Expanded Options for Influenza Protection by Haymarket Media

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Expanded Options for Influenza Protection A Vaccine Designed for Older Adults © Tetra Images/Getty Images

Dear Colleague: People 65 years of age and older experience flu-related morbidity and mortality in far greater numbers than do other age groups. That fact is of particular concern given that the first Baby Boomers turned 65 years of age in 2011. Traditional influenza vaccines help protect seniors against the disease and its complications, but not nearly as well as we’d like; many older adults simply don’t have as robust an immunologic response to vaccines as younger people do. In 2005, the Centers for Disease Control and Prevention and the National Institutes of Health called for better methods to protect the older population from influenza. In the 2010-2011 flu season, an influenza vaccine intended specifically for older adults became available for the first time. That vaccine—the focus of this newsletter—gives us an important new tool in the medical armamentarium aimed at influenza, and reflects the evolution in influenza vaccines away from “one size fits all” toward a more patient-specific approach. As clinicians, it’s imperative that we take seriously the very real risk that influenza poses to our patients, young and old, and make full use of the panoply of available tools to help minimize that risk. Flu will continue to exact an unacceptably high price unless we do.

Sincerely,

William Schaffner, MD FACULTY REVIEWER William Schaffner, MD Professor and Chair Department of Preventive Medicine, Vanderbilt University School of Medicine Nashville, Tennessee

ach year, an estimated 15 to 60 million people in the United States—some 5% to 20% of the population—become ill with influenza.1 In any given influenza season, 55,000 to 431,000 people are hospitalized as a result of the infection, and up to 49,000 people die from its complications.1-3 The burden of disease falls disproportionately on older adults: Adults ≥65 years of age represent approximately 15% of the US population but account for more than 60% of influenza-related hospitalizations and 90% of influenza-related deaths.2,3 Influenza and pneumonia, taken together, are the seventh leading cause of death in the US among older adults.4 The clinical consequences of influenza come with a high economic price. Across all ages, direct medical costs of an outbreak of seasonal influenza in the US can amount to more than $10 billion.5 Adults ≥65 years of age account for nearly two thirds of the total annual economic burden—direct and indirect costs combined—of seasonal influenza.5 Influenza vaccination rates for older adults have hovered in the 65%-70% range in recent years.2,6 Although well below the 90% Healthy People 2010 and 2020 goals for adults 65 years of age and older, those rates are nonetheless much higher than for younger age groups. Yet the majority of influenza hospitalizations and deaths still occur in the 65-plus population. Moreover, while older adults are at increased risk for influenza infection and its potentially severe complications, they exhibit a decreased immune response to traditional influenza vaccines, part of an age-related phenomenon known as immunosenescence. All of these facts and figures are of par-

ticular concern given the population surge among seniors. Between 2000 and 2030, the number of adults 65 years of age and older is expected to double, so that by 2030 approximately 1 in 5 people in the US will be in that age group.7 The growing risk when growing old

Influenza-related mortality rates increase with advancing age (Figure 1). The mortality rate for people 65-69 years of age, for example, is approximately 3 times higher than it is for adults 50-64 years of age and 60 times higher than it is for people 5-49 years of age.8 The increase in mortality rates accelerates to the end of life. The presence of a chronic medical condition significantly increases the risk of influenzarelated death in older patients. In a study conducted within a health maintenance organization during two influenza epidemics, the mortality rate from influenza and pneumonia among persons ≥65 years of age without any comorbid high-risk condition was 9 per 100,000.9 That rate was approximately 20-fold higher in patients with one high-risk condition and 90-fold higher in those with two or more such conditions. More than 90% of patients who died in this study had at least one chronic underlying condition.9 Nationwide, more than 80% of adults 65 years of age and older have at least one chronic condition, and more than 60% have two or more chronic conditions.10 The reported efficacy of traditional influenza vaccines in preventing laboratoryconfirmed influenza infection in older adults is lower than it is in younger persons.2,11 Age-related differences in the effectiveness of influenza vaccine at preventing influenza-like

1195

1200

Influenza-related mortality

Influenza-related hospitalizations

Per 100,000 population

1000

800

Figure 1. Rates of influenzarelated death (shown for the years 1976-2000) and hospitalization (1979-2001) accelerate with age.

