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APPENDIX 12
Influenza A and B

The variability of the influenza virus can explain why reinfection is so common. The two major structural proteins, nucleoprotein (NP) and matrix protein (M), produce antigenic differences which classify the influenza virus as type A, B, or C. Influenza A and B are pleomorphic-enveloped viruses with a genome of 8 different (-)RNA nucleocapsid segments. The reassortment of these segments along with mutations enhance genetic diversity upon infection with two different strains (Murray, Kibosh, et. al., 620). Both types are covered with the glycoprotein spikes, hemagglutinin (HA) and neuraminidase (NA). Influenza A is further subtyped into groups based on the characteristics of the NA and HA (Murray et. al., 918).

The HA is responsible for viral attachment to sialic acid on epithelial cell surfaces, fusion of the envelope to the cell membrane, and agglutination of erythrocytes. Mutagenic changes in HA can induce an antigenic shift which is seen only with influenza A (Murray, Kibosh et. al., 620). This antigenic shift is a result of genome reassortment between different virus strains, including animal strains. The NA cleaves the sialic acid, removing it from the virus and infected cells to prevent clumping and to allow the release of the virus from infected cells (Murray, 919). Minor mutagenic alterations (usually brought about by accumulated point mutations) in HA and/or NA prompts an antigenic drift of both influenza A and B. These two types of antigenic variations (antigenic shift and drift) allow the influenza virus to evade preexisting immunity and evolve into pandemics and epidemics.

The highly contagious influenza virus accounts for many epidemics and pandemics of respiratory illnesses. Some of the milder symptoms of this illness include fever, pharyngitis, rhinitis, cough, myalgia, and malaise. In children, otitis media may develop with influenza. Influenza A has been associated prima-



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Vaccines for the 21st Century: A Tool for Decisionmaking APPENDIX 12 Influenza A and B The variability of the influenza virus can explain why reinfection is so common. The two major structural proteins, nucleoprotein (NP) and matrix protein (M), produce antigenic differences which classify the influenza virus as type A, B, or C. Influenza A and B are pleomorphic-enveloped viruses with a genome of 8 different (-)RNA nucleocapsid segments. The reassortment of these segments along with mutations enhance genetic diversity upon infection with two different strains (Murray, Kibosh, et. al., 620). Both types are covered with the glycoprotein spikes, hemagglutinin (HA) and neuraminidase (NA). Influenza A is further subtyped into groups based on the characteristics of the NA and HA (Murray et. al., 918). The HA is responsible for viral attachment to sialic acid on epithelial cell surfaces, fusion of the envelope to the cell membrane, and agglutination of erythrocytes. Mutagenic changes in HA can induce an antigenic shift which is seen only with influenza A (Murray, Kibosh et. al., 620). This antigenic shift is a result of genome reassortment between different virus strains, including animal strains. The NA cleaves the sialic acid, removing it from the virus and infected cells to prevent clumping and to allow the release of the virus from infected cells (Murray, 919). Minor mutagenic alterations (usually brought about by accumulated point mutations) in HA and/or NA prompts an antigenic drift of both influenza A and B. These two types of antigenic variations (antigenic shift and drift) allow the influenza virus to evade preexisting immunity and evolve into pandemics and epidemics. The highly contagious influenza virus accounts for many epidemics and pandemics of respiratory illnesses. Some of the milder symptoms of this illness include fever, pharyngitis, rhinitis, cough, myalgia, and malaise. In children, otitis media may develop with influenza. Influenza A has been associated prima-

