42 fewer to 5 fewer) |
Level 2 Moderate |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated hospitalizations | ||||||||||||
| 4 | observational studies | very seriousg | not serious | not serious | not serious | none | /6133023* | -/4861653* | Rate ratio 0.88 (0.80 to 0.97) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| Observational Studies (person denominator): Influenza-associated hospitalizations | ||||||||||||
| 2 | observational studies | very seriousg | not serious | not serious | not serious | none | 230/85483 | 35/79610 | 0.75 (0.58 to 0.97) |
1 fewer per 10,000 (from 2 fewer to 0 fewer) |
Level 3 Low |
CRITICAL |
| Randomized studies: Solicited systemic events Grade 3 or higher | ||||||||||||
| 4 | randomized trials | not serious | not serious | not serious | very seriousi | none | 10/1016 (1.0%) | 13/1026 (1.3%) | RR 0.77 (0.34 to 1.76) |
29 fewer per 10,000 (from 84 fewer to 96 more) |
Level 3 Low |
CRITICAL |
| Randomized Studies: Guillain-Barre syndrome | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | very seriousk | none | 0/3545 (0.0%) | 1/3537 (0.0%) | RR 0.33 (0.01 to 8.16) |
2 fewer per 10,000 (from 3 fewer to 20 more) |
Level 3 Low |
CRITICAL |
| Observational studies: Guillain-Barre syndrome | ||||||||||||
| 1 | observational studies | seriousg | not serious | not serious | very seriousk | none | 0/88449 (0.0%) | 0/82539 (0.0%) | not estimable | Level 4 Very low |
CRITICAL | |
| Randomized studies: Any Serious Adverse Event (SAE) | ||||||||||||
| 8 | randomized trials | not serious | not serious | not serious | serioush | none | 300/5266 (5.7%) | 277/5055 (5.5%) | RR 1.07 (0.92 to 1.26) |
38 more per 10,000 (from 44 fewer to 142 more) |
Level 2 Moderate |
IMPORTANT |
| Randomized studies: Solicited injection site events Grade 3 or higher | ||||||||||||
| 4 | randomized trials | not serious | not serious | not serious | very seriousi,j | none | 18/952 (1.9%) | 5/957 (0.5%) | RR 3.39 (1.32 to 8.72) |
125 more per 10,000 (from 17 more to 403 more) |
Level 3 Low |
IMPORTANT |
*Counts not provided for all studies.
CI: confidence interval; RR: risk ratio
Explanations
a Symptom-based outcome definition
b 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 overlap
eMajority 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 estimable
Table 4c: Grade Summary of Findings Table: RIV3 vs. SD-IIV
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | RIV | SD-IIV | Relative (95% CI) |
Absolute (95% CI) |
||
| Randomized studies: Influenza-associated Illness | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | seriousa | none | 53/2168 (2.4%) | 64/2143 (3.0%) | RR 0.82 (0.57 to 1.17) |
54 fewer per 10,000 (from 128 fewer to 51 more) |
Level 2 Moderate |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated hospitalizations | ||||||||||||
| 1 | observational studies | very seriousb | not serious | not serious | not serious | none | 640/608433 | 2309/1584451 | Rate ratio 0.83 (0.76 to 0.91) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| RCTs: Systemic events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousa | none | 1/771 (0.1%) | 6/941 (0.6%) | RR 0.28 (0.05 to 1.67) |
5 fewer per 1,000 (from 6 fewer to 4 more) |
Level 3 Low |
CRITICAL |
| Guillain-Barre syndrome | ||||||||||||
