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If past history is predictive, during the 2009–2010 influenza season ~1 out of every 8333 Americans will die as a result of influenza and its complications. Although influenza kills ~36,000 Americans every year, >90% of those deaths occur among individuals aged ≥65 years . A long-standing recommendation in the United States has been to administer influenza vaccine to those aged ≥65 years on an annual basis. Antiviral drugs also provide prophylaxis and/or treatment for this high-risk age group, but influenza A viruses (i.e., the type most likely to cause morbidity and mortality in this age group) demonstrate worrisome resistance patterns to both the class of adamantane drugs, and more recently, to oseltamivir . Influenza in elderly individuals also leads to substantial morbidity, diminution of the capacity to perform the usual activities of daily living, and excess medical costs. This leads to increases in influenza-related health care costs, as well as increased morbidity and mortality rates, which are of particular concern as population demographics reveal an increasingly older population. The estimated annual direct and indirect influenza-related costs in the United States are estimated at $90 billion, with almost 611,000 life-years lost annually . Influenza has also become a more virulent disease with rising levels of associated mortality, despite increasing rates of influenza vaccination . For all these reasons, serious and sustained scientific and public health policy attention must be placed on the prevention of influenza in the elderly population by use of vaccines.
Unfortunately, this goal is not as simple as it may appear, because only trivalent, inactivated, influenza vaccine (TIV) is available in the United States. In other countries, MF59-adjuvanted TIV is also available for use. Although TIV provides varying levels of protection each season, depending on the match between vaccine and circulating viruses, it offers less than optimal protection . The only prospective, randomized, double-blind, placebo-controlled trial of TIV conducted in people aged >60 years demonstrated efficacy of 58% against serologically confirmed clinical influenza, but persons aged >70 years appeared to be less well protected . Thus, better vaccines for older people are clearly needed.
To address this need, a variety of creative vaccine approaches have been reported, prompted by evidence of lower hemagglutination inhibition (HAI) antibody responses in older individuals, relative to those observed in younger persons . These efforts to enhance HAI antibody levels in older people can be categorized into the following 5 candidate strategies:
Although all of these efforts have met with some level of success, it is imperative that innovative approaches specifically designed for older people be developed. The major problems with respect to vaccination in older people are immunosenescence [20, 21] and a need for rationally designed immunomodulatory approaches. Future technologies, such as the use of nanoparticles and muscosal vaccines, offer additional avenues of investigation.
The phase 3 trial of high-dose (HD) TIV reported by Falsey et al. in this issue of the Journal was conducted during the 2006–2007 influenza season and involved >3800 older adults aged ≥65 years at 30 United States trial sites . Both of the primary objectives for the study were achieved, according to predefined criteria for success. First, HD TIV demonstrated lot-to-lot consistency for immunogenicity, a mundane but essential criterion for any new vaccine formulation. Second, HD TIV induced superior HAI geometric mean titers and seroconversion rates against H3N2 and H1N1 influenza A antigens, as well as noninferior seroconversion rates against the influenza B antigen. Overall, the rate of adverse events in the HD vaccine group was acceptable although somewhat increased, as would be anticipated for HD TIV. During the 7 days after vaccination, local adverse events—arm pain, redness, and swelling—were observed with higher frequency and intensity in this group, but reactions were mild to moderate and had resolved by day 3. Moderate-to-severe fever was infrequent in HD TIV recipients (occurring in 1.1% of subjects), but it occurred more often than in TIV recipients (relative risk, 3.6). HD TIV was shown to be noninferior to TIV with respect to other systemic adverse events (headache, malaise, and myalgia). The study sample was made up of medically stable, community-dwelling, ambulatory adults aged ≥65 years—hence, the conclusions from this study may not be generalizable to very elderly individuals (e.g., those aged ≥85 years), the frail, the institutionalized, or those with unstable medical conditions. However, post hoc analyses—which cannot be viewed as definitive—suggested that HAI responses in people aged ≥75 years and those with a history of cardiopulmonary disease were similarly improved by receipt of HD TIV.
Thus, although it does not describe a novel idea, the study by Falsey et al. offers important and timely confirmatory data in a large phase 3 trial . The HD TIV strategy has advantages, in that it does not require the funding and prolonged development time typically associated with a new vaccine. Rather, it is a simple ”more is better” approach that takes a vaccine already licensed by the Food and Drug Administration and uses it as a tool to enhance immunogenicity in older people by raising the HA content of TIV from 15 to 60 μg, a 4-fold increase, for each of the 3 vaccine strains.