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Vaccines for the 21st Century: A Tool for Decisionmaking rily with increased mortality in the elderly population. Therefore, influenza encompasses a variety of clinical responses ranging from asymptomatic or mild respiratory infection to primary viral pneumonia or secondary bacterial pneumonia with fatal outcome. Recently, epidemics have alternated between those caused primarily by type A and those caused by type B. Both are transmitted by sneezing, coughing, speaking, and also by direct contact through small-particle aerosols. Transmission usually occurs during the initial stages when infected individuals shed substantial amounts of the virus through respiratory secretions. The episodes of winter influenza are partly explained by the ability of small droplets to remain infectious in the cold and in low humidity. DISEASE BURDEN Epidemiology For the purposes of the calculations in this report, the committee estimated that there are approximately 54,000,000 cases of influenza A and B each year in the United States. Incidence rates in children under 14 years of age are over twice that in adults 35 years of age and older. There were approximately 42,250 deaths each year due to influenza, with very high mortality in people 65 years of age and older. See Table A12–1. Disease Scenarios For the purposes of the calculation in this report, the committee assumed that 98% of influenza infections are associated with a moderate to severe respiratory illness not requiring hospitalization. It was assumed that most of these infections require only 3 days of bed rest and 2 weeks of mild recovery. Approximately 10% of infections are associated with a more serious sinusitis in conjunction with the 2-week recovery. It was assumed that approximately 5% of influenza infections are associated with a 3-month period of fatigue in addition to the scenario described above. It was assumed that 2% of influenza infections result in hospitalization for pneumonia. It was further assumed that a small number (.1%) of influenza infections exacerbate underlying cardiac or pulmonary conditions. This exacerbation of chronic disease was assumed to be associated with an extra disease burden of 8.5 days of an HUI of .53. See Table A12–2. COST INCURRED BY DISEASE Table A12–3 summarizes the health care costs incurred by influenza A and B infections. For the purposes of the calculations in this report, it was assumed

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A12–1 Incidence and Mortality of Influenza A and B Disease INCIDENCE RATES 5-Year Age Groups Total Population Incidence Rates (per 100,000) (5-yr age groups) Cases Age Groups Population Incidence Rates (per 100,000) % Distribution of Cases 0–4 20,182,000 33,700 6,801,334 <1 3,963,000 33,700 0.0246 5–9 19,117,000 39,300 7,512,981 1–4 16,219,000 33,700 0.1006 10–14 18,939,000 30,200 5,719,578 5–14 38,056,000 34,771 0.2435 15–19 17,790,000 30,200 5,372,580 15–24 36,263,000 24,851 0.1658 20–24 18,473,000 19,700 3,639,181 25–34 41,670,000 15,500 0.1189 25–29 19,294,000 15,500 2,990,570 35–44 42,149,000 14,800 0.1148 30–34 22,376,000 15,500 3,468,280 45–54 30,224,000 14,800 0.0823 35–39 22,215,000 14,800 3,287,820 55–64 21,241,000 14,800 0.0579 40–44 19,934,000 14,800 2,950,232 65–74 18,964,000 14,800 0.0517 45–49 16,873,000 14,800 2,497,204 75–84 11,088,000 14,800 0.0302 50–54 13,351,000 14,800 1,975,948 • 85 3,598,000 14,800 0.0098 55–59 11,050,000 14,800 1,635,400 Total 263,435,000 20,627 1.0000 60–64 10,191,000 14,800 1,508,268   65–69 10,099,000 14,800 1,494,652 70–74 8,865,000 14,800 1,312,020 75–79 6,669,000 14,800 987,012 80–84 4,419,000 14,800 654,012 • 85 3,598,000 14,800 532,504 Total 263,435,000   54,339,576

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Vaccines for the 21st Century: A Tool for Decisionmaking MORTALITY RATES 5-Year Age Groups Total Population Incidence Rates (per 100,000) (5-yr age groups) Cases Age Groups Population Incidence Rates (per 100,000) % Distribution of Cases 0–4 20,182,000 2.7 545 <1 3,963,000 2.7 0.0025 5–9 19,117,000 0.9 172 1–4 16,219,000 2.7 0.0104 10–14 18,939,000 0.9 170 5–14 38,056,000 0.9 0.0081 15–19 17,790,000 0.9 160 15–24 36,263,000 1.0 0.0086 20–24 18,473,000 1.1 203 25–34 41,670,000 1.1 0.0108 25–29 19,294,000 1.1 212 35–44 42,149,000 1.1 0.0110 30–34 22,376,000 1.1 246 45–54 30,224,000 10.2 0.0730 35–39 22,215,000 1.1 244 55–64 21,241,000 10.2 0.0513 40–44 19,934,000 1.1 219 65–74 18,964,000 103.5 0.4646 45–49 16,873,000 10.2 1,721 75–84 11,088,000 103.5 0.2716 50–54 13,351,000 10.2 1,362 • 85 3,598,000 103.5 0.0881 55–59 11,050,000 10.2 1,127 Total 263,435,000 16.0 1.0000 60–64 10,191,000 10.2 1,039   65–69 10,099,000 103.5 10,452 70–74 8,865,000 103.5 9,175 75–79 6,669,000 103.5 6,902 80–84 4,419,000 103.5 4,574 • 85 3,598,000 103.5 3,724 Total 263,435,000   42,250

