Influenza: Advances in the Vaccination of the Elderly
On 23 December 2009, the US FDA approved Fluzone® High Dose, a high-dose formulation of the trivalent inactivated influenza vaccine, for prevention of influenza in people 65 years of age and older. As it was approved via an accelerated process designed to allow expeditious availability of safe and effective products with promise to treat or prevent serious or life-threatening diseases, the manufacturer is required to conduct further studies to demonstrate effectiveness. Although these studies are underway, a recently completed randomized, controlled trial demonstrated that this vaccine, containing four-times more hemagglutinin than standard-dose inactivated influenza vaccines, can produce an enhanced immunologic response in subjects of 65 years of age and older, while maintaining a favorable safety profile. This article introduces the vaccine, presents currently available safety and immunogenicity data, discusses current recommendations for use, and proposes what we can expect in the coming years.
Influenza-related complications disproportionately affect the elderly. In the USA, more than 90% of the 36,000 influenza-related annual deaths occur in those age 65 years or older. The mean influenza-associated mortality rate for this age group is 22.1 deaths per 100,000 person years, compared with 0.2 deaths among those 5–49 years of age and 1.3 deaths per 100,000 person years in those aged 50–64 years. Influenza impacts the very elderly even more severely. Those older than 85 years of age are 16-times more likely to die of influenza-related illness and 32-times more likely to die of influenza-associated pneumonia than those between 65 and 69 years of age. In those 65 years of age or older with any influenza risk factors, influenza-related hospitalizations occur three-times more commonly than in younger, otherwise healthy individuals. The length of hospital stay increases from an average of 6 days in those between 50 and 64 years of age to 8 days for those older than 75 years of age. As outpatient treatment for this group is also more costly, the elderly account for an estimated 64% of influenza's total economic burden. The aging population in all Western industrialized nations is likely to further magnify this economic impact.
For these reasons, influenza prevention in the elderly through the use of vaccines is a public health priority. However, despite an increase in vaccination uptake in the elderly over the past three decades, influenza deaths have continued to increase. The reasons for this are unclear, but may include increasingly virulent influenza strains, a rapidly expanding elderly population with decreased vaccine efficacy due to immunosenescence, and other factors. Vaccine uptake rates for the 2008–2009 influenza season were 66.3% (95% CI: 64.2–68.3) for those greater than 65 years of age. These rates are lower than the Healthy People 2010 Objective to cover more than 90% of this age group.
The elderly have a significantly reduced antibody response to influenza vaccination. Although antibody response is a generally well?accepted correlate of protection against influenza illness, the data to support such a correlate in the elderly is sparse. Yet, the most established immunologic correlate for vaccine protectiveness remains the hemagglutination inhibition (HI) assay which measures hemagglutination (HA) of IgG antibodies. Both the amount and avidity of these neutralizing antibodies determine the level of protection. Postvaccination seroconversion is widely defined as a fourfold or more increase in antibody titers and seroprotection is considered achieved in those who demonstrate HI antibody titers of 1:40 or more against the antigen of interest.
A quantitative review of studies evaluating antibody-titer responses to influenza vaccination demonstrated that seroconversion and seroprotection rates are only 25% as robust for H1 and B antigens and 50% as robust for H3 antigens in the elderly, compared with younger subjects. This review selected papers reporting data on subjects with a mean age of 65 years or greater. Of the 4492 elderly vaccinated subjects, 42, 51 and 35% of subjects seroconverted to H1N1, H3N2 and influenza B, respectively, compared with 60, 62 and 58%, respectively, for younger subjects. Antibody responses among the very elderly (≥75 years of age) were especially impaired with seroconversion levels at 32, 46 and 29%, respectively.
