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Combined paediatric vaccines for national immunization programmes

Combined paediatric vaccines for national immunization programmes. Francis E. André Vice-President and senior Medical Director GlaxoSmithKline , Rixensart, Belgium. Current shifts in pediatric immunization. Replacement of DTPw by DTPa Introduction of universal hepatitis B vaccination

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Combined paediatric vaccines for national immunization programmes

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  1. Combined paediatric vaccines for national immunization programmes Francis E. André Vice-President and senior Medical Director GlaxoSmithKline, Rixensart, Belgium

  2. Current shifts in pediatric immunization • Replacement of DTPw by DTPa • Introduction of universal hepatitis B vaccination • Introduction of universal Hib vaccination • Switch from OPV to IPV

  3. DTPa DTPa / Hib DTPa - HBV DTPa - HBV/ Hib DTPa - IPV DTPa - IPV / Hib DTPa - HBV - IPV /Hib DTPa - HBV - IPV SB DTPa-based pediatric combinations DTP : Diphtheria/ Tetanus/ PT, FHA, Pertactin HBV : Recombinant HBsAg IPV : Inactivated enhanced-potency polio vaccine Hib : Lyophilized PRP-T conjugate

  4. DTPa DTPa / Hib DTPa - HBV DTPa - HBV/ Hib DTPa - IPV DTPa - IPV / Hib SB DTPa-based pediatric combinations DTP : Diphtheria/ Tetanus/ PT, FHA, Pertactin HBV : Recombinant HBsAg IPV : Inactivated enhanced-potency polio vaccine Hib : Lyophilized PRP-T conjugate DTPa - HBV - IPV /Hib Infanrix hexa DTPa - HBV - IPV Infanrix penta

  5. Infanrix penta DTPa components D: 25 Lf PT: 25 mcg T: 10 Lf FHA: 25 mcg PRN: 8 mcg Polio components Polio 1: 40 DU Polio 2: 8 DU Polio 3: 32 DU Hepatitis B component HBsAg: 10 mcg Excipients: Alum salts as adjuvant 2-Phenoxyethanol as antiseptic

  6. Infanrix penta and Infanrix hexa Hib component PRP: 10 mcg conjugated to TT DTPa components D: 25 Lf PT: 25 mcg T: 10 Lf FHA: 25 mcg PRN: 8 mcg Polio components Polio 1: 40 DU Polio 2: 8 DU Polio 3: 32 DU Hepatitis B component HBsAg: 10 mcg Excipients: Alum salts as adjuvant 2-Phenoxyethanol as antiseptic

  7. Antigens Adjuvant(s) Preservative(s) pH Contaminants Stabilizer(s) Excipient(s) Potentially deleterious interactions between vaccine components Possible adverse consequences • Reduced immunogenicity • Increased reactogenicity • Shortened shelf life • Complicated manufacture

  8. Infanrix penta and Infanrix hexa:Key objectives of clinical development Demonstration of • safety and acceptable reactogenicity • immunogenicity in various schedules • persistence of antibodies up to the booster dose • protective efficacy of each vaccine component • lot-to-lot consistency

  9. Infanrix penta and Infanrix hexa:Integrated clinical trial programme • Common inclusion and exclusion criteria • Common reactogenicity assessment • Common serological assays • Randomized controlled trials: predefined statistical criteria to demonstrate non-inferiority vs. licensed vaccines

  10. Infanrix penta: primary immunization trials * a dose of HBV was given at birth

  11. Infanrix hexa: primary immunization trials * one study group received a dose of HBV at birth

  12. Infanrix penta + Hib vs. separate administration of antigens: study design Group 2 mo 4 mo 6 mo DTPa-HepB-IPV + Hib  DTPa-HepB-IPV + Hib  DTPa-HepB + Hib + OPV DTPa-HepB + IPV + Hib  DTPa + HepB + Hib + OPV  Combined IPV-OPV IPV Separate (OPV) All groups N = 100 enrolled Study 015: Ward, USA

  13. Combined (N=89-90) Separate (N=77-78) Immunogenicity of D, T and HBsAg % Seroprotection GMTs: 1.3 0.8 3.7 2.3 1661 805 anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 015: Ward, USA

  14. Combined (N=91) Separate (N=77-78) Immunogenicity of PT, FHA and PRN % Vaccine Response GMTs: 97 47 119 153 150 109 anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 015: Ward, USA

  15. Combined (N=86) Separate OPV (N=73) Immunogenicity of Polio types 1, 2, and 3 % Seroprotection GMTs: 415 819 514 1262 1729 453 Study 015: Ward, USA

  16. Immunogenicity of Polio types 1, 2, and 3 Combined (N=86) Separate IPV (N=77) % Seroprotection GMTs: 415 213 514 329 1729 432 Study 015: Ward, USA

  17. o o o Study 015 - Local Reactions Group 1 = Combined Group 4 = Separate + OPV OPV DTPa-HepB-IPV Hib DTPa Hib HepB 2 injections 3 injections

  18. Study 015: Incidence (%) of redness by dose (N = 84 - 100 per dose) 4-day follow-up period

  19. Study 015: Incidence (%) of swelling by dose (N = 84 - 100 per dose) 4-day follow-up period

  20. Study 015: Incidence (%) of pain by dose (N = 84 - 100 per dose) 4-day follow-up period

  21. Study 015: Incidence (%) of solicited general symptoms per subject 4-day follow-up period over the full vaccination course