686

600 431

400

190

200

129

358

321

0.3 21

5-49

50-64

65-69

70-74

75-79

80-84

≥85

Age group (yrs) Source: Thompson WW, et al.8

illness (ILI) have also been observed. In one study, researchers analyzed data collected through a surveillance network in France in which practitioners reported ILI cases and vaccine status.12 In the seven influenza seasons spanning 1998-2005, vaccine effectiveness against ILI in persons ≥65 years of age was estimated to range from 26%-52%, compared with 62%-76% in persons 15-64 years of age (Figure 2).12,13 ANTIBODIES and immunity

What might account for the lower vaccine effectiveness observed in older adults? More

than one factor is probably responsible, but decreased antibody response to a traditional influenza vaccine appears to be a key determinant. Studies have found that antibody response to influenza vaccine in the elderly is considerably lower than it is in younger adults. Influenza immunization stimulates B cells to produce antibodies against antigens contained in the vaccine, antibodies that then bind to the surface glycoproteins of the virus. Antibody to hemagglutinin (HA), the dominant surface glycoprotein, is an established correlate of immunity to influ-

Figure 2. With the exception of the 2003-2004 season, influenza vaccines were significantly less effective at preventing ILI in persons ≥65 years of age than in younger persons for the seven seasons shown here.

≥65 years of age

15-64 years of age

Vaccine effectiveness (%)

100 80 60 40 20 0

19981999

19992000

20002001

20012002

20022003

Influenza season

Expanded Options for Influenza Protection

20032004

20042005

Sources: Legrand J, et al,12 Monto AS, et al.13 Adapted from Monto AS, et al.13

enza infection, and it can be measured in the serum by hemagglutination inhibition (HAI) testing. Elevated levels of immunoglobulin G (IgG) antibody to HA generally equate with a lower risk of infection among persons exposed to the virus, whereas lower levels are associated with a higher risk of illness.14-16 In a review of 31 studies conducted in the US and abroad and published from 1986-2002,17 researchers analyzed HAI IgG antibody responses in older and younger adults following influenza vaccination, including the percentage of subjects with post-vaccination titers greater than 1:40 (a level that has been associated with protection in up to half of individuals14). For all three vaccine antigens—A(H1), B, and A(H3)—antibody levels among adults ≥65 years of age were approximately 2- to 4-fold lower than among younger adults. Such findings, the investigators note, highlight the need for more immunogenic vaccine formulations for the elderly.17 AGING AND A WEAKENED DEFENSE SYSTEM

Older adults’ increased susceptibility to influenza illness and reduced response to influenza vaccine have been attributed to immunosenescence, the gradual decline in immune function that accompanies aging. A host of age-related changes occur in the innate and adaptive immune systems that make the body less able to defend against new infections or to recall past immune responses.18,19 Aging impairs both the B-cell and T-cell responses that are triggered by most vaccines.19-22 For example, aging alters the number and composition of T- and B-cell populations, decreases the capacity of T cells to replicate and respond to novel antigens, and hinders T-cell memory recall.18,19 Changes in cell subsets and cytokine production profiles affect the magnitude, quality, and persistence of antibody responses to vaccination.20,21 One change associated with immunosenescence—a decrease in T cells expressing the surface marker CD28, a molecule required for T-cell activation—has been directly linked to reduced response to influenza vaccine.23 In a Mayo Clinic study involving 153 community-dwelling adults ≥65 years of age, a 10% increase in the proportion of cytotoxic T cells that lacked CD28 was associated with a 24% decrease in antibody response to influenza vaccine.23

Increasing the vaccine’s antigen content is one way to address the decreased antibody response to immunization seen in older adults. In general, higher antigen doses, up to a certain level, increase the availability of antigen for B- and T-cell binding and activation and produce higher antibody responses.21

Fluzone High-Dose Vaccine

Fluzone Vaccine

Superiority of immune responses achieved for A(H1N1) and A(H3N2); noninferiority for Ba

140

700

120

filling an unmet medical need: A HIGH-DOSE VACCINE

500

GMT

609

600

116

100 69

400 333

300

200

100

A(H1N1)

A(H3N2) Source: Falsey AR, et al.24

Data demonstrating a decrease in influenza disease after vaccination with Fluzone High-Dose vaccine relative to Fluzone vaccine are not available.

influenza virus, inducing GMTs that were 70% higher for the A(H1N1) strain, 80% higher for the A(H3N2) strain, and 30% higher for the B strain (Figure 3).24 The higher dose vaccine met the end point for superiority for GMT—at least a 50% increase in antibody titers compared to the lower dose vaccine—for both A strains, and it met the noninferiority criterion for the B strain. Seroconversion rates were also higher in the high-dose vaccine group for all three strains. Both A strains met the superiority criterion for seroconversion, achieving rates at least 10% higher than

Fluzone High-Dose Vaccine

Figure 4. Solicited injectionsite and systemic reactions within seven days postvaccination were reported more frequently in recipients of the high-dose vaccine than in recipients of the lower dose vaccine.