| 1 | observational studies | seriousb | not serious | not serious | very seriouse | none | 0/21976 (0.0%) | 4/283683 (0.0%) | not estimable | Level 4 Very low |
CRITICAL | |
| Randomized studies: Any Serious Adverse Event (SAE) | ||||||||||||
| 5 | randomized trials | not serious | not serious | seriousc | seriousd | none | 191/6513 (2.9%) | 190/6697 (2.8%) | RR 1.03 (0.84 to 1.26) |
9 more per 10,000 (from 45 fewer to 74 more) |
Level 3 Low |
IMPORTANT |
| RCTs: Injection site events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousa | none | 7/771 (0.9%) | 11/941 (1.2%) | RR 0.67 (0.27 to 1.69) |
39 fewer per 10,000 (from 85 fewer to 81 more) |
Level 3 Low |
IMPORTANT |
CI: confidence interval; OR: odds ratio; RR: risk ratio
Explanations
a 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 estimable
Table 4d: Grade Summary of Findings Table: HD-IIV3 vs. aIIV3
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | HD-IIV3 | aIIV3 | Relative (95% CI) |
Absolute (95% CI) |
||
| Randomized studies: Influenza-associated Illness | ||||||||||||
| 1 | randomized trials | seriousa | not serious | not serious | very seriousb | none | 1/29 (3.4%) | 3/30 (10.0%) | RR 0.34 (0.04 to 3.13) |
660 fewer per 10,000 (from 960 fewer to 2130 more) |
Level 4 Very low |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated outpatient/ER visits | ||||||||||||
| 3 | observational studies | very seriousc | seriousd | not serious | not seriouse | none | -/11430788* | -/2262474* | Rate ratio 1.06 (0.92 to 1.23) |
— per 10,000 (from — to –) |
Level 4 Very low |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated hospitalizations | ||||||||||||
| 4 | observational studies | very seriousf | not serious | not serious | seriousg | none | -/25467741* | -/6356816* | Rate ratio 0.96 (0.90 to 1.01) |
— per 10,000 (from — to –) |
Level 4 Very low |
CRITICAL |
| Randomized studies: Solicited systemic events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousb | none | 8/887 (0.9%) | 11/886 (1.2%) | RR 0.73 (0.29 to 1.80) |
34 fewer per 10,000 (from 88 fewer to 99 more) |
Level 3 Low |
CRITICAL |
| Randomized studies: Guillain-Barre syndrome | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | very serioush | none | 0/377 (0.0%) | 0/378 (0.0%) | not estimable | Level 3 Low |
CRITICAL | |
| Randomized studies: Any Serious Adverse Event (SAE) | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousb | none | 13/887 (1.5%) | 20/886 (2.3%) | RR 0.65 (0.32 to 1.30) |
79 fewer per 10,000 (from 153 fewer to 68 more) |
Level 3 Low |
IMPORTANT |
| Randomized studies: Solicited injection site events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousb | none | 15/887 (1.7%) | 17/886 (1.9%) | RR 0.88 (0.45 to 1.75) |
23 fewer per 10,000 (from 106 fewer to 144 more) |
Level 3 Low |
IMPORTANT |
*Event counts not provided for all studies.
CI: confidence interval; RR: risk ratio
Explanations
a 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-confirmed
dDisparate 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 estimable
Table 4e: Grade Summary of Findings Table: HD-IIV3 vs. RIV4
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | HD-IIV3 | RIV4 | Relative (95% CI) |
Absolute (95% CI) |
||
| Randomized studies: Influenza-associated Illness | ||||||||||||
| 1 | randomized trials | seriousa | not serious | not serious | very seriousb | none | 1/29 (3.4%) | 4/30 (13.3%) | RR 0.26 (0.03 to 2.18) |