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A12–2 Disease Scenarios for Influenza A and B Infection   No. of Cases % of Cases Committee HUI Values Duration (years) Moderate to severe respiratory illness 45,264,867 83.30%   bed rest   0.75 0.0082 (3 days) discomfort following bed rest   0.90 0.0384 (14 days) Respiratory illness with sinusitis 5,325,278 9.80%   bed rest   0.75 0.0082 (3 days) sinusitis   0.75 0.0192 (7 days) discomfort following bed rest   0.90 0.0192 (7 days) Respiratory illness w/post-influenza fatigue 2,662,639 4.90%   bed rest   0.75 0.0082 (3 days) discomfort following bed rest   0.90 0.0384 (14 days) post-influenza fatigue   0.87 0.2466 (90 days) Pneumonia 978,112 1.80%   acute care hospitalization   0.65 0.0274 (10 days) recuperation   0.90 0.0384 (14 days) Pneumonia—ICU 108,679 0.20%   ICU hospitalization   0.52 0.0274 (10 days) recuperation   0.90 0.0384 (14 days) Exacerbation of underlying asthma/heart disease 54,340 0.10% 0.53 0.0233 (8.5 days) that everyone requiring bed rest for acute influenza infection incurs costs for an over-the-counter symptomatic treatment. The cost calculations include one visit to a physician and a prescription medication for 20% of the patients during the acute phase. Recovery phases were assumed to include costs for over-the-counter medications and physician visits for some of the patients with sinusitis and post-influenza fatigue. Hospitalization costs, diagnostics, inpatient and with outpatient physician visits, and medications were included costs for patients with pneumonia. There were no costs calculated for the exacerbation of underlying chronic disease states by influenza infection with pneumonia.

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A12–3 Health Care Costs Associated with Influenza A and B Disease   % with Care Cost per Unit Units per Case Form of Treatment Moderate to severe respiratory illness   bed rest 50% $50 1.0 physician a   20% $50 1.0 medication b 100% $10 1.0 medication a discomfort following bed rest 50% $10 1.0 medication a Respiratory illness with sinusitis   bed rest 50% $50 1.0 physician a   20% $50 1.0 medication b 100% $10 1.0 medication a sinusitis 50% $50 1.0 medication b   100% $10 1.0 medication a discomfort following bed rest 50% $50 1.0 physician a Respiratory illness with post-influenza fatigue   bed rest 50% $50 1.0 physician a   50% $50 1.0 medication b 100% $10 1.0 medication a discomfort following bed rest 50% $10 1.0 medication a post-influenza fatigue 50% $50 1.0 physician a Pneumonia   acute care and ICU together 100% $50 1.0 physician a percentage of cases adjusted 100% $4,000 1.0 hospitalization   100% $100 1.0 physician b 100% $100 1.0 diagnostic b recuperation 100% $50 1.0 physician a   100% $50 1.0 medication b 100% $10 1.0 medication a VACCINE DEVELOPMENT The committee assumed that it will take 7 years until licensure of a influenza vaccine and that $360 million needs to be invested. The committee assumed that the licensed vaccine would most likely be a DNA vaccine requiring immunization every 5 years. Table 4–1 summarizes vaccine development assumptions for all vaccines considered in this report.

