Indirect Benefits of Vaccinating Children >23 months of Age With Live Attenuated Vaccine (LAIV)

1. Indirect Benefits of Vaccinating Children >23 months of Age With Live Attenuated Vaccine (LAIV) W. Paul Glezen, M.D.

2. Thompson etal JAMA September 15, 2004;292:11:1337

3. Influenza and pneumococcal vaccination among adults >65 yrs: United States, 1989-2002 Influenza vaccination during past 12 months Pneumococcal vaccination ever 1991 1989 1995 1993 1997 1999 2002 NOTE: Data are for the civilian noninstitutionalized population and are age adjusted. See Data Table for data points graphed and additional notes. SOURCES: Centers for Disease Control and Prevention, National Center for Health Statistics, National Health Interview Survey. Centers for Disease Control and Prevention, National Center for Health Statistics. Health, United States, 2004 Percent Year

4. 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

5. 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)

6. 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.

7. 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

8. 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

9. 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

10. Site of CAIV-T Field Trial Central Texas

11. Non-randomized, Open Label Field Trial of Trivalent Cold Adapted Influenza Vaccine (CAIV-T) in Central Texas, 1998-2001 a) Indirect Effectiveness (Herd Immunity) b) Direct Effectiveness and Adjusted Efficacy c) Total Effectiveness d) Safety

12. MAARI Rates in the Intervention and Comparison Sites during Influenza Outbreaks for SWHP Members > 35 years old Piedra et al: Vaccine 2005;23:1540-8

13. 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 Gaglani et al. Arch Pediatr Adolesc Med 2004;158:65-73 Halloram et al. Am J Epidemiol 2003;158:305-11

14. 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). Piedra et al. Pediatrics 2005;116:e397

15. 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.

16. Virus Surveillance and Enrollment *Influenza A/Fujian/411/2002 (H3N2)Epidemic Period *October 12 to December 20, 2003 (CDC weeks 42-51) • Almost 60% of enrollees were vaccinated by end of week 46

17. Relative Risk of MAARI by Age Groups 0.81* 0.88 0.90 0.84* 1.02 1.08 1.02 0.99 0.87* 0.95* • Of 6,569 children who received LAIV, 66% were 5-11 years old

18. Adjusted Flumist analysis.; Halloran et al., September 28, 2005 Direct effectiveness based on MAARI (95% CI), and adjusted VEex using surveillance cultures of Flumist in 2003 (FM03) and inactivated vaccine in 2003 (TIV03), and vaccinated in 1998-2002, but not 2003 (PREV) Temple-Belton, Texas, 2003-2004. Vaccine VEex (95% CI) VEex (95% CI) MAARI adjusted FM03 0.26 (0.11, 0.39) 0.56 (0.32, 0.75) TIV03 -0.71 (-1.2, -0.25) -1.0 (-2.0, -.016) PREV 0.13 (-0.30, 0.03) 0.11 (-0.19, 0.37) Halloran ME, Schmotzer B, Longini I

19. Conclusion • Community-based LAIV immunization of school-age children during an influenza outbreak provided herd immunity against a drifted variant influenza A by reducing its spread, possibly from early non-specific and late specific immunity

20. 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: Jeff Stoddard, MedImmune Vaccines Program Officer: Linda Lambert, Sonnie Kim - NIAID