987 fewer per 10,000 (from 1,293 fewer to 1,573 more) |
Level 4 Very low |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated hospitalizations | ||||||||||||
| 1 | observational studies | very seriousc | not serious | not serious | not serious | none | 81492/7173433 | 640/608433 | Rate ratio 1.12 (1.03 to 1.21) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| Randomized studies: Solicited systemic events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousb | none | 4/663 (0.6%) | 4/486 (0.8%) | RR 0.86 (0.22 to 3.32) |
12 fewer per 10,000 (from 64 fewer to 191 more) |
Level 3 Low |
CRITICAL |
| Randomized studies: Any Serious Adverse Event (SAE) | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousb | none | 16/663 (2.4%) | 7/486 (1.4%) | RR 1.77 (0.73 to 4.27) |
111 more per 10,000 (from 39 fewer to 471 more) |
Level 3 Low |
IMPORTANT |
| Randomized studies: Solicited injection site events Grade 3 or higher | ||||||||||||
| 2 | randomized trials | not serious | not serious | not serious | very seriousb | none | 4/663 (0.6%) | 0/486 (0.0%) | RR 5.92 (0.32 to 109.56) |
0 fewer per 100,000 (from 0 fewer to 0 fewer) |
Level 3 Low |
IMPORTANT |
CI: confidence interval; RR: risk ratio
Explanations
aOpen-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. RIV4
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | aIIV3 | RIV4 | Relative (95% CI) |
Absolute (95% CI) |
||
| Randomized studies: Influenza-associated Illness | ||||||||||||
| 1 | randomized trials | seriousa | not serious | not serious | very seriousb | none | 3/30 (10.0%) | 4/30 (13.3%) | RR 0.75 (0.18 to 3.07) |
333 fewer per 10,000 (from 1,093 fewer to 2,760 more) |
Level 4 Very low |
CRITICAL |
| Observational studies (person-time denominator): influenza-associated hospitalizations | ||||||||||||
| 1 | observational studies | very seriousc | not serious | not serious | not serious | none | 2783/2565513 | 640/608433 | Rate ratio 1.12 (1.03 to 1.22) |
— per 10,000 (from — to –) |
Level 3 Low |
CRITICAL |
| Randomized studies: Solicited systemic events Grade 3 or higher | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | very seriousb | none | 3/508 (0.6%) | 0/335 (0.0%) | RR 4.62 (0.24 to 89.17) |
0 fewer per 10,000 (from 0 fewer to 0 fewer) |
Level 3 Low |
CRITICAL |
| Randomized studies: Any Serious Adverse Event (SAE) | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | very seriousb | none | 11/508 (2.2%) | 4/335 (1.2%) | RR 1.81 (0.58 to 5.65) |
97 more per 10,000 (from 50 fewer to 555 more) |
Level 3 Low |
IMPORTANT |
| Randomized studies: Solicited injection site events Grade 3 or higher | ||||||||||||
| 1 | randomized trials | not serious | not serious | not serious | very seriousb | none | 3/508 (0.6%) | 0/335 (0.0%) | RR 4.62 (0.24 to 89.17) |
0 fewer per 100,000 (from 0 fewer to 0 fewer) |
Level 3 Low |
IMPORTANT |
CI: confidence interval; RR: risk ratio
Explanations
aOpen-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 Interest
| Certainty, by comparison | ||||||||
|---|---|---|---|---|---|---|---|---|
| Vaccines of interest vs SD-IIVs | EIVs vs one another | |||||||
| Outcome | Importance | Included in profile? | HD-IIV3 vs SD-IIV |
aIIV3 vs SD-IIV |
RIV vs SD-IIV |
HD-IIV3 vs aIIV3 |
HD-IIV3 vs RIV4 |
aIIV3 vs RIV4 |
| BENEFITS | ||||||||
| Influenza illnesses | Critical | Yes | Level 1 High |
