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Challenges of Influenza Control

Challenges of Influenza Control. W. Paul Glezen, M.D. Baylor College of Medicine Houston. Newly Recognized Respiratory Agents. SARS coronavirus – SARS - CoV Human metapneumonvirus - hmpv Avain influenzaviruses a) A (H5N1) b) A (H7N7) 4. Hendra – Nipah viruses.

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Challenges of Influenza Control

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  1. Challenges of Influenza Control W. Paul Glezen, M.D. Baylor College of Medicine Houston

  2. Newly Recognized Respiratory Agents • SARS coronavirus – SARS - CoV • Human metapneumonvirus - hmpv • Avain influenzaviruses a) A (H5N1) b) A (H7N7) 4. Hendra – Nipah viruses

  3. Hemagglutinin Subtypes of Influenza A Virus Adapted with permission from Levine AJ. Viruses. 1992;165.

  4. Influenza Virus Nomenclature Neuraminidase Type of Nucleoprotein Hemagglutinin A/USSR/90/77 (H1N1) VirusType GeographicOrigin StrainNumber Year ofIsolation VirusSubtype

  5. Antigenic Variants of Influenza A (H3N2) and Changing Hemagglutinin Amino Acid Positions YearVariant 1968-72 A/Hong Kong/68 1972-73A/England/72 1974-75 A/Port Chalmers/73 1975-76 A/Victoria/75 1977-78 A/Texas/77 1980-83 A/Bangkok/79 1984-85 A/Philippines/73 1985-86 A/Stockholm/85 1987-88 A/Sichuan/87 1989-90 A/Shanghai/87 1991-92 A/Beijing/89 1993-94 A/Beijing/92 1994-95 A/Shangdong/93 1995-96 A/Johannesburg/94 1996-97 A/Wuhan/95 1997-00 A/Sydney/97 2001-02 A/Panama/99 Smith etal J Infect Dis 2002;185:980-5.

  6. ESTIMATED ANNUAL AGE-SPECIFIC INFLUENZA DEATHS FOR 1990-1991 THROUGH 1998-1999 SEASONS* Age Influenza Influenza Influenza Group A(H1N1) A(H3N2) B Total  < 1 0 3 85 88 1 - 4 34 103 38 175 5 - 49 501 1,685 383 2569 50 - 64 348 3,360 684 4,392 65+ 1954 34,866 7,159 43,979 Totals 2,837 40,017 8,349 51,203 *Thompson, WW, et al, JAMA 2003; 289:179-86

  7. Estimated Annual Influenza-Associated Deaths for 1990-1991 Through 1998-1999 Seasons Using the Influenza Model All-Cause Deaths No. of Influenza Deaths Season A(H1N1) A(H3N2) B Total 1990-1991 1,988 6,033 17,549 25,570 1991-1992 6,518 45,928 566 53,012 1992-1993 1,190 19,892 19,030 40,112 1993-1994 173 48,923 404 49,500 1994-1995 572 33,767 7,129 41,468 1995-1996 14,727 23,605 7,509 45,841 1996-1997 0 55,937 12,609 68,546 1997-1998 66 70,701 649 71,416 1998-1999 293 55,367 9,698 65,358 Mean (SD) 2,836 (4,909) 40,017 (20,656) 8,349 (7,105) 51,203 (15,081) Abbreviations: NA, not applicable.*Pneumonia and influenza estimates are based on the 1990-1991 through 1997-1998 seasons. Thompson WW et al. JAMA. 2003;289:179-186.

  8. AGE-SPECIFIC ANNUAL AVERAGE RATES FOR INFLUENZA-ASSOCIATED HOSPITALIZATIONS, 1979-2001 Age Number Rate/10,000  < 5 21,156 11.4 5 - 49 47,745 2.8 50 - 64 39,198 11.1 65-69 22,168 23.0 70-74 40,552 49.2 75-79 31,319 48.9 80-84 34,640 82.9 >85 57,350 166.9 Totals 294,128 11.5

