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Immunogenicity of influenza vaccines in children, healthy adults and the elderly

Immunogenicity of influenza vaccines in children, healthy adults and the elderly. John Treanor University of Rochester. Assessment of immune responses to influenza vaccine. Humoral immunity Hemagglutination-inhibition (HAI, HI) Neuraminidase-inhibition (NI) Neutralization

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Immunogenicity of influenza vaccines in children, healthy adults and the elderly

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  1. Immunogenicity of influenza vaccines in children, healthy adults and the elderly John Treanor University of Rochester

  2. Assessment of immune responses to influenza vaccine • Humoral immunity • Hemagglutination-inhibition (HAI, HI) • Neuraminidase-inhibition (NI) • Neutralization • Ig ELISA (e.g., HA-specific sIgA) • Cellular immunity • Lymphocyte proliferation • Cytokine production/ELISPOT assays • Cytotoxicity assays/tetramers

  3. Agreement in HAI results Lab A Lab B

  4. Agreement in HAI results Lab A Lab B Lab A = 786/963 (81.6%)

  5. Agreement in HAI results Lab A Lab B Lab B=662/963 (68.7%)

  6. Serum HAI responses to TIV1995-1999 • Healthy adults (mean age = 32 yrs) • Community elderly (mean age = 72 yrs) • Nursing home elderly (mean age = 83 yrs) • Renal transplant recipients (ma = 44 yrs) • Chronic pulmonary disease (ma = 46 yrs) • Toddlers (2 dose) (mean age = 11 mo) • ~ 50 subjects per group (except toddlers)

  7. Vaccines used

  8. Response to the H3 component

  9. H3 Antibody Titers 1024 512 128 64 GMT HAI antibody 32 16 8 4 Sera

  10. Response to the H1 component

  11. H1 Antibody Titers 1024 512 128 64 GMT HAI antibody 32 16 8 4 Sera

  12. Response to the B component

  13. B Antibody Titers 1024 512 128 64 GMT HAI antibody 32 16 8 4 Sera

  14. Effects of strain change and prior vaccination: summary

  15. Factors affecting the serum HI response to TIV • Year of study/strain • Age of subject (Y>O) • History of prior vaccination (N>Y) • Titer of pre-vaccination antibody (L>H) • Sex (F > M) • Dose (H>L)

  16. Recognition of drift variants by sera following inactivated vaccine Mean ratio of serum HI titer to drift variant/homologous virus

  17. Kinetics of the serum antibody response to inactivated vaccine Brokstad et al JID 171:198-203, 1995

  18. NI response to TIV 32 32 16 16 8 8 4 4 N1 N2 Powers, et. al. Clin Diagn Lab Immunol 3:511-516

  19. Comparison of HAI and NI response

  20. Factors impacting NA-specific responses • Stability of the NA and content in the vaccine • Mode of presentation • Assay methodology • Host priming/exposure • Age

  21. Systemic and mucosal routes of immunization

  22. Antibody responses to live and inactivated vaccines in healthy adults Results in subjects selected for pre HAI < 1:8 22/23 (96) 11/12 (92) 16/17 (94) GMT Serum HAI 9/23 (39) 7/24 (29) 1/10 (10) H1N1 H3N2 B Vaccine 18:899-906, 2000

  23. Antibody responses to live and inactivated vaccines in healthy adults 7/30 (23) 4/28 (14.3) 9/30 (32.1) Nasal sIgA (units/mL) 5/28 (16.7) 5/28 (17.9) 5/30 (16.7) H1N1 H3N2 B Vaccine 18:899-906, 2000

  24. Comparison of post vaccination nasal and serum antibody TIV CAIV

  25. Prechallenge antibody titers and infection Pre-challenge antibody Nasal IgA Serum HAI % > 1000 69 29 55 19 56 0 % > 1:8 38 14 64 6 96 75 Vaccine Group CAIV Placebo TIV Infection No Yes No Yes No Yes n 16 7 12 16 25 4 GMT 1705 736 1323 550 1048 324 GMT 8.4 4.4 18.1 3.4 151.2 22.6

  26. Relationship between antibody and protection • Infection induced serum NI > 1:4 • Nasal wash HA IgA > 1:64 • Nasal wash HA Fab > 1:80 • Inactivated vaccine induced serum HI > 1:32 Clements et al J Clin Micro 24:157, 1986

  27. Serum and nasal antibody in elderly subjects given CAIV 256 128 64 32 16 Nasal KELISA Serum HAI Powers et al J Clin Microbiol 29:498, 1991

  28. Immune responses to combined vaccination Percent responding H1 H3 H1 H3 H1 H3 HAI SERUM IgG NASAL IgA

  29. Relationship between pre-vaccination antibody and protection Intranasal: % with lab confirmed influenza Pre-vaccination serum HAI titer

  30. H3N2 response to CAIV in children 128 64 32 GMT serum HAI antibody 16 8 4 < 4 Bernstein et al Pediatr Infect Dis J 22:28-34, 2003

  31. H1N1 response to CAIV in children 128 64 32 GMT serum HAI antibody 16 8 4 < 4 Bernstein et al Pediatr Infect Dis J 22:28-34, 2003

  32. Pre-challenge antibody and shedding of ca H1N1 virus after challenge No. of subjects with or without CAIV-M shedding following challenge among those who initially received: Pre-challenge antibody status CAIV-T Placebo Test shed no shed shed no shed positive negative positive negative 2 4 1 5 94 41 77 36 0 19 3 16 25 31 20 28 HAI IgA Protective efficacy of CAIV-T against CAIV-M challenge 83% (60%,93%)

  33. Cross-protective antibody response to CAIV in children 128 Wuhan 64 Ann Arbor Sydney 32 Yamanashi Shenzhen GMT HAI antibody 16 Beijing 8 Beijing 4 2 Nolan, et. al. Vaccine 21:1224-1231, 2003

  34. Conclusions • Responses to both TIV and CAIV vary by year for a variety of reasons • In general, TIV generates higher levels of serum ab, CAIV mucosal ab • Serum HI responses to TIV are greatest in young adults, to CAIV are highest in children • Responses in the elderly are often suboptimal • Relatively little is known re NA-specific response • Multiple factors influence the response to TIV and to CAIV

  35. Unresolved issues that might be important for universal vaccination • Should vaccine performance be monitored in a more systematic way? • What strategies should be pursued to improve vaccine performance in the elderly and other groups with poor immune response? • Is a “one size fits all” strategy (type of vaccine, dose, route of administration) compatible with the goal of universal vaccination? • Are vaccines that do not require yearly administration feasible?

  36. Unresolved issues that might be important for universal vaccination • Should the NA content of the vaccine and the NA-specific response to vaccination be monitored more closely? • Can standardized assays of mucosal responses to live vaccine be developed as surrogate endpoints for protection? • Generally, to what extent can improved laboratory assays facilitate the introduction of new influenza vaccines? • What would be the impact of a universal recommendation on new vaccine development?

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