Although not routinely measured, cell-mediated immunologic responses to influenza vaccines may also significantly impact protection against influenza disease. Likewise, an impaired cell-mediated response to vaccination has been correlated with the risk of developing influenza; however, the risk of developing influenza disease is highest among the elderly, who demonstrate neither an antibody nor cell-mediated response to vaccination. Even though waning immunity during the typical 4-month influenza season has been of historic concern, it appears that the main reason for inadequate protection 4 months after vaccination is failure to respond at 1 month, suggesting that the primary response is the most important immunologic consideration.
The impaired ability of the elderly to mount an adequate immunologic response to influenza vaccine has been attributed to immunosenescence, defined as a decline in the body's ability to fight infection, mount novel immune responses and recall immune responses. Both innate and adaptive immunity are implicated. Dysregulation of innate immunity occurs through impaired function of costimulatory molecules, altered secretion of inflammatory cytokines, and diminished function of natural killer cells, macrophages and neutrophils. This occurs in combination with a decreased proliferative capacity of the B cells, diminished antibody potency and impaired T-cell memory recall.
Vaccine efficacy is demonstrated by protection against laboratory or culture-confirmed influenza, whereas vaccine effectiveness is demonstrated by prevention of clinical illness. Studies to evaluate the efficacy/effectiveness of influenza vaccines in older adults have evaluated a variety of outcomes, including infection rates, illness rates confirmed either clinically or by laboratory testing, and complication rates. Up until now, most efficacy data concern the only previously available influenza vaccination for this vulnerable age group: the trivalent, inactivated influenza vaccine (TIV). The sole prospective, randomized, double-blind, placebo-controlled trial of TIV in individuals aged over 60 years demonstrated an efficacy of 58% (95% CI: 26–77%) against serologically confirmed clinical influenza and 47% (95% CI: 27–61%) against clinical influenza. It was less effective in those older than 70 years of age who had a relative risk of serologically confirmed influenza of 0.77 (95% CI: 0.39–1.51) compared with those vaccinated with placebo. Meta-analyses of the remaining, mostly observational studies, have concluded that influenza vaccination is associated with significant reductions in hospitalizations and deaths. However, some concerns have been raised regarding the quality of evidence available relative to the efficacy and effectiveness of currently available influenza vaccines for people aged 65 years or older. The Cochrane Collaboration systemic review concluded that "the available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered, publicly funded, randomized, placebo-controlled trial run over several seasons should be undertaken". Many, if not most, experts in the field would consider such a study unethical.
Furthermore, although chemoprophylaxis and treatment options with antiviral agents are available, viral resistance to these agents is a considerable issue and has increasingly limited their usefulness. For example, seasonal influenza A/H1N1 isolates have exhibited high-level resistance to oseltamivir, and the M2 ion channel inhibitors (amantadine and rimantadine) are ineffective against B strains and have shown limited effectiveness against many influenza A strains. This worrisome trend supports recently adopted recommendations by the Advisory Committee on Immunization Practices (ACIP) to broaden the application of our best available option in the prevention of influenza illness by vaccination. This resulted in the recent recommendation for vaccinating all individuals over 6 months of age against influenza.
For the elderly, however, it remains particularly imperative that more effective vaccines be developed. To this end, several strategies have been proposed and tested, including high-dose TIV (HD-TIV), adjuvanted TIV, intradermal delivery of TIV, priming recipients with live-attenuated influenza virus vaccine (LAIV) prior to TIV administration, and other emerging vaccine technologies such as virosomal subunit vaccines and others. Other data support the idea that strategies to increase influenza vaccine uptake in children and adolescents can protect the elderly through herd immunity.
However, this article will focus on HD-TIV, as recently a Phase III trial that compared HD-TIV (Fluzone® High Dose, Sanofi Pasteur Inc., Swiftwater, PA, USA) to standard-dose TIV (Fluzone) demonstrated superior HI geometric mean titers and seroconversion rates against H1N1 and H3N2 influenza A antigens, and noninferior serocoversion rates against influenza B antigens in the elderly. Given favorable safety and efficacy data, the US FDA approved Fluzone High Dose via an accelerated process for this high-dose seasonal influenza vaccine specifically intended for people aged 65 years and older.
