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Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine

Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine Carolyn B. Bridges, MD National immunization Program, CDC for NVAC/ACIP Influenza Vaccine Working Group April 20, 2005 Influenza Vaccine Effectiveness (VE)

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Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine

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  1. Influenza Vaccine Effectiveness: Considerations for Prioritization of Pandemic Influenza Vaccine Carolyn B. Bridges, MD National immunization Program, CDC for NVAC/ACIP Influenza Vaccine Working Group April 20, 2005

  2. Influenza Vaccine Effectiveness (VE) • Reviewed by ACIP Influenza Working Group January 2005 meeting on inter-pandemic prioritization • Kristin Nichol • John Treanor • Wendy Keitel • Lone Simonsen • Litjen Tan • Niranjan Bhat • Guillermo Herrera • Raymond Strikas

  3. Outline • VE TIV during inter-pandemic years • By age group and chronic condition • VE LAIV • 1 versus 2 doses in immunologically naïve populations • TIV in children • LAIV in children • Swine flu and “Russian flu” H1N1 vaccines • Studies of H5 vaccines

  4. Vaccine Effectiveness • Varies by age group, risk group, and antigenic match • Variety of outcomes/methods in literature • Influenza-like illness • Laboratory-confirmed influenza • Influenza-related hospitalization and death largely based on modeling • Herd immunity effects may also be considered

  5. Healthy Adults < 65 Yrs • Key literature reviewed • US military trials • Cochrane review (updated 2004) • 8 clinical trial papers published since 1988

  6. Efficacy of Influenza Vaccine in Healthy Young Adults US Army Field Trials* US Air Force Field Trials+ * Adapted from Davenport, Med J Aust 1973 (suppl): 33-8. + Adapted from Meiklejohn. J Infect Dis 1983; 148: 775-84.

  7. VE Healthy Adults • VE estimates (Cochrane review for IV) • Lab-C illness 70% (56% - 80%) • Clinical ILI 25% (13% - 35%) • Work loss reduction: • 0.16 days per person vaccinated (0.04 – 0.29) • Other studies generally similar • Vaccination also associated with reductions in health care provider visits & antibiotic use due to URI / ILI • Insufficient data on serious complications

  8. VE During Pregnancy (1 cohort study) • Black SB, Am J Perinatology 2004 • Subjects: 49,585 women with live births Nov thru Feb 97-98 thru 00-01 (KPNC) • Results • Hospitalizations: very rare • Outpt visits for resp illness: HR 1.15 (p = .09) • Note: vaccination rates low (4.7% - 11.9%)

  9. Community Dwelling Elderly • 4 clinical trials published from 1994 on • Numerous observational studies • 1 meta analysis

  10. VE in Community Dwelling Elderly Persons (meta analysis) Vu T, et al. Vaccine 2002; 20: 1831.

  11. VE by Risk Status

  12. VE: Elderly in Nursing Homes • 1 meta analysis • Several observational studies

  13. VE Nursing Home Residents

  14. VE: Poor Match Yrs

  15. Summary of VE in Adults • Healthy adults • Vaccination reduces illness / work loss • Elderly • Vaccination reduces illness & serious complications of influenza • Vaccination provides benefits for healthy & high risk elderly & for community dwelling & NH residents • VE with mismatch is variably reduced • Even with lower VE, NNT must be considered

  16. Influenza VE Studies in Children • Data more limited compared with adults • Hoberman, et al JAMA 2003 • 2 dose TIV vs placebo among children 6-24 months • 66% VE in year 1 and 0% in year 2 with low incidence influenza • No VE versus otitis media • Good immune responses to vaccine

  17. Pediatric VE Summary TIV • Influenza vaccine is efficacious in children • 21-76% for ILI • 30-95% for lab-confirmed influenza • 32-36% for otitis media • Generally similar results for healthy and high risk

  18. Pediatric VE Summary, cont • Vaccine efficacy in children increases with age • Limited data in children aged 6-23 months

  19. LAIV vs. TIV

  20. Live and inactivated vaccines • Theoretical considerations • Live vaccines must replicate • Level of replication depends on the host • Children > adults > elderly • Live vaccine stimulate mucosal immunity • May be more effective at limiting shedding • No well standardized immune correlates

  21. Live and inactivated vaccines • Theoretical considerations • Inactivated vaccines do not replicate • Level of immunity depends on host priming • Adults > children > elderly • Inactivated vaccines stimulate serum antibody • Well standardized immune correlate

  22. Live and inactivated vaccines • There are few direct comparisons • Indirect comparisons can be difficult to interpret • Randomized direct comparisons • Pediatric • Adult • Elderly • More definitive comparisons in adult and pediatric populations are underway

