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High Dose Influenza Vaccination of the Elderly

By Amesh A. Adalja, MD, July 2, 2009

Despite high vaccination rates, the elderly disproportionately bear the burden of seasonal influenza morbidity and mortality. Immunosenescence is thought to be the cause, as higher vaccine seroconversion rates are seen in younger populations. Several approaches have been proposed to overcome this barrier to effective protection of the elderly, including: use of adjuvants, use of live-attenuated vaccines, novel vaccine constructs, and higher dose vaccines. Higher dose vaccination has been employed in several scenarios, with encouraging results. An article in the July 15, 2009, issue of the Journal of Infectious Diseases reports the results of a large Phase 3 trial, conducted in 2006, that adds more support to the high dose influenza vaccine strategy.1

High Dose Seasonal Influenza Vaccine vs. Standard Formulation

In this trial, Falsey and colleagues utilized a high dose formulation of the trivalent seasonal influenza vaccine that, instead of containing just 15 micrograms of each influenza strain (45 micrograms total), contained 60 micrograms per dose (180 microgram total)—a level 4 times higher than the seasonal vaccine.1

The trial was a multi-center, double-blind, randomized control trial that involved subjects 65 years and older. Subjects were randomized to receive either the standard formulation vaccine or the high dose formulation. In total, 2,575 subjects received the high dose formulation, while 1,262 were randomized to receive the standard formulation. Baseline characteristics did not reveal any differences between the 2 groups, including in baseline titers to the influenza strains contained in the vaccine. The primary objective of the study was to confirm higher immunogenicity of the high dose formulation of vaccine, while a secondary objective was to assess the rates of adverse events.1

Post-Vaccine Titers to All Strains Increased in the High Dose Vaccine Group

Serological analysis of post-vaccine titers revealed that those receiving the high dose formulation had higher antibody titers via hemagglutinin agglutinin inhibition (HAI) to both of the A strains and the B strain contained in the vaccine. Seroconversion rates (i.e., titers of at least 1:40) were 25.4% greater in the high dose group to A/H1N1, 18.4% greater for A/H3N2, and 11.8% greater for B—reaching superiority definitions for the A strains and non-inferiority for the B strain. Significantly more subjects in the high dose group also developed antibody titers of at least 1:80, a level higher than the 1:40 level needed for seroconversion. Post-hoc analysis of subgroups revealed the findings held within the 75 years and older age group.1

Local Reactions More Common in the High Dose Subgroup

Among those who received the higher dose formulation, local reactions at the vaccine site were reported at significantly higher rates. Systemic reaction rates were not significantly different between the 2 groups. However, there were more body temperatures greater than 38° Centigrade in the high dose group (see table).1

Table: Adverse Effects

 High dose
vaccine group
vaccine group
Swelling 6% 4%
Temperature > 38°C1.1%0.3%

Are High Dose Vaccines the Key to Protecting the Elderly from Influenza?

This study provides more evidence that simple augmentation of the seasonal flu vaccine can achieve statistically meaningful increases in seroprotection rates without unduly increasing adverse events. This approach is promising, but as HAI titers are only a correlate of protection, clinical studies that demonstrate decreased rates of illness, morbidity, and mortality amongst high dose vaccine recipients are needed.

Alternatively, an approach employing adjuvanted vaccines, as is currently done in the EU, should be pursued in the U.S. Whole virus vaccines are another method worthy of consideration. Importantly, neither of these 2 methods may require 4-fold increases in vaccine doses, which is an advantage when influenza vaccine manufacturing capacity is limited. Also worthy of exploration is expansion of the age groups in which the live-attenuated influenza vaccine is used; it is not currently indicated for those older than 49 years of age.

In an editorial accompanying this article, Greg Poland and Mark Mulligan rightly assert that “efforts to achieve better influenza vaccination options must be a scientific and public health priority,” and that “stewards of the public health would be irresponsible to do otherwise.”2 Indeed, any improvement in vaccination of the elderly will refine the entire influenza vaccine landscape.


  1. Falsey AR, Treanor JJ, Tornieporth N, et al. 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. Accessed June 27, 2009.

  2. Poland GA, Mulligan MJ. The imperative of influenza vaccines for elderly individuals—an evolving story. J Infect Dis 2009;200:161-3.