TABLE 3. Summary of studies of efficacy/effectiveness of HD-IIV3, aIIV3, and RIV4 compared with unadjuvanted SD-IIVs against laboratory-confirmed influenza among older adults*.

Comparator (proprietary name)	Study design	Ages enrolled	No. participants	Season(s) (predominant viruses)†	Location	Primary outcome	Main efficacy/effectiveness findings
HD-IIV3 (Fluzone High-Dose, Sanofi Pasteur)
SD-IIV3 (Fluzone)§	RCT, double-blind	≥65 years	6,107 HD-IIV3 3,051 SD-IIV3	2009–10 ([H1N1]pdm09; not contained in HD-IIV3 or SD-IIV3)	U.S. (99 sites)	Culture- and/or RT-PCR-confirmed ILI, caused by types/subtypes similar to those contained in the vaccine	Primary outcome not evaluable due to emergence of (H1N1)pdm09 pandemic (no cases meeting primary endpoint of laboratory-confirmed influenza caused by viral types/subtypes similar to those in vaccine were observed; all confirmed cases were due to [H1N1]pdm09)
SD-IIV3 (Fluzone)¶	RCT, double-blind	≥65 years	15,990 HD-IIV3 15,993 SD-IIV3	2011–12 (H3N2) and 2012–13 ([H3N2], mismatch)	U.S., Canada (126 sites)	Laboratory confirmed (culture- and/or RT-PCR) influenza caused by any influenza viral types or subtypes, in association with protocol-defined ILI	Culture- and/or RT-PCR-confirmed influenza; any type or subtype, with protocol-defined ILI: All influenza: RE 24.2% (95% CI = 9.7–36.5) Influenza A: RE 24.0% (95% CI = 7.8–37.4) Influenza B: RE 25.5% (95% CI =-15.7–52.4) Culture- and/or RT-PCR-confirmed influenza; strains similar to vaccine, with protocol-defined ILI: All influenza: RE 35.4% (95% CI = 12.5–52.5) Influenza A: RE 31.7% (95% CI = 2.9–52.3) Influenza B: RE 45.2% (95% CI = -2.2–71.5) Culture-confirmed influenza; any type or subtype, with protocol-defined ILI: All influenza: RE 23.1% (95% CI = 7.5–36.2) Influenza A: RE 23.4% (95% CI = 6.0–37.6) Influenza B: RE 21.7% (95% CI =-23.8–50.8) Culture-confirmed influenza; strains similar to vaccine. with protocol-defined ILI: All influenza: RE 31.5% (95% CI = 4.6–51.1) Influenza A: RE 27.0% (95% CI = -8.5–51.2) Influenza B: RE 41.4% (95% CI =-10.3–69.8)
RIV4 (Flublok Quadrivalent, Protein Sciences)
SD-IIV4 (Fluarix Quadrivalent)**	RCT, double-blind	≥50 years	4,303 RIV4 4,301 IIV4	2014–15 (H3N2, mismatch)	U.S. (40 sites)	RT-PCR-confirmed ILI caused by any type or subtype.	RT-PCR-positive protocol-defined ILI; Aged ≥50 years: All influenza: RE 30% (95% CI = 10–47) Influenza A: RE 36% (95%CI = 14–53) Influenza B: RE 4% (95% CI =: -72–46) RT-PCR-positive protocol-defined ILI; Aged 50 through 64 years: All influenza: RE 42% (95% CI = 15–61) Aged ≥65 years: All influenza: RE 17% (95% CI = -20–43) Culture-positive protocol-defined ILI: Aged ≥50 years: All influenza: RE 43% (95% CI = 21–59) Influenza A: RE 44% (95% CI = 22–61) Influenza B: RE 25% (95% CI =-121–75) Culture-positive protocol-defined ILI: Aged 50–64 years: All influenza: RE 44% (95% CI = 10–65) Aged ≥65 years: All influenza: RE 42% (95% CI = 9–65)
aIIV3 (Fluad, Seqirus)
SD-IIV3; unvaccinated††	Nonrandomized, observational, prospective test negative case-control	≥65 years, presenting with symptoms of ILI	165 aIIV3 62 IIV3 55 unvaccinated	2011–12 (H3N2)	Canada (3 health authorities)	RT-PCR- confirmed ILI	Effectiveness of aIIV3 vs. unvaccinated: 58% (95% CI = 5–82) Effectiveness of IIV3 vs. unvaccinated: -2% (95% CI = -139–57) Relative effectiveness of aIIV3 vs. IIV3: 63% (95% CI = 4–86)

Abbreviations: aIIV3=trivalent inactivated influenza vaccine, adjuvanted; CI = confidence interval; ILI=influenza-like illness; HD-IIV3 = High-Dose Inactivated Influenza Vaccine, trivalent ; RE=relative efficacy (compared to active comparator vaccine); RIV4 = Recombinant Influenza Vaccine, quadrivalent; SD-IIV3 = Standard-Dose Inactivated Influenza Vaccine, trivalent.

* Studies conducted among human participants of laboratory-confirmed (by viral culture and/or RT-PCR) influenza outcomes. Modeling and medical record database studies are not included in this Table, but are discussed in the Background Document.

^† Information on predominant viruses is from U.S. national surveillance data (CDC, FluView, available at https://www.cdc.gov/flu/weekly/index.htm).

^§ Source: DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK. High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009–2010 season. Vaccine 2013;31:861–6.

^¶ Source: DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med 2014;371:635–45.

** Source: Dunkle LM, Izikson R, Patriarca P, et al.; PSC12 Study Team. Efficacy of recombinant influenza vaccine in adults 50 years of age or older. N Engl J Med 2017;376:2427–36.

^†† Source: Van Buynder PG, Konrad S, Van Buynder JL, et al. The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly. Vaccine 2013;31:6122–8.