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

Background

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

Methods

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

Table 1: Policy Question and PICO

* 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

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

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

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

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

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

†Analyses included cases associated with influenza A viruses only.

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

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

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

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

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

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

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

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

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

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

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

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

Table 5: Summary of Evidence for Outcomes of Interest

Appendix 1: Studies Included in the Review of Evidence

Appendix 2. Literature Search Strategies

Main search (1990 through September 7, 2021):

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

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