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New research comparing the the new Fluzone High-Dose vaccine and the seasonal flu vaccine sheds light on how ineffective the latter vaccine has been for the elderly.
By Keith Berman, MPH, MBA, and Luke Noll
“Old age is no place for sissies,” the film actress Bette Davis observed late in her life while lying in a hospital bed. When this year’s influenza season comes around, Americans over age 65 will be gently reminded of this fact as they’re urged and prodded to get their annual flu shot. And, more than two-thirds of seniors do so these days — not the 90 percent that public health experts have called for, but a lot better than the woefully low 30 percent vaccination rate in this age group just 20 years ago.1
People over 65 years of age, and particularly those well beyond 65, are hit especially hard by seasonal influenza. In fact, in this age group, a case of the flu is most likely to lead to serious or life-threatening complications, especially in those with chronic pre-existing conditions, such as cardiac and pulmonary disease. In the elderly in particular, a bout of the flu also can progress to primary influenza pneumonia or secondary bacterial pneumonia.
Each year, seniors account for an estimated 46 percent of all flu-related clinic visits, nearly 60 percent of all annual flu-related hospital days, three-quarters of life-years lost (Table 1)2 and 90 percent of this country’s estimated 36,000-41,000 annual flu-related deaths. And, while the seasonal flu vaccine has been said to protect this group from contracting the flu, new research suggests that this has not been the case. But, with a new high-dose flu vaccine now on the market, the elderly will likely be much better protected from the flu.
With more than a doubling of the vaccination rate since 1990, one would expect a healthy drop in flu-related hospitalizations and deaths. But those numbers haven’t dropped. In fact, overall hospital admission and death rates in the U.S. have actually increased over the last two decades,3 even after accounting for changing age demographics and ups and downs in this customized vaccine’s effectiveness against each season’s new flu strain.
The actual life- and health-sparing value of flu vaccine in the elderly has been a subject of some controversy. Nearly all the evidence for protective benefit in this population comes from non-randomized observational studies. Typical of these was a large 2003 medical record review of 286,000 community-dwelling Americans at least 65 years old. In this review, those who got a flu vaccine experienced nearly a 20 percent reduction in risk of hospitalization for cardiac disease, about a 30 percent lower risk of hospitalization for pneumonia or influenza, and an impressive 49 percent average reduction in risk of death from all causes over the span of two flu seasons.4
But many experts have pointed out the strong potential for bias when studies look at health outcomes in people who choose themselves whether to get a flu vaccine or not. One research team decided to take a closer look at the issue. They followed a large cohort of 72,527 people aged 65 and older during an eight-year period to assess the risk of death or hospitalization for pneumonia or the flu before, during and after flu seasons.5 Their findings have all but discredited the rosy results of earlier “observational” flu studies in seniors. Before the flu season even arrived, the relative risk of death for vaccinated persons compared to unvaccinated persons was 0.39. In other words, people who lined up for their flu shot were about 60 percent less likely to die from any cause compared with those who didn’t — before they received the vaccine or got exposed to the new flu virus!
This obvious bias is built into any study that simply tallies deaths or hospitalizations of people who decided on their own whether to get a flu shot. People who choose on their own to get the vaccine clearly tend to be much healthier than those who don’t, and they appear to take better care of themselves when they do get sick.
The underlying answer to the paradox of more flu-related deaths despite higher vaccination rates in the elderly is straightforward: Standard trivalent inactivated influenza vaccine (TIV) isn’t nearly as protective for older adults as it is for non-elderly adults. After age 65, the competency of our immune system steadily declines with passing years. Sooner or later, this natural course of “immunosenescence” translates to a poor, nonprotective antibody response to the standard dose of influenza vaccine.6 It also accounts for why people 85 years of age and older are roughly 16 times more likely to die of any flu-related cause and more than 30 times more likely to die of influenza or associated pneumonia than those between age 65 and 69.7
The overall chances that elderly persons will have a potentially protective antibody response to flu vaccine has been estimated to be somewhere between 24 percent and 59 percent of that of younger adults. According to U.S. Centers for Disease Control and Prevention (CDC) estimates, healthy adults under age 65 can expect a 70 percent to 90 percent overall clinical vaccine efficacy rate when the vaccine and circulating virus are antigenically similar. But the clinical efficacy of flu vaccine is clearly far lower in the elderly.8
As flu experts have pointed out for decades, what is needed is a more immunogenic flu vaccine for the elderly, one that more consistently and effectively mobilizes their available antibody and cellular immunity.
For the first time since the flu vaccine’s introduction in the 1940s, Americans aged 65 and older will have the option of receiving a high-potency flu vaccine during the current 2010-2011 season.
