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 Introduction of universal Hib vaccination Switch from OPV to 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 DTPa - HBV DTPa DTPa - IPV DTPa - HBV - IPV DTPa / Hib DTPa - HBV / Hib DTPa - IPV / Hib DTPa - HBV - 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 DTPa DTPa - IPV DTPa / Hib DTPa - HBV / Hib DTPa - IPV / Hib DTPa - HBV - IPV Infanrix penta DTPa - HBV - IPV / Hib Infanrix hexa

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

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 Hepatitis B component HBsAg: 10 mcg Polio components Polio 1: 40 DU Polio 2: 8 DU Polio 3: 32 DU Excipients: Alum salts as adjuvant 2-Phenoxyethanol as antiseptic

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

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

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

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

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

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) Study 015: Ward, USA All groups N = 100 enrolled

Immunogenicity of D, T and HBsAg Combined (N=89-90) Separate (N=77-78) % 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

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

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

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

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

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

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

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

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

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

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

Immunogenicity of D, T and HBsAg Combined (N=134) Separate (N=134) % 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

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

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

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

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

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

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

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) - “Non-inferiority” : ADD a * with legend : “for a 10% limit of non-inferiority” (MCU)

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

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

1)Good start as suggested by Achim to outline that I was part of this group who looked at all the available data Lancet 1999, 354: 2063-68

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 and DTPa-IPV/Hib under conditions of routine use

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 + HepB 168 Infanrix hexa 544 - “N” : Number of subjects with safety documented (MCU) Study 058: Zepp, Germany

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

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

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

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

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