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Licensure of a High-Dose Inactivated Influenza Vaccine for Persons Aged ≥65 Years (Fluzone High-Dose) and Guidance for Use --- United States, 2010

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Persons aged ≥65 years are at greater risk for hospitalization and death from seasonal influenza compared with other age groups (1,2), and they respond to vaccination with lower antibody titers to influenza hemagglutinin (an established correlate of protection against influenza) compared with younger adults (3). On December 23, 2009, the Food and Drug Administration (FDA) licensed an injectable inactivated trivalent influenza vaccine (Fluzone High-Dose, Sanofi-Pasteur) that contains an increased amount of influenza virus hemagglutinin antigen compared with other inactivated influenza vaccines such as Fluzone. Fluzone High-Dose is licensed as a single dose for use among persons aged ≥65 years and will be available beginning with the 2010--11 influenza season. The Advisory Committee on Immunization Practices (ACIP) reviewed data from prelicensure clinical trials on the safety and immunogenicity of Fluzone High-Dose and expressed no preference for the new vaccine over other inactivated trivalent influenza vaccines (4). This report summarizes the FDA-approved indications for Fluzone High-Dose and provides guidance from ACIP for its use.

Standard dose inactivated trivalent influenza vaccines contain a total of 45 µg (15 µg of each of the three recommended strains) of influenza virus hemagglutinin antigen per 0.5mL dose (5). In contrast, Fluzone High-Dose is formulated to contain a total of 180 µg (60 µg of each strain) of influenza virus hemagglutinin antigen in each 0.5mL dose. Like other inactivated influenza vaccines, Fluzone High-Dose is administered as an intramuscular injection (6). Fluzone High-Dose is available as a single-dose prefilled syringe formulation and is distinguished from Fluzone by a gray syringe plunger rod. As with other 2010--11 influenza vaccines, Fluzone High-Dose will contain antigens of the three recommended virus strains: A/California/7/2009 (H1N1)-like, A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like (7).

Immunogenicity data from three studies among persons aged ≥65 years indicated that, compared with standard dose Fluzone, preparations of Fluzone High-Dose elicited significantly higher hemagglutination inhibition (HI) titers against all three influenza virus strains that were included in seasonal influenza vaccines recommended during the study period (8--10). In one study, prespecified criteria for superiority, defined as when the lower 95% confidence limit of 1) a ratio of geometric mean HI titers is >1.5 for at least two strains and 2) the difference in fourfold rise of HI titers is >10% for at least two strains, were demonstrated for persons aged ≥65 years who received Fluzone High-Dose compared with Fluzone for influenza A(H1N1) and influenza A(H3N2) antigens. Prespecified criteria for noninferiority to Fluzone were demonstrated for the influenza B antigen (6,9). Whether the higher postvaccination immune responses observed among Fluzone High-Dose vaccine recipients will result in greater protection against influenza illness is unknown.

Solicited injection site reactions and systemic adverse events were more frequent after vaccination with Fluzone High-Dose compared with standard Fluzone, but typically were mild and transient (8--10). In the largest study, 915 (36%) of 2,572 persons who received Fluzone High-Dose, compared with 306 (24%) of 1,275 persons who received Fluzone, reported injection site pain ≤7 days after vaccine administration. In the same study, significantly more Fluzone High-Dose recipients (1.1%) reported moderate (>100.4°F--≤102.2°F [>38°C--≤39°C]) to severe (>102.2°F [>39°C]) fever, compared with Fluzone recipients (0.3%)(9).

ACIP Guidance for Use of Fluzone High-Dose

Fluzone High-Dose may be used for persons aged ≥65 years. All persons aged ≥6 months are recommended for annual influenza vaccination beginning with the 2010--11 influenza season. ACIP has not expressed a preference for any specific licensed inactivated trivalent influenza vaccine, including Fluzone High-Dose, for use in persons aged ≥65 years (4). Data demonstrating greater protection against influenza illness after vaccination with Fluzone High-Dose are needed to evaluate whether Fluzone High-Dose is a more effective vaccine for persons aged ≥65 years. A 3-year postlicensure study of the vaccine effectiveness of Fluzone High-Dose compared with standard dose inactivated influenza vaccine (Fluzone) was begun in 2009 and should be completed in 2012. As with other inactivated influenza vaccines, Fluzone High-Dose should not be administered to anyone with a known hypersensitivity to egg proteins or influenza vaccine. Adverse events after receipt of any vaccine should be reported to the Vaccine Adverse Event Reporting System at


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  4. CDC. ACIP provisional recommendations for the use of influenza vaccines. Atlanta, GA, US Department of Health and Human Services, CDC; 2010. Available at Accessed April 23, 2010.
  5. CDC. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR 2009;58(No. RR-8).
  6. Sanofi Pasteur, Inc. Fluzone and Fluzone High-Dose [prescribing information]. Swiftwater, PA: Sanofi Pasteur, Inc.; 2009. Available at Accessed April 23, 2010.
  7. Food and Drug Administration. Influenza virus vaccine for the 2010--2011 season. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2010. Available at Accessed April 23, 2010.
  8. Couch RB, Winokur P, Brady R, et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 2007;25:7656--63.
  9. Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 2009;200:172--80.
  10. Keitel WA, Atmar RL, Cate TR, et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med 2006;166:1121--7.

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