  22. Study 015: Incidence (%) of “grade 3” solicited general symptoms per subject 4-day follow-up period over the full vaccination course

  23. Infanrix hexa vs. separate administration of antigens (standard of care) Group N Vaccine(s) # injections Combined 134 DTPa-HBV-IPV/Hib 1 Separate 134 DTPa + HBV + Hib + OPV 3 • Open, randomized, multicenter • Schedule: 2, 4, 6 months • Study 001: Blatter, USA

  24. Combined (N=134) Separate (N=134) Immunogenicity of D, T and HBsAg % Seroprotection GMTs: 1.43 1.01 1.98 1.49 1240 934 anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 001, Blatter, USA

  25. Combined (N=134) Separate (N=134) Immunogenicity of PT, FHA, and PRN % Vaccine Response GMTs: 67.4 41.8 288 303 168 137 anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 001: Blatter, USA

  26. Combined (N=134) Separate (N=134) Immunogenicity of Polio types 1, 2, and 3 % Seroprotection GMTs: 495 1278 507 1350 1275 368 Study 001: Blatter, USA

  27. Combined (N=134) Separate (N=134) Immunogenicity of Hib: anti-PRP antibodies 100 % 96.9 % 84.0 % 91.8 % % Seroprotection GMCs: 2.65 5.52 Study 001: Blatter, USA

  28. DTPa-HBV-IPV/Hib (N=134) DTPa + HBV + Hib + OPV (N=134) Study 001: reactogenicity % subjects reporting the symptom(regardless of injection site) Pain Redness Swelling Fever Grade 3 > 20 mm > 20 mm > 39.5 °C

  29. DTPa-HBV-IPV/Hib (N =166) DTPw-IPV/Hib (Pentacoq TM) + HBV (Engerix TM) (N =82) Pain Redness Swelling Fever Grade 3 > 20 mm > 20 mm Reactogenicity of Infanrix hexa vs. whole-cell pertussis - containing combination % subjects reporting the symptom(regardless of injection site) > 39.5 °C Study 025: Cohen, France, schedule 2-3-4

  30. Infanrix hexa: seroprotection rates for antigens with established surrogate markers of protection(all studies, all schedules) * by ELISA

  31. Infanrix hexa: D, T, Pa, HepB, IPV • Non-inferiority of Infanrix hexa post-primary vaccination as compared to licensed vaccines • DTPa-IPV/Hib • DTPw-IPV/Hib • Separate administration of DTPa, HepB, Hib and OPV • Similar distribution of antibody titres (Reverse Cumulative Distribution Curves - RCCs)

  32. Anti-PT antibody titres following administration of DTPa-HBV-IPV/Hib and of DTPa (Infanrix™) vaccine Household contact study* Household contact study ** DTPa-HBV-IPV/Hib DTPa-HBV-IPV/Hib Percentage of subjects Anti-PT antibody titre (EU/ml) RCCs generated for lots that induced the highest (*) and lowest (**) antibody response Study 048, PI: Heininger, Germany, schedule 3-4-5

  33. Hib immunogenicity Anti-PRP antibody titres are lower when Hib vaccines are combined with DTPa-based vaccines as compared to the separate injection of the vaccines

  34. Lancet 1999, 354: 2063-68

  35. Infanrix hexa: Hib In all clinical trials, regardless of vaccination schedule, 96 % of subjects achieved concentrations  0.15 µg/ml Non-inferiority of Infanrix hexa as compared to licensed DTPa-IPV/Hib vaccine Identical functional capacity of anti-PRP antibodies induced by Infanrix hexa and by licensed Hib vaccines Effective induction of immune memory Proven field effectiveness of DTPa/Hib andDTPa-IPV/Hib under conditions of routine use

  36. Infanrix hexa as a 4th dose: reactogenicity • Subjects primed with 3 doses of Infanrix hexa(study 039) • Randomised at 12-18 months to 3 booster groups • N • DTPa-IPV/Hib 163 • DTPa-IPV/Hib + HepB168 • Infanrix hexa 544 Study 058: Zepp, Germany

  37. DTPa-IPV/Hib (N=163) DTPa-IPV/Hib + HBV (N=168) Infanrix hexa (N=544) Incidence of solicited symptomsfollowing 3 different boosters % of subjects with a symptom

  38. DTPa-IPV/Hib (N=163) DTPa-IPV/Hib + HBV (N=168) Infanrix hexa (N=544) = Grade 3; fever > 39.5°C Incidence of solicited symptomsfollowing 3 different boosters % of subjects with a symptom

  39. DTPa-IPV/Hib (N=163) DTPa-IPV/Hib + HBV (N=168) Infanrix hexa (N=544) Incidence of solicited symptomsfollowing 3 different boosters 60 50 40 % of subjects with a symptom 30 20 10 0 Irritability Sleepiness Loss of appetite

  40. In all clinical trials,no cases reported of • Hypotonic hyporesponsiveness • Encephalopathy • Anaphylaxis Infanrix penta: 23 439 doses Infanrix hexa: 15 920 doses

  41. Infanrix penta and Infanrix hexa: conclusions Protective efficacy not affected by combination of antigens Tolerability of primary and booster doses in line with that of other licensed vaccines Reduced number of injections Make room for new (pneumococcal, meningococcal) vaccines Add value to current standard of medical care

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