Abstract and Introduction
Abstract
On 23 December 2009, the US FDA approved Fluzone® High Dose, a high-dose formulation of the trivalent inactivated influenza vaccine, for prevention of influenza in people 65 years of age and older. As it was approved via an accelerated process designed to allow expeditious availability of safe and effective products with promise to treat or prevent serious or life-threatening diseases, the manufacturer is required to conduct further studies to demonstrate effectiveness. Although these studies are underway, a recently completed randomized, controlled trial demonstrated that this vaccine, containing four-times more hemagglutinin than standard-dose inactivated influenza vaccines, can produce an enhanced immunologic response in subjects of 65 years of age and older, while maintaining a favorable safety profile. This article introduces the vaccine, presents currently available safety and immunogenicity data, discusses current recommendations for use, and proposes what we can expect in the coming years.
Introduction
Influenza-related complications disproportionately affect the elderly. In the USA, more than 90% of the 36,000 influenza-related annual deaths occur in those age 65 years or older. The mean influenza-associated mortality rate for this age group is 22.1 deaths per 100,000 person years, compared with 0.2 deaths among those 5–49 years of age and 1.3 deaths per 100,000 person years in those aged 50–64 years. Influenza impacts the very elderly even more severely. Those older than 85 years of age are 16-times more likely to die of influenza-related illness and 32-times more likely to die of influenza-associated pneumonia than those between 65 and 69 years of age. In those 65 years of age or older with any influenza risk factors, influenza-related hospitalizations occur three-times more commonly than in younger, otherwise healthy individuals. The length of hospital stay increases from an average of 6 days in those between 50 and 64 years of age to 8 days for those older than 75 years of age. As outpatient treatment for this group is also more costly, the elderly account for an estimated 64% of influenza's total economic burden. The aging population in all Western industrialized nations is likely to further magnify this economic impact.
For these reasons, influenza prevention in the elderly through the use of vaccines is a public health priority. However, despite an increase in vaccination uptake in the elderly over the past three decades, influenza deaths have continued to increase. The reasons for this are unclear, but may include increasingly virulent influenza strains, a rapidly expanding elderly population with decreased vaccine efficacy due to immunosenescence, and other factors. Vaccine uptake rates for the 2008–2009 influenza season were 66.3% (95% CI: 64.2–68.3) for those greater than 65 years of age. These rates are lower than the Healthy People 2010 Objective to cover more than 90% of this age group.
The elderly have a significantly reduced antibody response to influenza vaccination. Although antibody response is a generally well?accepted correlate of protection against influenza illness, the data to support such a correlate in the elderly is sparse. Yet, the most established immunologic correlate for vaccine protectiveness remains the hemagglutination inhibition (HI) assay which measures hemagglutination (HA) of IgG antibodies. Both the amount and avidity of these neutralizing antibodies determine the level of protection. Postvaccination seroconversion is widely defined as a fourfold or more increase in antibody titers and seroprotection is considered achieved in those who demonstrate HI antibody titers of 1:40 or more against the antigen of interest.
A quantitative review of studies evaluating antibody-titer responses to influenza vaccination demonstrated that seroconversion and seroprotection rates are only 25% as robust for H1 and B antigens and 50% as robust for H3 antigens in the elderly, compared with younger subjects. This review selected papers reporting data on subjects with a mean age of 65 years or greater. Of the 4492 elderly vaccinated subjects, 42, 51 and 35% of subjects seroconverted to H1N1, H3N2 and influenza B, respectively, compared with 60, 62 and 58%, respectively, for younger subjects. Antibody responses among the very elderly (≥75 years of age) were especially impaired with seroconversion levels at 32, 46 and 29%, respectively.
