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

4. 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

5. 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

6. 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

7. Infanrix penta and Infanrix hexa
Hib component
PRP: 10 mcg
conjugated to TT
DTPa components
D: 25 Lf PT: 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

8. 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)

9. 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

10. 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

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

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

13. Infanrix penta + Hib vs. separate administration of antigens: study design
Group 2 mo mo 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

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

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

16. Immunogenicity of Polio types 1, 2, and 3
Combined (N=86)
Separate OPV (N=73)
% Seroprotection
GMTs:
Study 015: Ward, USA

17. Immunogenicity of Polio types 1, 2, and 3
Combined (N=86)
Separate IPV (N=77)
% Seroprotection
GMTs:
Study 015: Ward, USA

18. 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

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

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

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

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

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

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

25. Immunogenicity of D, T and HBsAg
Combined (N=134)
Separate (N=134)
% Seroprotection
GMTs:
anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 001, Blatter, USA

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

27. Immunogenicity of Polio types 1, 2, and 3
Combined (N=134)
Separate (N=134)
% Seroprotection
GMTs:
Study 001: Blatter, USA

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

29. 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)

30. % 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

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

32. 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)

33. 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

34. 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

35. 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:

36. 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

37. Infanrix hexa as a 4th dose: reactogenicity
Subjects primed with 3 doses of Infanrix hexa (study 039)
Randomised at 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

38. 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

39. 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

40. 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

41. In all clinical trials,no cases reported of
Hypotonic hyporesponsiveness
Encephalopathy
Anaphylaxis
Infanrix penta: doses Infanrix hexa: doses

42. 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