  23. Pooled results of experimental infection studies in adults Vaccine 18:899 (2000) Virus shedding Infection Influenza illness 0.36 0.14 0.18 TIV 0.64 0.35 0.10 CAIV 0 1 0 1 0 1 Pooled Odds Ratio (95% CI) compared to placebo

  24. Natural infection in adults • Edwards (1994) J Infect Dis 169:68-76 • Multiple years, subjects remain in group • Control vaccines monovalent B/allantoic fluid • Children did notreceive 2-dose schedule • LAIV given by drops • Outcomes included ILI, serologic and culture-confirmed illness

  25. Evaluation of the protective efficacy of LAIV in adults Rate per 1,000 subjects H1N1 H3N2

  26. Pediatric subgroup analysisNeuzil (2001) Pediatr Infect Dis J 20:733 • Analysis restricted to children younger than 16 at the time of immunization • 474 age 1 to 5 • 744 age 6 to 10 • 591 age 11 to 15 • Two outcomes • Culture positive illness • Seroconversion

  27. Evaluation of the protective efficacy of LAIV in kids Per 1,000 Per 100 Rate per 1,000 or per 100 subjects Cx positive Ab positive

  28. Elderly • LAIV is not infectious – less than 10% have detectable shedding by culture • Low antibody response rates, even in subjects with low prevaccination antibody • Combined vaccine may provide additional protection • Nursing home – yes • COPD - no

  29. One Versus 2 Doses In Naïve Populations

  30. 1976 Swine Flu and 1977 “Russian” Flu Vaccine Trials • For persons born before H1N1 viruses last circulated (circa 1957) • 2 doses needed for best antibody response • 7 μg + doses gave comparable responses with 2 doses • “Shallow” doses response with 1 dose with >50 μg needed • Whole virus vaccine more immunogenic, but more reactogenic at high doses

  31. VE of LAIV in children 15-71 monthsBelshe RB, et al. JAMA 1998;338:1405-12 • Trivalent LAIV versus placebo • N=532 received placebo • N=1070 received 1 or 2 doses • VE against culture-confirmed influenza • 89% with 1 dose • 94% with 2 doses

  32. VE of TIV with 1 versus 2 dosesRitzwoller DR. Pediatrics 2005 (in press) • Retrospective cohort study children 6-23 months enrolled Kaiser Colorado • 2003-04 when suboptimal antigenic match • >5000 in cohort • Controlled for high risk conditions using administrative data • No laboratory confirmation • VE NS with 1 dose, 25% for ILI and 49% for P&I with 2 doses

  33. LAIV vs Inactivated Vaccine • One dose alone of inactivated vaccine in immunologically naïve persons • Less likely to provide protective immune response unless use high doses • Not protective in young children • 2 doses inactivated vaccine likely to provide ‘protective’ immune response at lower antigenic content • LAIV may provide better protection with 1 dose • Immune-correlate less well defined, so assessment of probable efficacy based on immune response difficult

  34. H5 vaccines

  35. Response to Recombinant H5 VaccineTreanor JJ, et al Vaccine 2001;19:1732-7. • Placebo-controlled trial • 2 doses at 21, 28 or 42 day intervals • 25, 45, or 90μg x 2 doses or 90 then 10μg • Serum collected days 0, 14 days after 1st dose, dose 2 day 0, the 1,2,3,4 weeks after dose 2 • 21%-45% with ELISA immune response • 17%-52% with micro-neutralization response • Dose-response, highest at 90 μg x 2 • No significant effect by dosing interval

  36. Use of adjuvant MF59-H5N3 vaccineStephenson I, et al JID 2005;191:1201-5and Stephenson I, et al Vaccine 2003;21:1687-93 • Adults 18-45 yrs given 7.5, 15 or 30μg A/duck/Singapore/97 (H5N3) • IM injection with and without MF-59 • 2 doses, 21 days apart • 7-14% with MF-59 versus 0-9% without • 3rd dose 16 months later to subset • Serum tested by micro-neutralization against HPAI H5N1 1997-2004 strains • No dose response detected • Seroconversion 43%-100% with MF-59 and 0%-27% without • No 3rd dose booster effect with non-MF-59 • Conclusions • 3 doses and adjuvant needed to improve response • No difference among doses used, but small numbers

  37. Overall Summary • Responses to inter-pandemic influenza vaccines • Varies by age and chronic condition • Within an age group, generally higher VE against complications than influenza illness • LAIV and TIV options for children and adults <65 • Immunologically naïve persons need 2 doses to reach “protective” immune response for inactivated vaccines • May be able to achieve with high single dose • May need only 1 dose for live attenuated vaccines? • Testing of H5 needed to assess safety and immunogenicity • Clinical studies H5 vaccines to date suggest lower immunogenicity without adjuvant • Further trials pending

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