Although not routinely measured, cell-mediated immunologic responses to influenza vaccines may also significantly impact protection against influenza disease. Likewise, an impaired cell-mediated response to vaccination has been correlated with the risk of developing influenza; however, the risk of developing influenza disease is highest among the elderly, who demonstrate neither an antibody nor cell-mediated response to vaccination. Even though waning immunity during the typical 4-month influenza season has been of historic concern, it appears that the main reason for inadequate protection 4 months after vaccination is failure to respond at 1 month, suggesting that the primary response is the most important immunologic consideration.
The impaired ability of the elderly to mount an adequate immunologic response to influenza vaccine has been attributed to immunosenescence, defined as a decline in the body's ability to fight infection, mount novel immune responses and recall immune responses. Both innate and adaptive immunity are implicated. Dysregulation of innate immunity occurs through impaired function of costimulatory molecules, altered secretion of inflammatory cytokines, and diminished function of natural killer cells, macrophages and neutrophils. This occurs in combination with a decreased proliferative capacity of the B cells, diminished antibody potency and impaired T-cell memory recall.
Vaccine efficacy is demonstrated by protection against laboratory or culture-confirmed influenza, whereas vaccine effectiveness is demonstrated by prevention of clinical illness. Studies to evaluate the efficacy/effectiveness of influenza vaccines in older adults have evaluated a variety of outcomes, including infection rates, illness rates confirmed either clinically or by laboratory testing, and complication rates. Up until now, most efficacy data concern the only previously available influenza vaccination for this vulnerable age group: the trivalent, inactivated influenza vaccine (TIV). The sole prospective, randomized, double-blind, placebo-controlled trial of TIV in individuals aged over 60 years demonstrated an efficacy of 58% (95% CI: 26–77%) against serologically confirmed clinical influenza and 47% (95% CI: 27–61%) against clinical influenza. It was less effective in those older than 70 years of age who had a relative risk of serologically confirmed influenza of 0.77 (95% CI: 0.39–1.51) compared with those vaccinated with placebo. Meta-analyses of the remaining, mostly observational studies, have concluded that influenza vaccination is associated with significant reductions in hospitalizations and deaths. However, some concerns have been raised regarding the quality of evidence available relative to the efficacy and effectiveness of currently available influenza vaccines for people aged 65 years or older. The Cochrane Collaboration systemic review concluded that "the available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered, publicly funded, randomized, placebo-controlled trial run over several seasons should be undertaken". Many, if not most, experts in the field would consider such a study unethical.
Furthermore, although chemoprophylaxis and treatment options with antiviral agents are available, viral resistance to these agents is a considerable issue and has increasingly limited their usefulness. For example, seasonal influenza A/H1N1 isolates have exhibited high-level resistance to oseltamivir, and the M2 ion channel inhibitors (amantadine and rimantadine) are ineffective against B strains and have shown limited effectiveness against many influenza A strains. This worrisome trend supports recently adopted recommendations by the Advisory Committee on Immunization Practices (ACIP) to broaden the application of our best available option in the prevention of influenza illness by vaccination. This resulted in the recent recommendation for vaccinating all individuals over 6 months of age against influenza.
For the elderly, however, it remains particularly imperative that more effective vaccines be developed. To this end, several strategies have been proposed and tested, including high-dose TIV (HD-TIV), adjuvanted TIV, intradermal delivery of TIV, priming recipients with live-attenuated influenza virus vaccine (LAIV) prior to TIV administration, and other emerging vaccine technologies such as virosomal subunit vaccines and others. Other data support the idea that strategies to increase influenza vaccine uptake in children and adolescents can protect the elderly through herd immunity.
However, this article will focus on HD-TIV, as recently a Phase III trial that compared HD-TIV (Fluzone® High Dose, Sanofi Pasteur Inc., Swiftwater, PA, USA) to standard-dose TIV (Fluzone) demonstrated superior HI geometric mean titers and seroconversion rates against H1N1 and H3N2 influenza A antigens, and noninferior serocoversion rates against influenza B antigens in the elderly. Given favorable safety and efficacy data, the US FDA approved Fluzone High Dose via an accelerated process for this high-dose seasonal influenza vaccine specifically intended for people aged 65 years and older.
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