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Evidence to Recommendations (EtR) Framework: Higher Dose and Adjuvanted Influenza Vaccines for Persons Aged ≥65 Years						Print
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										**Question:** Do the relative benefits and harms of high-dose inactivated influenza vaccine (HD-IIV), MF59-adjuvanted inactivated influenza vaccine (aIIV), and recombinant influenza vaccine (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**: High-dose inactivated influenza vaccine (HD-IIV), recombinant influenza vaccine, (RIV), MF59-adjuvanted inactivated influenza vaccine (aIIV).
**Comparison**: Standard-dose unadjuvanted inactivated influenza vaccines (SD-IIVs), HD-IIV, RIV, aIIV.
**Outcomes**:
Influenza illness (Critical)
Influenza-associated outpatient/ER visits (Critical)
Influenza-associated hospitalizations (Critical)
Influenza-associated deaths (Critical)
Any solicited systemic adverse event grade ≥3 (Critical)
Guillain-Barre syndrome (Critical)
Any solicited injection site adverse event grade ≥3 (Important)
Any serious adverse event (Important)**Background:**Estimated rates of influenza-associated hospitalization and death are generally highest among individuals 65 years of age and older (1-4), an age group for whom influenza vaccine effectiveness is often lower relative to younger populations (5, 6).   Two inactivated influenza vaccines approved in the United States for persons aged ≥65 years have features intended to promote a better immune response for this age group. These include a high-dose inactivated influenza vaccine containing four times the antigen dosage per virus compared with standard-dose inactivated vaccines (approved as a trivalent formulation [HD-IIV3] in 2009 and a quadrivalent formulation [HD-IIV4] in 2019), and an inactivated vaccine containing the adjuvant agent MF59 (approved as a trivalent formulation [aIIV3] in 2015 and a quadrivalent formulation [aIIV4] in 2020).  These two vaccines, as well as a recombinant influenza vaccine containing three times the antigen dosage per virus compared with SD-IIVs (initially licensed as a trivalent formulation [RIV3] in 2013 and as a quadrivalent [RIV4] in 2016 and approved for ages ≥18 years), have been evaluated for relative efficacy and effectiveness compared with standard dose unadjuvanted inactivated influenza vaccines (SD-IIVs) among older adults (7-9).  This assessment sought to review the available published evidence for relative efficacy, effectiveness, and safety of HD-IIV, aIIV, and RIV to support ACIP discussion of whether any one or more of these three vaccines should be preferentially recommended over other age-appropriate influenza vaccines for persons ages 65 years and older.Problem
Problem
Criteria
Work Group Judgements
Evidence
Additional InformationIs the problem of public health importance?
Yes
Persons aged ≥65 years bear a substantial annual burden of influenza-associated hospitalizations and deaths.
In surveillance of laboratory confirmed influenza hospitalizations (FluSurv-NET), cumulative hospitalization rates among persons aged ≥65 years  averaged ~225/100,000 during the 2013-14 through 2019-20 seasons (10).
A modeling analysis of influenza burden by age group for the 2010-11 through 2015-16 seasons (which used data from routine influenza surveillance, outbreak investigations, and survey data describing proportions of persons seeking health care) estimated an annual burden of 87,000—523,000 hospitalizations, 3,000—17,000 pneumonia and influenza deaths, and 9,000—43,000 respiratory and circulatory deaths among persons aged ≥65 years (4).
Persons aged ≥65 years comprise the majority of influenza-associated deaths (2).Benefits and Harms
Benefits and Harms
Criteria
Work Group Judgements
Evidence
Additional InformationHow substantial are the desirable anticipated effects?
Moderate/ Varies
**Comparisons of higher dose and adjuvanted influenza vaccines with unadjuvanted SD-IIVs:**
There are few RCTs comparing higher dose and adjuvanted influenza vaccines with SD-IIVs during non-pandemic influenza seasons.
HD-IIV3 was more effective than SD-IIV3 in prevention of polymerase chain reaction (PCR)- or culture-confirmed influenza-like illness (ILI) in a two-season randomized study conducted among 32,000 persons aged ≥65 years (relative efficacy: 24%; 95% CI: 10%–36%) (7).
