High-Dose Flu Vaccine: Is The Hype Real?

High-Dose Flu Vaccine: Is The Hype Real?



The CDC estimates that during the 2019-2020 influenza season, approximately 38 million people were infected with the flu in the U.S. With COVID-19 and flu season overlapping this year, it is crucial for patients to receive the flu vaccine to prevent hospitalizations and mortality. Studies show that people 65 years and older are most vulnerable to the flu and account for approximately 70-85% of flu-related deaths. Many patients who are 65+ years old often have questions regarding the high-dose flu vaccine and which vaccine is the right choice for them. This article will analyze data and trials comparing the high-dose, adjuvanted, and standard vaccine and will provide information and recommendation for the best vaccine for the patient.

The vaccines indicated for patients 65+ are: Fluzone High-Dose Quadrivalent and adjuvanted flu vaccines (FLUAD and FLUAD Quadrivalent). The Fluzone High-Dose Quadrivalent (HD) is a four-ingredient, inactivated vaccine that contains four times the antigen to provide extra protection for those 65+. It’s manufactured using an egg-based process and is one of the more expensive options at approximately $64 for each prefilled syringe.

FLUAD and FLUAD Quadrivalent vaccines contain the ingredient squalene that helps increase immune response and allows the manufacturer to use less virus in the vaccine to produce a greater supply. Similarly, these are also made with the egg-based process and cost approximately $60 for both the quadrivalent or standard dose adjuvant vaccine.

In addition to the ones above, there are a number of other less costly options available for standard flu vaccines (SD) priced at around $20. So the question remains: is the high-dose or adjuvanted vaccine better than the standard dose for the senior population?

“Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults” was a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial that compared the SD vs HD vaccine with an enrollment of 31,989 patients for the trial. The results were statistically significant with the HD trial resulting in 228 influenza cases versus the SD trial’s 301 cases. Similarly, hemagglutination inhibition immunogenicity was measured for the two groups. A month after vaccination, the HD showed significantly higher levels than the SD.

The second trial discussed in this article is by Gravenstein PS, Davidson HE, Taljaard M, et. al. They performed a single-blind, pragmatic, comparative effectiveness, cluster-randomized trial. The study compared HD versus SD in nursing home residents with the primary outcome being hospital admissions. The respiratory-related hospital admissions were significantly lower in the facilities in which the residents received HD than in those that received SD. To expand, there were 185/1000 residents hospitalized in the HD versus 211/1000 in the SD group.

The third study, “Prevention of serious events in adults 65 years of age or older”, was a double-blind, randomized, active-controlled, multicenter trial. Participants were adults ≥65 years, randomized to receive trivalent HD or trivalent SD. The trial length followed participants 6 to 8 months post-vaccination and the primary endpoint was lab-confirmed influenza. The randomization of participants was as follows: 15,991 to IIV-HD and 15,998 to IIV-SD. The rate of all-cause hospitalization was 6.9% (95% CI, 0.5–12.8%) lower in the HD cohort. Likewise, there were 71 pneumonia events in HD vs 118 in SD.

As far as the data for the adjuvant vaccine, a meta-analysis was conducted including all prospective, randomized, and observer-blinded clinical studies. A total of 20 trials were included over the span of 2 years. In each of these studies, a single dose of FLUAD or control vaccine (standard vaccine) was given to each patient. The study population was those aged 65+ and mostly ambulatory patients. The results of the study were statistically significant in that the adjuvant vaccine had a higher immunogenicity than the SD. Another analysis performed showed that patients with cardiovascular diseases, respiratory diseases, or diabetes had a greater benefit from the adjuvant vaccine than SD.

Which leads us to the next question: is the high dose or adjuvant vaccine really better for patients 65 and older? To date, there are no trials comparing the high-dose against the adjuvant vaccine, and the CDC does not recommend one vaccine over another for this age group.

In summary, the trials discussed above have shown that all approved flu vaccines are efficacious at preventing the flu. When comparing the two, however, the HD performed better than the standard dose in patients over 65 years of age. For the prevention of influenza cases, hospitalizations, or pneumonia, the HD was superior.

On the other hand, the adjuvant vaccine also performed better than the standard dose vaccine and resulted in higher rates of immunogenicity in the elderly. However, the CDC does not recommend or prefer one influenza vaccination over another. The most important recommendation one can make as a provider is ensuring that patients over 65 receive one of these vaccinations annually.

In conclusion, both the high dose and adjuvant vaccines are generally well-tolerated and efficacious and are the preferred choice when choosing a vaccine for the elderly population.


Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths in the United States – 2019–2020 Influenza Season. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/about/burden/2019-2020.html. Published October 6, 2020. Accessed October 17, 2020.

Fluzone High-Dose Seasonal Influenza Vaccine. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/prevent/qa_fluzone.htm. Published September 3, 2020. Accessed October 17, 2020.

Influenza Virus Vaccine (Inactivated). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: https://www.reliasmedia.com/articles/143915-influenza-cases-rising-what-clinicians-need-to-know. Accessed October 20, 2020.

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(7):635-645. doi:10.1056/NEJMoa1315727

Gravenstein S, Davidson HE, Taljaard M, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: a cluster-randomised trial. Lancet Respir Med. 2017;5(9):738-746. doi:10.1016/S2213-2600(17)30235-7

Izurieta HS, Chillarige Y, Kelman J, et al. Relative Effectiveness of Cell-Cultured and Egg-Based Influenza Vaccines Among Elderly Persons in the United States, 2017-2018 [published correction appears in J Infect Dis. 2019 Jun 5;220(1):179]. J Infect Dis. 2019;220(8):1255-1264. doi:10.1093/infdis/jiy716

DiazGranados CA, Robertson CA, Talbot HK, Landolfi V, Dunning AJ, Greenberg DP. Prevention of serious events in adults 65 years of age or older: A comparison between high-dose and standard-dose inactivated influenza vaccines. Vaccine. 2015;33(38):4988-4993. doi:10.1016/j.vaccine.2015.07.006

Adjuvanted Flu Vaccine. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/prevent/adjuvant.htm. Published August 21, 2020. Accessed October 20, 2020.

Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine. 2001;19(17-19):2673-2680. doi:10.1016/s0264-410x(00)00499-0

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