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Vaccines for the 21st Century: A Tool for Decisionmaking VACCINE PROGRAM CONSIDERATIONS Target Population For the purposes of the calculations in this report, it is assumed that the target population for this vaccine is one-fifth of the entire population every year. It was assumed that 30% of the target population would utilize the vaccine. Vaccine Schedule, Efficacy, and Costs For the purposes of the calculations in this report, it was estimated that this vaccine would cost $50 per dose and that administration costs would be $10 per dose. It was assumed that 1 dose would be required every 5 years. It is assumed that the current influenza immunization program would no longer be needed. Default assumption of 75% effectiveness were accepted. Table 4–1 summarizes vaccine program assumptions for all vaccines considered in this report. RESULTS If a vaccine program for influenza were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the QALYs gained would be 800,000. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the QALYs gained would be 125,000. If a vaccine program for influenza were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the health care costs saved would be $6.4 billion. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the health care costs saved would be $1 billion. If a vaccine program for influenza were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the program cost would be $3.2 billion. Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the program cost would be $430 million. Using committee assumptions of time and costs until licensure, the fixed cost of vaccine development has been amortized and is $10.8 million for an influenza vaccine.

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Vaccines for the 21st Century: A Tool for Decisionmaking If a vaccine program were implemented today and the vaccine were 100% efficacious and utilized by 100% of the target population, the annualized present value of the cost per QALY gained is -$4,000. A negative value represents a saving in costs in addition to a saving in QALYs. Using committee assumptions of less-than-ideal utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the cost per QALY gained is -$4,500. See Chapters 4 and 5 for details on the methods and assumptions used by the committee for the results reported. READING LIST Barker WH. Excess Pneumonia and Influenza Associated Hospitalization during Influenza Epidemics in the United States, 1970–78. American Journal of Public Health 1986; 76:761–765. Betts RF. Influenza Virus. In: Principles and Practice of Infectious Diseases. GL Mandell, JE Bennett, Dolin R eds. New York, NY: Churchill Livingstone, 1995, pp. 1546–1567. CDC. Influenza Surveillance—United States, 1992–3 and 1993–4. Morbidity and Mortality Weekly Report 1997; 46:1–12. CDC. Prevention and Control of Influenza. Morbidity and Mortality Weekly Report 1996; 45:9–24. CDC. Prevention and Control of Influenza. Morbidity and Mortality Weekly Report 1997; 46:1–25. Glezen WP. Influenza in an urban area. Canadian Journal of Infectious Diseases 1993; 4:272–4. Glezen WP, Cherry JD. Influenza Viruses. In: Textbook of Pediatric Infectious Diseases. RD Feigin and JD Cherry eds. Philadelphia, PA: WB Saunder Company, 1992, pp. 1688–1704. Glezen WP, Couch RB. Influenza Viruses. In: Virus Infections of Humans. Evans AS, ed. 3rd ed. New York, NY: Plenum Medical Book Company, 1989. Gruber WC, Belshe RB, King JC. Evaluation of Live Attenuated Influenza Vaccines in Children 6–18 Months of Age: Safety, Immunogenicity, and Efficacy. The Journal of Infectious Diseases 1996; 173:1313–1319. Marwick C. Facing Inevitable Future Flu Seasons, Experts Set 1996 Vaccine and Plan for Unpredictable Pandemic. JAMA 1995; 273:1079–1080. McBean AM, Babish JD, Warren JL. The Impact and Cost of Influenza in the Elderly. Archives of Internal Medicine 1993; 153:2105–2111. Mullooly JP, Bennett MD, Hornbrook MC, et al. Influenza Vaccination Programs for Elderly Persons: Cost-effectiveness in a Health Maintenance Organization. Annals of Internal Medicine 1994; 121:947–952. Nichol KL, Lind A, Margolis KL, et al. The Effectiveness of Vaccination Against Influenza in Healthy, Working Adults. The New England Journal of Medicine 1995; 333:889–893.

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Vaccines for the 21st Century: A Tool for Decisionmaking Nichol KL, Margolis KL, Wuorenma J, et al. The Efficacy and Cost Effectiveness of Vaccination Against Influenza Among Elderly Persons Living in the Community. The New England Journal of Medicine 1994; 331:778–784. Patriarca PA, Strikas RA. Influenza Vaccine for Healthy Adults? The New England Journal of Medicine 1995; 333:933–934. Sullivan KM, Monto AS, Longini IM. Estimates of the U.S. Health Impact of Influenza. American Journal of Public Health 1993; 83:1712–1716.

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