Two single-season randomized trials of RIV versus nonadjuvanted SD-IIV, one a comparison of RIV3 versus nonadjuvanted SD-IIV3 that assessed culture-confirmed ILI (11) and the second a comparison of RIV4 versus nonadjuvanted SD-IIV4 that examined PCR-confirmed ILI (8), did not demonstrate relative benefit of RIV among those aged ≥65 years (pooled relative efficacy: 18%; 95% CI: −17% to 43%). The larger of these two studies noted relative benefit of RIV4 over nonadjuvanted SD-IIV4 in prevention of PCR-confirmed influenza among the full study population of persons aged ≥50 years (relative efficacy: 30%; 95% CI: 10%–47%) as well as against culture-confirmed ILI among those aged ≥65 years (relative efficacy: 42%; 95% CI: 9%–65%) (8).
No individually randomized studies assessing aIIV vs. SD-IIV against laboratory-confirmed influenza outcomes during non-influenza pandemic seasons were identified.
Two single-season, cluster-randomized studies evaluated prevention of pneumonia- and influenza-diagnostic coded hospitalizations among persons aged ≥65 years in U.S. nursing homes. One such study noted benefit of HD-IIV3 relative to nonadjuvanted SD-IIV3 (relative risk 0.79; 95% CI: 0.66–0.95) (12). A second noted benefit of aIIV3 relative to nonadjuvanted SD-IIV3 (relative risk 0.79, 95% CI: 0.65–0.96) (13).
Observational studies, (predominantly retrospective cohort designs using diagnostic code-defined outcomes) cover a broader range of influenza seasons.  These studies suggest modest potential benefit of higher dose and adjuvanted influenza vaccine (14-27) in the prevention of diagnostic-code defined influenza- or pneumonia and influenza-associated hospitalizations (14-25). The most data are available for HD-IIV, with less for aIIV, and the least for RIV.  However, the magnitude of relative benefit varied, and was not seen in all studies and all seasons.
**Comparisons of higher dose and adjuvanted influenza vaccines with one another:**
Overall, fewer studies are available for comparisons of these vaccines with one another (15, 17, 18, 22, 28, 29).  While there is evidence of better efficacy of RIV4 compared with HD-IIV3 and aIIV3 in one study, these data covered only one influenza season (18).
Effectiveness of one vaccine relative to another varies from study to study and season to season.  WG discussion reflected acknowledgement of this variability.  In further considering how substantial the desired anticipated effects of higher dose and adjuvanted influenza vaccines vs. SD-IIVs are on average, the majority responded that they are “Moderate”; a minority responded that they are “Small.”
Randomized trials generally provide the highest certainty evidence but are few in number and were conducted over few influenza seasons.  Given the variability of influenza vaccine effectiveness from season to season, it cannot be assumed that findings from studies conducted over one or a few seasons will be generalizable to all or most seasons.
Observational studies are subject to bias and provide lower certainty evidence.  However, they are more numerous and reflect a larger range of influenza seasons than randomized trials.  They therefore can provide insight into the variability and potential generalizability of the relative benefits of higher dose and adjuvanted influenza vaccines vs. SD-IIVs across multiple influenza seasons
Overall, the body of evidence suggests potential benefit of higher dose and adjuvanted influenza vaccine compared with SD-IIVs.  The available evidence from studies comparing these vaccines with one another was felt to be insufficient to support a conclusion that any one vaccine will be consistently better than the others across multiple influenza seasons.How substantial are the undesirable anticipated effects?
Minimal
Data reflecting the potential for severe solicited systemic adverse events and serious adverse events (SAEs) from randomized studies comparing higher dose and adjuvanted influenza vaccines with SD-IIVs suggest that the risks of such events are similar.  Frequency of some injection site adverse events was higher among those receiving HD-IIV and aIIV compared with SD-IIVs in some randomized studies (30, 31).  Insufficient data were available for Guillain-Barre syndrome.Do the desirable effects outweigh the undesirable effects?
Favors interventionWhat is the overall certainty of this evidence for the critical outcomes?

**Benefits:**
HD-IIV vs. SD-IIVs,
aIIV vs SD-IIVs,
RIV vs SD-IIVs:*Level 3, Low*
HD-IIV vs aIIV
HD-IIV vs RIV
aIIV vs RIV:*Level 4, Very low*
**Harms:**
HD-IIV vs. SD-IIVs,
aIIV vs SD-IIVs
HD-IIV vs aIIV
HD-IIV vs RIV
aIIV vs RIV:*Level 3, Low*
RIV vs. SD-IIVs:*Level 4, Very low*
For benefits, downgrading of certainty was driven primarily by lack of availability of randomized studies for some critical outcomes.