Systemic reactions 40

% of subjects

30 24

20 15 11

those obtained with the lower dose vaccine. Seroconversion rates for the B strain did not meet the superiority criterion but did meet the noninferiority criterion. In addition, the improved immunogenicity seen with the high-dose vaccine compared to the lower dose formulation was maintained in both older (≥75 years of age) and younger (≥65-74 years of age) subjects, in persons with or without a history of cardiopulmonary disease, and in both males and females.24 No data are currently available that demonstrate whether the superior immune

Fluzone Vaccine

Injection-site reactions

% of subjects

In December 2009, the US Food and Drug Administration (FDA) licensed for use in adults ≥65 years of age an influenza vaccine that contains 4 times as much antigen as the typical adult vaccine for each of the three recommended strains: 60mcg per antigen (180mcg per dose) versus 15mcg per antigen (45mcg per dose). Fluzone® High-Dose, Influenza Virus Vaccine (Sanofi Pasteur, Swiftwater, PA) was designed specifically to strengthen the immune response in people ≥65 years of age and was licensed through the FDA’s accelerated approval process, which brings drugs that fill an unmet medical need to the public expeditiously. Like Fluzone vaccine, the high-dose formulation is a trivalent, inactivated, splitvirus vaccine. In the primary Phase III trial upon which licensure was based, Falsey and colleagues compared the high-dose vaccine with the lower dose formulation in medically stable, community-dwelling adults ≥65 years of age.24 A large number of subjects had one or more chronic conditions, such as cardiovascular or respiratory disease, typifying many elderly patients who are seen in office settings. The immunogenicity analysis for this randomized, double-blind, controlled trial included 2576 Fluzone High-Dose vaccine recipients and 1275 Fluzone vaccine recipients. Blood samples were drawn before and then 28 days after vaccination, and antibody to each of the three vaccine strains was measured by HAI testing. Immunogenicity was assessed by geometric mean titers (GMTs)—the average antibody levels in the two study groups—and by seroconversion rates. Seroconversion was defined as a rise in HAI titers from <1:10 prior to vaccination to ≥1:40 post-vaccination, or at least a 4-fold rise in antibody levels after vaccination from a pre-vaccination titer of ≥1:10. The high-dose vaccine produced significantly higher antibodies than the lower dose vaccine against all three strains of the

Figure 3. Post-vaccination HAI GMT values for the high-dose vaccine recipients were higher than those of the lower dose vaccine recipients for all three antigens.

9 6

Pain

Erythema Swelling

30 21

17 14

10 4

Myalgia

Malaise Headache Fever Source: Falsey AR, et al.24

Expanded Options for Influenza Protection

responses seen following immunization with Fluzone High-Dose vaccine will decrease influenza disease in vaccine recipients. A large (26,000 subjects ≥65 years of age) multicenter trial comparing the efficacy of Fluzone High-Dose vaccine and Fluzone vaccine against laboratory-confirmed influenza is under way, with results expected in 2014-2015. Subjects are randomized to receive Fluzone High-Dose vaccine or Fluzone vaccine in a 1:1 ratio. Vaccine safety and adverse events

In the Phase III trial, participants were instructed to record the presence or absence of local and systemic symptoms daily for one week following vaccination. Solicited injection-site reactions (pain, erythema, and swelling) were reported more frequently in recipients of Fluzone High-Dose vaccine than in recipients of Fluzone vaccine (Figure 4), as would be expected given the increased amount of antigen in the vaccine.24 The reactions in both groups were generally mild to moderate and resolved within three days.25 Pain was the most commonly reported reaction for both groups, occurring in 36% of the high-dose vaccine recipients and 24% of the lower dose vaccine recipients. Most of the subjects who experienced pain reported it as mild. Solicited systemic complaints (myalgia, malaise, headache, and fever) occurred more frequently in recipients of Fluzone HighDose vaccine (34%) than in recipients of Fluzone vaccine (29%).24 The reactions were generally mild to moderate and resolved within 72 hours. Significantly more highdose vaccine recipients (29 of 2569, or 1.1%) reported moderate or severe fever compared with the lower dose recipients (4 of 1258, or 0.3%). Most fevers were mild,25 with only one report of severe fever in each group. Rates of serious adverse events (SAEs) occurring up to six months after vaccination were comparable in the two study groups: 6% for Fluzone High-Dose vaccine and 7% for Fluzone vaccine.24 Two SAEs were reported by investigators as vaccine-related: an exacerbation of Crohn’s disease two days

after vaccination with Fluzone High-Dose vaccine, and a new diagnosis of myasthenia gravis approximately one month after vaccination with Fluzone vaccine. acip Recommendations