Level 2 Moderate |
Level 2 Moderate |
Level 4 Very low |
Level 4 Very low |
Level 4 Very low |
| Influenza outpatient/ER visits | Critical | Yes | Level 3 Low |
Level 3 Low |
Level 4 Very Low |
|||
| Influenza hospitalizations | Critical | Yes | Level 2 Moderate |
Level 2 Moderate |
Level 3 low |
Level 4 Very Low |
Level 3 Low |
Level 3 Low |
| Influenza deaths | Critical | Yes | Level 3 Low |
|||||
| HARMS | ||||||||
| Any Serious Adverse Event (SAE) | Important | Yes | Level 1 High |
Level 2 Moderate |
Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
| Solicited injection site adverse events Grade ≥3 | Important | Yes | Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
| Solicited systemic adverse events Grade ≥3 |
Critical | Yes | Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
Level 3 Low |
| Guillain-Barré syndrome | Critical | Yes | Level 3 Low |
Level 3 Low |
Level 4 Very low |
Level 3 Low |
||
| OVERALL: | Level 3 Low |
Level 3 Low |
Level 4 Very low |
Level 4 Very low |
Level 4 Very low |
Level 4 Very low |
||
Appendix 1: Studies Included in the Review of Evidence
| Last name first author, Publication year |
Study design | Country | Age | Total population | N Intervention |
N comparison |
Outcomes | Funding source |
|---|---|---|---|---|---|---|---|---|
| Balasubramani 2020 (13) | TNCC | US (US Flu VE Network) |
≥65 years | 2,993 | 1,573 HD-IIV3 | 1,420 SD-IIV3/4 | Outpatient/ER | US government |
| Belongia 2020 (12) | Randomized | US | 65 through 74 years | 99 | 29 HD-IIV3 30 aIIV3 30 RIV4 |
Illnesses | US government | |
| Cocchio 2020 (18) | Retro. cohort | Italy | ≥65 years | 479,397 | 68660 aIIV3 | 410,737 Conventional vaccine strategy (classified as use in ≥90% of cases) |
Hospitalizations | No external funding. |
| Couch 2007 (57) | Randomized | US | ≥65 years | 214 | 206 HD-IIV3 | 208 SD-IIV3 | Reactogenicity | US government |
| Cowling 2020 (37) | Randomized | Hong Kong | 65 through 82 years | 1,861 | 510 HD-IIV3 508 aIIV3 335 RIV4 |
508 SD-IIV4 | SAEs Reactogenicity |
US government |
| DiazGranados 2014 (7) | Randomized | US/Canada | ≥65 years | 31,983 | 15,993 HD-IIV3 |
15,990 SD-IIV3 | Illnesses SAEs |
Sanofi Pasteur |
| DiazGranados 2015 (22) | Randomized | US Canada |
≥65 years | 31,983 | 15,993 HD-IIV3 |
15,990 SD-IIV3 | Hospitalizations | Sanofi Pasteur |
| De Bruijn 2007 (49) | Randomized | Germany, Sweden, Lithuania, Bulgaria | ≥61 years | 259 | 130 aIIV3 | 129 SD-IIV3 | SAEs | Unclear; Solvay authors. |
| De Donato 1999 (50) | Randomized | Italy | ≥65 years | 481 | 248 aIIV3 | 233 SD-IIV3 | SAEs | Unclear; Chiron authors. |
| Della Cioppa 2012 (55) | Randomized | Poland, Belgium, Germany | ≥65 years | 91 | 47 aIIV3 | 44 SD-IIV3 | SAEs | Novartis |
| Doyle 2021 (25) | TNCC | US (HAIVEN) |
≥65 years | 1,107 | 622 HD-IIV3 | 485 SD-IIV | Hospitalization | US government |
| Dunkle 2017 (8) | Randomized | US | ≥50 years | 9,003 ≥50 yrs 3,452 ≥65 yrs |
4,498 ≥50 yrs 1,743 ≥65 yrs RIV4 |
4,505 ≥50 1,710 ≥65 SD-IIV4 |
Illnesses SAEs |
BARDA; Protein Sciences authors |
| Falsey 2009 (46) | Randomized | US | ≥65 years | 3,781 | 2,541 HD-IIV3 | 1,240 SD-IIV3 | SAEs | Sanofi Pasteur |
| Frey 2014 (10) | Randomized | US, Colombia, Panama Philippines |
≥65 years | 6,961 | 3,479 HD-IIV3 | 3,482 SD-IIV3 | Illnesses SAEs Reactogenicity GBS |
Novartis |
