Combined paediatric vaccines for national immunization programmes
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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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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


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


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


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 adjuvant2-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

Polio components

Polio 1: 40 DU

Polio 2: 8 DU

Polio 3: 32 DU

Hepatitis B component

HBsAg: 10 mcg

Excipients:Alum salts as adjuvant2-Phenoxyethanol as antiseptic


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


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

Group2 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


Combined (N=89-90)

Separate (N=77-78)

Immunogenicity of D, T and HBsAg

% Seroprotection

GMTs:1.30.83.72.31661805

anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 015: Ward, USA


Combined (N=91)

Separate (N=77-78)

Immunogenicity of PT, FHA and PRN

% Vaccine Response

GMTs:9747119153150109

anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 015: Ward, USA


Combined (N=86)

Separate OPV (N=73)

Immunogenicity of Polio types 1, 2, and 3

% Seroprotection

GMTs:415 819514 12621729 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


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


Study 015: Incidence (%) of redness by dose

(N = 84 - 100 per dose)

4-day follow-up period


Study 015: Incidence (%) of swelling by dose

(N = 84 - 100 per dose)

4-day follow-up period


Study 015: Incidence (%) of pain by dose

(N = 84 - 100 per dose)

4-day follow-up period


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)

GroupNVaccine(s)# injections

Combined 134 DTPa-HBV-IPV/Hib1

Separate 134 DTPa + HBV + Hib + OPV3

  • Open, randomized, multicenter

  • Schedule: 2, 4, 6 months

  • Study 001: Blatter, USA


Combined (N=134)

Separate (N=134)

Immunogenicity of D, T and HBsAg

% Seroprotection

GMTs:1.431.011.981.491240934

anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 001, Blatter, USA


Combined (N=134)

Separate (N=134)

Immunogenicity of PT, FHA, and PRN

% Vaccine Response

GMTs:67.441.8288303168137

anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 001: Blatter, USA


Combined (N=134)

Separate (N=134)

Immunogenicity of Polio types 1, 2, and 3

% Seroprotection

GMTs:495127850713501275368

Study 001: Blatter, USA


Combined (N=134)

Separate (N=134)

Immunogenicity of Hib: anti-PRP antibodies

100 %

96.9 %

84.0 %

91.8 %

% Seroprotection

GMCs:2.655.52

Study 001: Blatter, USA


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


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


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)


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


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 andDTPa-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 + HepB168

    • Infanrix hexa544

Study 058: Zepp, Germany


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


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


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


In all clinical trials,no cases reported of

  • Hypotonic hyporesponsiveness

  • Encephalopathy

  • Anaphylaxis

    Infanrix penta: 23 439 dosesInfanrix 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


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