Expert Commentary

Does a high-dose influenza vaccine protect older adults to a greater extent than the standard-dose vaccine?

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Yes, it does, among people aged 65 years or older, according to this phase IIIb-IV, multicenter, randomized, double-blind, active controlled trial comparing high-dose, trivalent, inactivated flu vaccine with the standard dose.

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;371:635–645.



The objective of this investigation was to compare a standard-dose trivalent influenza vaccine with a high-dose vaccine in adults older than 65 years. The standard dose of the vaccine contained 15 µg of hemagglutinin per strain, and the high dose contained 60 µg hemagglutinin per strain. The study was conducted during the 2011–2012 and 2012–2013 flu seasons. Key outcome measures were efficacy, as assessed by the occurrence of laboratory-confirmed influenza at least 14 days after vaccination; immunogenicity of the vaccines; and frequency of adverse events.

Details of the study
The study involved 15,991 patients in the high-dose group and 15,998 patients in the standard-dose group. Two hundred twenty-eight participants (1.4%) in the high-dose group developed influenza, compared with 301 participants (1.9%) in the standard-dose group.

The overall efficacy of the high-dose vaccine was 24.2% (95% confidence interval [CI], 9.7–36.5), meaning that approximately 24% of influenza cases could have been prevented if the high-dose vaccine had been administered to all patients.

In the high-dose group, 8.3% of patients had at least 1 adverse event, compared with 9% in the standard-dose group (relative risk, 0.92; 95% CI, 0.85–0.99).

After vaccination, the hemagglutination inhibition titers were significantly higher in the high-dose group.

Fewer adverse events with the higher dose, but some events were graver
Influenza is a serious viral illness, and it can be associated with mortality in certain populations, such as very young children, pregnant women, and people older than 65 years.

As a general rule, older patients do not respond as well to the vaccine as younger patients do. The standard dose of vaccine provides about 50% protection against influenza in older patients, compared with approximately 60% to 65% in younger individuals. With the added protection of the high-dose vaccine (overall efficacy, 24.2%), approximately 62% of adults older than age 65 would be protected—a figure similar to that reported for younger patients.

The increase in effectiveness was achieved with no increase in the overall frequency of adverse effects. In fact, the frequency of adverse effects was actually slightly lower in the recipients of the higher dose. However, in 3 recipients of the high-dose vaccine the adverse effects were notable. One had a transient sixth cranial nerve palsy that started 1 day after vaccination. One had hypovolemic shock due to diarrhea that started 1 day after vaccination. One had acute disseminated encephalomyelitis that started 117 days after vaccination. All 3 patients recovered fully. No such serious events occurred in the standard-dose group.

Several barriers prevent widespread vaccination
The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices strongly recommends influenza vaccination for everyone over the age of 6 months. Barriers to widespread vaccination include reluctance on the part of the patient, failure on the part of the physician to advocate for vaccination, and cost of the vaccine for patients who have suboptimal insurance or no insurance.

We should strongly advise older women in our practice to receive the high-dose influenza vaccine. We should caution them that the overall risk of adverse effects is actually lower than with the standard-dose vaccine but that serious effects can occur in rare instances.
—Patrick Duff, MD

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