| Gravenstein 2017 (24) | Cluster Randomized | US | ≥65 years | 53,008 | 26,639 HD-IIV3 | 26,369 SD-IIV3 | Hospitalization | Sanofi Pasteur |
| Iob 2005 (18) | Cohort | Italy | Mean 85 years, range 23-100 (3.65% were <65 years) | 2,966 | 1,487 aIIV3 | 1,479 SD-IIV3 | Illnesses | Not stated |
| Izikson 2015 (53) | Randomized | US | ≥50 years | 2,627 | 1,314 RIV3 | 1,313 SD-IIV3 | SAEs | BARDA; Protein Sciences authors |
| Izurieta 2015 (14) | Retro. cohort | US (Medicare) |
≥65 years | 2,545,275 | 929,730 HD-IIV3 | 1,615,545 SD-IIV3 |
Outpatient/ER | US government |
| Izurieta 2019 (15) | Retro. Cohort | US (Medicare) |
≥65 years | 11,737,916 | 8,488,136 HD-IIV3 1,466,918 aIIV3 |
1,822,862 SD-IIV4 |
Outpatient/ER, Hospitalizations |
US government |
| Izurieta 2020 (20) | Retro. Cohort | US (Medicare) |
≥65 years | 11,717,822 | 7,905,252 HD-IIV3 2,100,512 aIIV3 257,718 RIV4 |
1,454,340 SD-IIV4 |
Hospitalizations | US government |
| Izurieta 2021 (21) | Retro. cohort | US (Medicare) |
≥65 years | 11,931,830 | 7,173,433 HD-IIV3 2,565,513 aIIV3 608,433 RIV4 |
1,584,451 SD-IIV4 |
Hospitalizations | US government |
| Hansen 2020 (45) | Retro. cohort | US | ≥65 years | 305,659 | 21,976 RIV3 | 283,683 SD-IIV3 | GBS | Protein Sciences |
| Keitel 2006 (11) | Randomized | US | ≥65 years | 101 | 50 HD-IIV3 | 51 SD-IIV3 | SAEs Reactogenicity |
US government |
| Keitel 2010 (41) | Randomized | US | ≥65 years | 869 | 436 RIV3 | 433 SD-IIV3 | SAEs Reactogenicity |
Unclear; Protein Sciences author |
| Li 2008 (51) | Randomized | China | ≥60 years | 589 | 391 aIIV3 | 198 SD-IIV3 | SAEs | Novartis |
| Lu 2019 (26) | Retro. cohort | US | ≥65 years | 19,922,120 | 13,770,207 HD-IIV3 |
6,151,913 SD-IIV |
Hospitalizations | US government |
| Mannino 2012 (34) | Prospective cohort | Italy | ≥65 years | 164,254 person-seasons | 84,665 person-seasons | 79,589 person-seasons |
Hospitalizations | Novartis |
| McConeghy 2020 (31) | Cluster Randomized | US | ≥65 years | 50,012 | 24,926 aIIV3 | 25,086 SD-IIV3 | Hospitalization | Seqirus |
| Menegon 1999 (38) | Randomized | Italy | Mean 68.6 years, range 23-97 | 194 | 96 aIIV3 | 98 HD-IIV3 | Reactogenicity | Ministry grant |
| Nace 2015 (47) | Randomized | US | ≥65 years | 187 | 89 HD-IIV3 | 98 SD-IIV3 | SAEs | Sanofi Pasteur |
| Paudel 2020 (27) | Retro. cohort | US | ≥65 years | 2,420,450 Pharmacy cohort 2,421,758 Outpatient cohort |
1210225 Pharmacy cohort 1,210,879 Outpatient cohort |
1,210,225 Pharmacy cohort 1,210,879 Outpatient cohort |
Hospitalizations | Sanofi Pasteur |
| Pebody (35) | TNCC | UK | ≥65 years | 835 | 818 | 17 | Hospitalizations | UK Government |
| Pelton 2020 (19) | Retro. cohort | US | ≥65 years | 446,600 | 1,269,855 HD-IIV3 234,313 aIIV3 |
212,287 SD-IIV |
Outpatient/ER | Seqirus |
| Pelton 2021 (56) | Retro. cohort | US | ≥65 years | 2,234,040 | 1,672,797 HD-IIV3 561,243 aIIV3 |
Outpatient/ER | Funding not stated. Seqirus authors. | |
| Richardson 2015 (28) | Retro. cohort | US (VA) |
≥65 years | 165,225 | 25,714 HD-IIV3 | 139,511 SD-IIV | Hospitalizations | US government |
| Robison 2018 (29) | Matched cohort | US | ≥65 years | 47,424 | 23,712 HD-IIV3 | 23,712 SD-IIV | Hospitalizations | Funding not stated. No industry authors. |
| Shay 2017 (16) | Retro. cohort | US (Medicare) |
≥65 years | 9,722,909 | 1,039,645 HD-IIV3 |
1,683,264 SD-IIV3 |
Outpatient/ER Deaths |