Last December’s U.S. Food and Drug Administration (FDA) approval of Sanofi Pasteur’s Fluzone High-Dose (Fluzone HD) proves once again that sometimes successful ideas also are the simplest ones. Instead of the 15 micrograms (mcg) of each of the three hemagglutinin viral surface antigens included in standard TIV preparations, Fluzone HD delivers 60 mcg — four times as much — in the same 0.5 mL dose for intramuscular injection. A different colored syringe plunger distinguishes it from regular Fluzone provided in a prefilled syringe. Everything else about the two products is the same.
Immunogenicity findings from three clinical trials in persons 65 years of age and older demonstrate that Fluzone HD elicits substantially higher hemagglutinin inhibition (HI) titers than the standard dose.9,10,11 In the largest of these studies, the mean post-vaccination antibody titer elicited by Fluzone HD against the A/H1NI, A/H3N2 and B flu strains was 70 percent, 80 percent and 30 percent higher, respectively, than the titer elicited by the standard-dose vaccine. Additional important evidence of the enhanced immunogenicity of Fluzone HD is revealed by comparative seroconversion and seroprotection findings, as summarized in Table 2.
In studies over the last 40 years, higher HI titers have been shown to directly correlate with lower rates of influenza infection.12,13,14 To the extent that higher post-vaccination HI titers are predictive for increased protective immunity in older adults, there is every reason to hope and expect that Fluzone HD can reduce the frequency of laboratory-confirmed flu and its serious complications.
With four times as much hemagglutinin antigen (HA) being introduced into the muscle tissue as the same volume of traditional flu vaccine, more injection site and systemic reactions are to be expected. This is exactly what was observed in a pivotal trial involving 2,573 subjects aged 65 years and older who were administered Fluzone HD and 1,260 subjects who were given Fluzone. Table 3 summarizes these adverse event findings.15 Most of these local and systemic reactions were mild and resolved within three days. However, significantly more Fluzone HD recipients (1.1 percent) reported moderate to severe fever than those who received standard Fluzone (0.3 percent).16
The more important comparative measure — the rate of serious adverse events — was not found to be different between subjects who received the high-dose (156/2573; 6.1 percent) and standard (93/1260; 7.4 percent) Fluzone products. No one looks forward to a higher likelihood of injection site reactions, transient headaches, fever and the like. But, there is an upside: Along with increased anti-HA antibody titers, a higher frequency of these events signals a more active and potentially more protective immune response.
As noted earlier, better HI antibody responses are known to correlate with protection against influenza infection and reduced clinical disease risk. Yet while it is very encouraging that Fluzone HD induces higher serum antibody titers without significant safety concerns, the jury is still out on whether this actually translates into fewer confirmed cases and serious complications from the flu.
As a condition of licensure under FDA’s “accelerated approval” process, the agency instructed Sanofi Pasteur to conduct a head-to-head study to compare Fluzone HD and Fluzone (the “active control”) in 27,000 to 30,000 adult subjects 65 years of age and older. That study will be conducted over three flu seasons to try to account for typical fluctuation in vaccine efficacy, which is related to differences between the flu virus that arrives and the strains picked in advance to make the vaccine. The first season (2009-2010) is already enrolled, with the 2010-2011 and 2011-2012 seasons to follow.
Until that study is finished and the results are known, Fluzone HD’s labeling informs providers and recipients that “there have been no controlled studies demonstrating a decrease in influenza disease after vaccination with Fluzone High-Dose.”
Among leading flu vaccine candidates in advanced clinical development (Table 4) are a high-dose recombinant HA vaccine, a recombinant “virus-like particle” vaccine, a vaccine that fuses HA antigens to a bacterial protein called flagellin, and a pair of established flu vaccines spiked with “adjuvants” to punch up the recipient’s antibody and cellular immunity to the HA antigens they contain.
Should any of these vaccines ultimately be licensed — and the ongoing Fluzone HD trial proves that it confers superior protection against lab-confirmed influenza to standard-dose TIV — it’s entirely imaginable that large head-to-head trials may eventually be organized to try to resolve which high-immunogenicity vaccine confers the best protection against the flu.
This year, more than 30 million seniors will dutifully show up for an appointment or at a vaccination clinic and bare their arms for the annual flu shot. The reason, they’ll be assured, is to help protect themselves from infection with this season’s influenza virus and the potential health ravages it can cause.
If the goal of the flu vaccination exercise is to boost the odds of beating the 2010-2011 flu virus coming their way, this new Medicare-covered high-dose vaccine may be an easy choice for many seniors to make.
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14. Gorse, GJ, O’Connor, TZ, Newman, FK, et al. Immunity to influenza in older adults with chronic obstructive pulmonary disease. Journal of Infectious Diseases, 2004, 190: 1-19.
15. Fluzone and Fluzone High-Dose (Influenza Virus Vaccine). Full prescribing information, July 2010.
16. Centers for Disease Control and Prevention (CDC). Licensure of a high-dose inactivated influenza vaccine for persons aged > or = 65 years (Fluzone High-Dose) and