  9. ANNUAL INFLUENZA-ASSOCIATED HOSPITALIZATIONS, U.S., 1990-2001 Year Predominant Number Rate/10,000 Virus 1990-91 B 221,412 8.8 1991-92 A(H3N2) 326,331 12.8 1992-93 B+A(H3N2) 304,898 11.9 1993-94 A(H3N2) 322,736 12.4 1994-95 A(H3N2)+B 288,417 11.0 1995-96 A(H1N1)+(H3N2) 296,312 11.2 1996-97 A(H3N2)+B 490,246 18.3 1997-98 A(H3N2) 530,225 19.6 1998-99 A(H3N2)+B 503,896 18.4 1999-00 A(H3N2) 544,909 19.7 2000-01 A(H1N1)+B 316,588 11.3

  10. Estimated number of persons, influenza vaccine target groups, United States, July 1, 2002 Group Population (millions) Increased Risk 82.8 Aged > 65 y 35.6 Chronic illness 39.7 Pregnant women 2 Other children aged 6-23 mo 5.5 Other (healthy) target groups 102.6 Health care personnel aged < 65 y 7 Household contacts of persons at increased risk 75.5 Other persons aged 50-64 y 20.1 Total, target groups 185.4 Total, persons aged > 6 mo 286.4 O’Mara etal, Infect Med 2003 (Nov) 548-54.

  11. Problems With TargetingHigh Risk Patients • High risk patients are not easily accessible for vaccination • Many high risk patients are debilitated or immunocompromized and fail to respond optimally to vaccine

  12. Update: Influenza Activity, US. January 18--24, 2004 - Centers for Disease Control and Prevention. www.cdc.gov/flu.MMRW January 30, 2004 / 53(03);63-65

  13. Influenza Mortality in U.S. Children 2003/04 152 Children <18 years reportedly died of Influenza-related causes* <6 months old 11% 6-23 months old 30% 2-5 years old 22% >5 years old 37% ACIP high-risk condition 27% Other underlying medical condition 31% Previously healthy 40% Unknown 2% *70 percent of these children had not been vaccinated. Bhat N. ACIP, June 23, 2004.

  14. Influenza Virus Infection and Illness Rates Houston Family Study, 1976-1984 Rate Per 100 Persons <2 2-5 6-10 11-17 18-24 25-34 ³35 Age (years)

  15. Impact of Influenza on School Children and Their Families Influenza-associated outcomes Rate/100* Excess illness episodes 28* Secondary illness episodes (family members) 22* Days of work missed by parents 20* Average school days missed/child 2.25* *Prospective cohort study of 313 children (K-8) in 216 families followed during 1 influenza season. Neuzil KM, et al. Arch Pediatr Adolesc Med., 2002;156:986-991.

  16. Excess Hospitalizations per 10,000 Children/Year Average Excess Hospitalizations per 10,000 Children/Year* Patient Age *Values are weighted averages of annual excess hospitalizations for a population of 10,000 persons within the specified age group. Neuzil KM et al. N Engl J Med. 2000;342:225-231.

  17. Respiratory Virus Infections Associated with Hospitalizations for Acute Respiratory Conditions, Houston, 1991-1995 30 20 10 0 Influenza Viruses 30 20 10 0 Number Positive per 100 Parainfluenza Viruses 30 20 10 0 <5 5-17 18-44 45-64 ³65 Age (years)

  18. Bacterial Disease in Children with Proven Precursor Influenza • Severe Pneumococcal Pneumonia in Previously Healthy Children: The Role of Preceding Influenza Infections. O’Brien KL et al. Clin Infect Dis 2000;30:784-9. • Risk-Factors for Meningococcal Disease in Victoria, Australia, in 1997. Robinson P et al. Epidemiol Infect 2001;127:261-8. • Is Bacterial Tracheitis Changing? A 14-Month Experience in a Pediatric Intensive Care Unit. Bernstein T et al. Clin Infect Dis 1998;27:459-62 • Glezen WP. Prevention of Acute Otitis Media by Prophylaxis and Treatment of Influenza Virus Infections. Vaccine 2001; 19:S56-S58.

