Despite the widespread availability of seasonal flu vaccines, influenza continues to be responsible for significant morbidity and mortality in the United States. Each year, influenza causes 3.1 million hospitalization days and 34.1 million outpatient visits at an estimated direct medical cost of $10.4 billion.1 While influenza strikes people of all ages, those aged 65 years and older are disproportionately affected in terms of both death and hospitalization, with the oldest of the old at the greatest risk.2
“Influenza hits the elderly very hard,” said Marvin Bittner, MD, associate professor of medicine and medical microbiology, Creighton University School of Medicine, and staff physician, VA Medical Center, Omaha, Neb. “Last summer, the U.S. Centers for Disease Control and Prevention issued a report showing that over 20,000 people a year die in the U.S. as a result of influenza. About 90% of those people are over age 65, even though people over 65 make up only about 15% of the population.”
That report, published in the Aug. 27, 2010, Morbidity and Mortality Weekly Report (MMWR), reviewed influenza-related deaths from 1976-2007. “Among adults aged ≥65 years, an estimated annual average of 5,546 (range: 673 in 1978–79 to 13,245 in 2003–04) influenza-associated deaths with underlying pneumonia and influenza causes occurred. The average annual rate of influenza-associated deaths for this age group was 17.0 deaths per 100,000 (range: 2.4–36.7). Deaths among persons aged ≥65 years accounted for 87.9% of the overall estimated average annual influenza-associated deaths with underlying pneumonia and influenza causes,” CDC noted.
As researchers began to study the problem of increased influenza in the elderly, they examined the role of age-related changes in T-cell subsets and cytokine production profiles in the quality of immune response to vaccination. “They looked to see what kind of antibody levels were obtained with influenza immunization,” explained Bittner. “They compared people who were older with people who were younger, and there were very dramatic differences. The younger patients had a very dramatic increase in their antibody level when they got influenza vaccines. For older patients, the increase was far less dramatic. The older people ended up with substantially lower antibody levels than the younger people.”
Increased Antigen Equals Increase in Antibodies
These initial findings regarding decreased antibody levels in the elderly following influenza immunization led to two studies, funded by the National Institutes of Health, designed to determine if increasing the antigen strength would improve antibody levels in the elderly.
A 2006 study by Keitel et al3 looked at 202 ambulatory adults aged 65 years and older. Using the 2001-2002 formulation of trivalent inactivated influenza vaccine, the participants were randomly assigned to receive a single intramuscular injection of 15, 30, or 60 mcg of hemagglutinin per strain (up to a total dose of 180 mcg) or placebo. One month post-inoculation, clinical and serologic responses were assessed.
The researchers found that the increased dosage of vaccine resulted in significantly higher serum antibody levels, frequencies of antibody responses, and putative protective titers after vaccination. One month after immunization, the mean serum hemagglutination inhibition antibody titers were 23, 37, 50 and 61 against influenza A/H1N1; 43, 86, 91 and 125 against influenza A/H3N2; and 10, 14, 18 and 24 against influenza B, in the 0-, 15-, 30- and 60-mcg dosage group, respectively. They found that the 60-mcg dosage nearly doubled the antibody titers in patients with the least antibodies prior to immunization. They also found that in participants in the 60-mcg group, the mean serum hemagglutination inhibition and neutralizing antibody levels against the three vaccine antigens were 44% to 71% and 54% to 79% higher, respectively, than in those given the standard 15-mcg dosage. The authors concluded that “improved immunogenicity of high-dose influenza vaccine among elderly persons should lead to enhanced protection against naturally occurring influenza.” In other words, Bittner noted, “For influenza A, the general result was more antigen, more antibody.”
A second study funded by the NIH, by Couch and coworkers4 directly compared 15-mcg and 60-mcg doses of a trivalent inactivated vaccine (A/H3N2, A/H1N1, B). The researchers found that the increased dosage led to a fourfold or greater increase in the frequency of serum antibody in both hemagglutination-inhibiting (HAI) and neutralization tests for all three viruses in both those who had and who had not been vaccinated the prior year. They also found that the “mean titers of antibody attained, the magnitude of antibody increases and the frequencies of persons with final HAI antibody titers ≥1:32, ≥1:64, and ≥1:128 were all greater for the high-dosage group in both serologic tests, for all groups, and for all vaccine viruses.” Some increases in local and systemic reactions were reported by the higher-dosage group, but only the increases in local pain and myalgia reached statistical significance. The authors concluded, “These increased immune responses should provide increased protection against influenza in the elderly.”
In a larger study, in 2009, Falsey et al5 conducted a multicenter randomized, double-blind, phase three trial designed to compare the immunogenicity of high-dose influenza vaccine (60 mcg of hemagglutinin per strain) to that of standard-dose vaccine (15 mcg of hemagglutinin per strain) in older adults. Some 2,575 subjects were given the high-dose vaccine, while 1,262 received the standard dose. At 28 days post-inoculation, the researchers found statistically significant increases in the rates of seroconversion and mean hemagglutination inhibition titers in participants in the high-dose group compared with those in the standard-dose group. Specificially, they found “mean post vaccination titers for individuals who received high-dose vaccine were 116 for H1N1, 609 for H3N2, and 69 for B strain; for those who received standard-dose vaccine, mean post-vaccination titers were 67 for H1N1, 333 for H3N2, and 52 for B strain.” They concluded that the high-dose vaccine met the pre-set superiority criteria for both A strains, and the non-inferiority criteria for the B strain. In addition, for all strains, the seroprotection rates were higher for those in the high-dose group compared to those in the standard-dose group. As in the earlier study, there was a small increase in the reporting of local reactions with the higher dose, but the reactions were mild to moderate.
The researchers concluded, “These results suggest that the high-dose vaccine may provide improved protective benefits for older adults.”
In December 2009, Sanofi-Pasteur, Inc. introduced Fluzone® High-Dose, a 60-mcg version of their standard Fluzone® vaccine, designed specifically for adults aged 65 and older. It was available for use for the first time during the 2010-2011 flu season. A three-year, post-licensure study was begun in September 2009 and is expected to enroll as many as 33,000 patients by 2012. This randomized, blinded study is designed to assess the efficacy of Fluzone® HD compared to standard Fluzone® in patients aged 65 years and older.
“There is always the question of how well the vaccine works, and there are a variety of ways of looking at it,” said Bittner. “There are data in the literature that say that people who have higher levels of antibody directed against influenza are less likely to have influenza illness or infection. So that is an important consideration in thinking about vaccination.”
As in all health-care facilities dealing with the elderly, influenza is a significant concern for the VA. “I think the VA has addressed the issue of influenza very seriously for several years,” said Bittner. “In Omaha, we looked at the data from a year ago. We wanted to see how many of the people who received the influenza vaccine in our system were over 65 and how many were under 65. It was about 50/50. Nationally, those over 65 are only about 15% of the population, so in our system, the elderly are heavily represented
“The elderly suffer the effects of influenza disproportionately,” concluded Dr. Bittner. “One factor that may explain this is a less-vigorous response to the standard vaccine. The high-dose vaccine produces a more robust response, and that’s a basis for, at the very least, hope for making an impact on the problem of influenza in the elderly.”
- Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25:5086-5096.
- Thompson WW, Comanor L, Shay DK. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis. 2006;194(Suppl 2):S82-S91.
- Keitel WA, Atmar RL, Cate TR, Petersen NJ, et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med. 2006;166: 1121-1127.
- Couch RB, Winokur P, Brady R, et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine. 2007;25:7656-7663.
- 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: 172-180.