US government |
| Scheifele 2013 (39) | Randomized | Canada | ≥65 years | 608 | 301 aIIV3 | 307 SD-IIV3 | SAEs Reactogenicity |
Canadian government |
| Schmader 2021 (42) | Randomized | US | ≥65 years | 755 | 378 aIIV3 377 HD-IIV3 |
SAEs Reactogenicity GBS |
US government | |
| Seo 2014 (40) | Randomized | S. Korea | ≥65 years | 224 | 113 aIIV3 | 111 SD-IIV3 | Reactogenicity | S. Korean government |
| Sindoni 2009 (52) | Randomized | Italy | ≥65 years | 195 | 96 aIIV3 | 99 SD-IIV3 | SAEs | Not stated. No industry authors. |
| Shinde 2022 (43) | Randomized | US | ≥65 years | 304 | 153 HD-IIV3 151 RIV5 |
SAEs Reactogenicity GBS |
Novavax | |
| Treanor 2006 (54) | Randomized | US | ≥65 years | 199 | 100 RIV3 | 99 SD-IIV3 | SAEs | US government; Protein Sciences author |
| Tsang 2014 (48) | Randomized | US | ≥65 years | 639 | 320 HD-IIV3 | 319 SD-IIV3 | SAEs | Sanofi Pasteur |
| Van Aalst 2020 (36) | Retro. cohort | US | ≥65 years | 2,124,713 | 1,900,920 HD-IIV3 223,793 aIIV3 |
Hospitalizations | Sanofi Pasteur | |
| Van Buynder 2013 (9) | TNCC | Canada | ≥65 years | 227 | 165 aIIV3 | 62 SD-IIV3 | Outpatient/ER | Unrestricted grant, Novartis; Fraser Health Authority |
| Vardeny 2021 (30) | Randomized | US, Canada | Mean 65.5 (SD 12) years | 5,260 | 2,630 HD-IIV3 | 2,630 SD-IIV4 | Hospitalization | US government, Sanofi Pasteur |
| Villa 2013 (44) | Retro. Cohort | Italy | ≥65 years | 170,988 | 88,449 aIIV3 | 82,539 SD-IIV3 | GBS | Unclear; Novartis authors. |
| Young-Xu 2018 (17) | Retro. Cohort | US (VA) |
≥65 years | 73,773 | 24,682 HD-IIV3 |
49,091 SD-IIV3 |
Outpatient/ER, Hospitalizations |
Sanofi Pasteur; Sanofi authors |
| Young-Xu 2019 (30) | Retro. Cohort | US (VA) |
≥65 years | 3,638,924 | 158,636 HD-IIV3 |
3,480,288 SD-IIV3 |
Hospitalizations | Unrestricted grant, Sanofi Pasteur; Sanofi authors |
| Young-Xu 2020 (33) | Retro. Cohort | US (VA) |
≥65 years | 569,552 person-seasons | 207,574 person-seasons HD-IIV3 |
361,978 person-seasons SD-IIV3 |
Deaths | Unrestricted grant, Sanofi Pasteur; Sanofi authors |
References in this appendix: 78910111213141516171819202122242526272829303133343536373839404142434445464748495051525354555657
Abbreviations: GBS = Guillain-Barré syndrome, HAIVEN = US Hospitalized Adult Influenza Vaccine Effectiveness Network, Retro. Cohort = retrospective cohort, SAE = Serious Adverse Event, TNCC = test negative case-control, VA = Veterans Administration
Appendix 2. Literature Search Strategies
Main search (1990 through September 7, 2021):
Medline
(OVID)
1946-
(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-
(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)
(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):
Medline
(OVID)
1946-
(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-
(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)
(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 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
Scopus
TITLE-ABS-KEY((influenza W/5 vaccin*) OR (flu W/5 vaccin*) OR MF59* OR MF-59*) AND TITLE-ABS-KEY(safe* OR effect* OR efficacy OR adverse OR dose OR dosage OR high-dose OR anaphylaxis OR harm* OR benefit*) AND TITLE(review* OR systematic OR meta*) AND NOT INDEX(medline)
Limit 1990 – ; publication type = Review
View the complete list of GRADE evidence tables
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