Although these HD TIV data are encouraging, several provisos are appropriate. First, more studies need to be done to determine the vaccine’s efficacy against infection and illness. Nonetheless, generally speaking, antibody levels are a reasonable correlate of protection, and this phase 3 trial as well as earlier, smaller studies have demonstrated superior antibody levels in response to HD TIV. Second, it will be important to determine whether the severity of local and systemic reactions will increase, should annual HD vaccination become routine. Third, antibody titers at 3–5 months after vaccination would be helpful in determining the longevity of the immune response, given the usual administration of vaccine during October and November and frequent influenza outbreaks in February and March. Lastly, more data on immunogenicity, reactogenicity, and efficacy among older elderly individuals (i.e., those aged >80 years) would be particularly useful.
The study by Falsey et al.  reminds us of an important public health goal—the development of a more immunogenic vaccine addressing the reality of the immunosenescent immune system in the older patient. This exposes an important and overdue paradigm shift in our public health approach to preventing disease by recognizing that the landscape of influenza vaccination is evolving from a “one size fits all” population-level approach to an approach that is more individualized. Our approach is currently individualized on the basis of age, but in the future, other considerations such as immune state and immunogenetics will be increasingly important . Prior to 2003, all persons eligible for influenza vaccination received TIV. In the last few years, a more individualized approach has evolved in which children aged 6 months–8 years receive 2 doses of split-virus TIV during their first vaccination season; persons aged 2–49 years receive either LAIV or TIV, depending on comorbidities; adults aged ≥50 years receive a single annual dose of TIV; and perhaps older adults will soon receive HD vaccine, adjuvanted vaccine, or other types or combinations of influenza vaccines possibly administered in combination with LAIV . In the meantime, it is estimated that only 65%–70% of the highly vulnerable older population in the United States was vaccinated during the 2006–2007 influenza season , and enhanced immunization efforts are warranted.
Multiple studies now demonstrate uniform evidence of enhanced immunogenicity, acceptable reactogenicity, safety, and some evidence of efficacy for HD TIV influenza vaccines. For this reason, we encourage TIV manufacturers to seek Food and Drug Administration licensure for HD vaccines. Potential barriers include inadequate motivation on the part of manufacturers to do so, Food and Drug Administration regulatory hurdles, and perhaps concerns about the ability to produce such vaccines, given the continuing use of egg-derived manufacturing processes with variable viral yields. Despite all of these barriers, however, there are already developed and acceptable solutions available.
To reduce the annual epidemics of influenza morbidity and mortality, it is critical that scientists, manufacturers, policy makers, and eventually health care providers move with alacrity toward the goal of licensing and using influenza vaccines designed for elderly individuals that offer enhanced protection over current vaccines. In part, the solution to this public health need must be informed by an enhanced science base and more research funding to understand the mechanisms of immunosenescence, particularly given the changing age demographics of the population. Until then, and given the increasing difficulties created by influenza antiviral resistance, it will be difficult to stem the tide of morbidity, lost productivity, needless health care costs, and mortality resulting from annual influenza epidemics. Efforts to achieve better influenza vaccination options must be a scientific and public health priority and be further codified in new research funding and delivery mechanisms. Stewards of the public health would be irresponsible to do otherwise.
NIH (grants AI 33144, AI 48793, and AI 40065 to G.A.P. and awards AI 80005, AI 69418, AI 50409, and AI 57266 to M.J.M.); Centers for Disease Control and Prevention (grant FED200–2000–10062 to G.A.P.); Georgia Research Alliance (award to M.J.M.).
Potential conflicts of interest: G.A.P. serves as an investigator for vaccine clinical studies funded by Wyeth and the National Institutes of Health (NIH). G.A.P. also serves as the chair of a safety evaluation committee for a novel influenza vaccine and other vaccines being developed by Merck Research Laboratories and offers consultative advice on new vaccine development to GlaxoSmithKline, Merck, Novartis, Novavax, Avianix, CSL Limited, and Spaldataq. M.J.M. directs NIH-funded clinical trials of influenza vaccines and adjuvants produced by sanofi pasteur and Novartis. He is an investigator for non-influenza vaccine trials funded by Merck and sanofi pasteur.