For harms, downgrading of certainty was driven primarily by imprecision of effect estimates, due to low event counts and small denominators in some studies.Values
Values
Criteria
Work Group Judgements
Evidence
Additional InformationDoes the target population feel that the desirable effects are large relative to undesirable effects?
Probably yes
None identified.Is there important uncertainty about or variability in how much people value the main outcomes?
Probably not important uncertainty or variability
None identified.Acceptability
Acceptability
Criteria
Work Group Judgements
Evidence
Additional InformationIs the intervention acceptable to key stakeholders?
Yes
Relative use of HD-IIV3, RIV4, and aIIV3 among vaccinated Medicare beneficiaries aged ≥65 years included in retrospective cohort studies of relative vaccine effectiveness suggest that the majority of community-dwelling elderly have already received a higher dose or adjuvanted influenza vaccine in recent seasons (approximately 80% during the 2018-19 and 2019-20 seasons) (15, 17, 18).
Data from studies of Medicare beneficiaries suggest that most have received a higher-dose or adjuvanted influenza vaccine in recent seasons.  This information is derived from descriptions of analytic datasets from studies of vaccinated beneficiaries.  These analyses excluded those residing in nursing homes, and do not encompass the entire U.S. population aged ≥65 years.  However, this information suggests that use of the higher dose and adjuvanted vaccines as a group in this population is established and was felt to provide some indirect evidence of acceptability among providers and recipients.Resource Use
Resource Use
Criteria
Work Group Judgements
Evidence
Additional InformationIs the intervention a reasonable and efficient allocation of resources?
Yes
No economic analyses were identified which considered potential impact of a recommendation for use of higher dose or adjuvanted vaccines as a group.  An analysis using average estimates of relative effectiveness against influenza-associated hospital encounters from the 2017-18, 2018-19, and 2019-20 seasons (15, 17, 18) applied to 10 consecutive seasons from 2010-11 through 2019-20 found incremental cost effectiveness ratios which varied considerably based upon underlying vaccine effectiveness and influenza season severity.  In modeling multiple scenarios, 20% were cost-saving ($/QALY=0); the 95th percentile was $195,000/QALY.
Some WG members responded “Probably yes” to the question of whether a preferential recommendation is a reasonable and efficient use of resources.  A smaller proportion responded “Varies”, acknowledging the variability of cost effectiveness based upon various factors.Equity
Equity
Criteria
Work Group Judgements
Evidence
Additional InformationWhat would be the impact of the intervention on health equity?
Probably increased
No evidence was found which predicts an impact on equity.  Racial and ethnic disparities in burden of severe influenza illness (32) and in influenza vaccine coverage (33) have been identified. Mahmud et al documented disparities in receipt of HD-IIV3 compared with all other influenza vaccines among Medicare beneficiaries aged ≥65 years during the 2015-16 season. Persons of Black or Asian race and of Hispanic ethnicity were less likely to receive HD-IIV3 than White persons (34).
Some WG members responded that the impact of a preferential recommendation would be increased equity, or that it would probably have no impact.Feasibility
Feasibility
Criteria
Work Group Judgements
Evidence
Additional InformationIs the intervention feasible to implement?
Yes
Relative use of HD-IIV3, aIIV3, and RIV4 compared with SD-IIVs among vaccinated Medicare beneficiaries aged ≥65 years included in retrospective cohort studies of relative vaccine effectiveness suggest that the majority of community-dwelling elderly have already received a higher dose or adjuvanted influenza vaccine in recent seasons (approximately 80% during the 2018-19 and 2019-20 seasons) (15, 17, 18).
Some WG members responded “Probably Yes” to the question of whether a preferential recommendation would be feasible to implement.
Retrospective cohort studies among Medicare beneficiaries (15, 17, 18) excluded persons living in nursing homes at the time of vaccination.  Additionally, not all vaccination is captured in the Medicare data.  While these datasets are large (including approximately 12 to 13 million persons each season), they do not encompass the entire US population aged ≥65 years.Balance of Consequences
The majority of the WG respondents expressed that the desirable consequences *clearly outweigh*undesirable consequences in most settings.  A minority expressed that the desirable consequences *probably outweigh*undesirable consequences in most settings
ACIP Recommendation:
ACIP recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines:  quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4).  If none of these three vaccines is available at an opportunity for vaccine administration, then any other age-appropriate influenza vaccine should be used.References
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							Last Reviewed:  August 24, 2022						Source: 	National Center for Immunization and Respiratory Diseases
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