  19. Other Complications of Influenza • Acute myositis • Neurologic • Reye’s syndrome • Encephalopathy • Febrile convulsions • Cardiac • Pericarditis • Myocarditis

  20. Rationale forAlternative Approaches • School children and working adults are the major spreaders of influenza in the community and introducers into the household • School children have the highest annual attack rate for influenza

  21. Rationale forAlternative Approaches • Immunization of school children and working adults to: • decrease absenteeism for school and work • decrease visits for medical care • decrease antibiotic prescriptions

  22. Influenza Vaccinations in Japanese School Children P&I deaths/100,000 (age adj LT/GE 65 & ref US 1970 pop) all-cause deaths/100,000 B D A C (A) all cause baseline (B) all cause excess (C) P & I baseline (D) P& I excess Reichert, TA Seminars Pediatr Infect Dis; 13:104-11

  23. Site of CAIV-T Field Trial Central Texas

  24. Non-randomized, Open Label Field Trial of Trivalent Cold Adapted Influenza Vaccine (CAIV-T) in Central Texas, 1998-2001 Indirect Effectiveness (Herd Immunity) – Age-specific rates of medically-attended acute respiratory illness (MAARI) for the intervention site compared to those for the comparison sites. Direct Effectiveness and Adjusted Efficacy – MAARI rates in CAIV-T recipients compared to rates in 9,325 age-eligible non-recipients at the intervention site and adjusted for culture-positive MAARI. Total Effectiveness – MAARI rates in CAIV-T recipients compared to rates in 16,264 age-eligible non-recipients in the comparison sites. Safety: a) Occurrence of serious adverse events (SAEs) for 42 days after vaccination b) Occurrence of rare events associated with natural influenza virus infection c) Comparison of MAARI rates 0-14 days after vaccination to the pre- vaccination.

  25. MAARI Rates in the Intervention and Comparison Sites during Influenza Outbreaks for SWHP Members > 35 years old

  26. CAIV-T Direct Effectiveness for all MAARI and Adjusted Efficacy for Culture-Positive MAARI with both Influenza A(H1N1) and B, Temple-Belton, TX, 2000-01 Age Direct (95% CI) Adjusted (95% CI) (years) Effectiveness Efficacy 1.5-4 0.20* (0.14,0.25) 0.91 (-0.34,0.99)   5-9 0.25 (0.15,0.34) 0.80 (0.26,0.95)   10-18 0.14 (0.01, 0.26) 0.70 (0.13,0.90)   Total 0.18 (0.11,0.24) 0.79 (0.51,0.91) Subsets Influenza A(H1N1) 0.92 (0.42,0.99) Influenza B 0.66 (0.09,0.87) *statistically significant in bold numbers

  27. Safety Summary • Years 1, 2, 3 and 4: 18,780 doses of CAIV-T have been administered to 11,096 children in this community-based, open-label trial • No CAIV-T vaccine attributable serious adverse event has been observed • No CAIV-T vaccine attributable rare or unusual adverse event has been observed • Six pregnancies originating proximal to receipt of vaccine were uncomplicated (healthy full-term infants).

  28. CAIV-T FIELD TRIAL Summary • Safe-side effects do not increase direct medical costs. • Direct Effectiveness • Protection inversely related to age (VEadj 0.70-0.91) • Persists through two seasons • Heterovariant • Single dose is sufficient • Indirect Effectiveness (Herd Immunity) – For proportion vaccinated compatible with Longini Model.

  29. Implications for Control of Both Interpandemic and Pandemic Influenza • School children have the highest attack rates for influenza. • School children are the principle spreaders of influenza. • School children are accessible for rapid distribution of influenza vaccine.

  30. Acknowledgements W. Paul Glezen – Control of Epidemic Influenza Grant Co-Investigators: Pedro A. Piedra – PI, Baylor College of Medicine Mangusha Gaglani – PI, Scott & White Clinics Gayla Herschler – Coordinator, S & W Mark Riggs – Biostatistics, S & W Claudia Kozinetz – Analysis and Data Management, BCM Consultants: Ira Longini – Emory University Elizabeth Halloran – Emory University Vaccine: Paul Mendelman, MedImmune Vaccines Colin Hessel, Biostatistics, Safety Analysis, MedImmune Program Officer: Linda Lambert - NIAID

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