In 2010, the Advisory Committee on Immunization Practices (ACIP) expanded its recommendation for annual influenza vaccination to include all people ≥6 months of age. The ACIP included Fluzone High-Dose vaccine as one of the options available for adults ≥65 years of age during the 2010-2011 influenza season,2,26 and has done so again in its influenza prevention recommendations for the current influenza season.27 As with other inactivated influenza vaccines, Fluzone High-Dose vaccine should not be administered to anyone who has had a severe allergic reaction to influenza vaccine. The vaccine is covered under Medicare Part B and has its own CPT ® a code, 90662. In summary, the high-dose vaccine has been shown to elicit substantially improved antibody responses compared with the typical dose vaccine in older adults. The large post-licensure trial will provide data demonstrating whether that improved response translates into better protection against influenza disease. In the meantime, the highdose vaccine is an available option to address a well-documented public health concern: the high disease burden of influenza among the elderly and the diminished antibody response in this age group to traditional influenza vaccines. a CPT = Current Procedural Terminology is a registered trademark of the American Medical Association.

REFERENCES 1. Centers for Disease Control and Prevention (CDC). Questions & answers: seasonal influenza. http://www.cdc.gov/ flu/about/qa/disease.htm. Accessed August 23, 2011. 2. CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR. 2010;59(RR-8):1-62. 3. Thompson WW, Shay DK, Weintraub E, et al. Influenzaassociated hospitalizations in the United States. JAMA. 2004;292(11):1333-1340. 4. Minino AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. Natl Vital Stat Rep. 2010;59(2):1-52. 5. 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(27):5086-5096.

6. CDC. Final estimates for 2009-10 seasonal influenza and influenza A (H1N1) 2009 monovalent vaccination coverage—United States, August 2009 through May 2010. http://www.cdc.gov/flu/professionals/vaccination/ coverage_0910estimates.htm. Accessed August 23, 2011. 7. US Census Bureau. Projected population of the United States, by age and sex: 2000 to 2050. http://www.census. gov/population/www/projections/usinterimproj/ natprojtab02a.pdf. Accessed August 29, 2011. 8. 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. 9. Barker WH, Mullooly JP. Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med. 1982;142(1):85-89, Correction: 1982;142(6):1194. 10. Wolff JL, Starfield B, Anderson G. Prevalence, expenditures, and complications of multiple chronic conditions in the elderly. Arch Intern Med. 2002;162(20):2269-2276. 11. Govaert TM, Thijs CT, Masurel N, et al. The efficacy of influenza vaccination in elderly individuals. JAMA. 1994;272(21):1661-1665. 12. Legrand J, Vergu E, Flahault A. Real-time monitoring of the influenza vaccine field effectiveness. Vaccine. 2006;24(4446):6605-6611. 13. Monto AS, Ansaldi F, Aspinall R, et al. Influenza control in the 21st century: optimizing protection of older adults. Vaccine. 2009;27(37):5043-5053. 14. Bridges CB, Katz JM, Levandowski RA, Cox NJ. Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th edition. Philadelphia, PA: Saunders Elsevier, 2008:259-290. 15. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res. 2004; 103(1-2):133-138. 16. Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond). 1972;70(4):767-777. 17. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24(8):1159-1169. 18. Sullivan SJ, Jacobson R, Poland GA. Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine. Expert Rev Vaccines. 2010;9(10):1127-1133. 19. Grubeck-Loebenstein B, Della Bella S, Iorio AM, et al. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res. 2009;21(3):201-209. 20. Doria G, Biozzi G, Mouton D, Covelli V. Genetic control of immune responsiveness, aging and tumor incidence. Mech Ageing Dev. 1997;96(1-3):1-13. 21. Siegrist CA. Vaccine immunology. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th edition. Philadelphia, PA: Saunders Elsevier, 2008:17-36. 22. Zheng B, Zhang Y, He H, et al. Rectification of age-associated deficiency in cytotoxic T cell response to influenza A virus by immunization with immune complexes. J Immunol. 2007;179(9):6153-6159. 23. Targonski PV, Jacobson RM, Poland GA. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine. 2007;25(16):3066-3069. 24. 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(2):172-180. 25. Fluzone vaccine [Prescribing Information]. Swiftwater, PA: Sanofi Pasteur Inc.; 2011. 26. CDC. Licensure of a high-dose inactivated influenza vaccine for persons aged ≥65 years (Fluzone High-Dose) and guidance for use — United States, 2010. MMWR. 2010;59(16):485-486. 27. CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR. 2011;60(33):1128-1132.

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