19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 1 European Regulatory Authorities´ Perspective and View

19th VHPB meeting on "combined hepatitis B vaccines", Malta 22-23.10.01, Dr. M. Pfleiderer, PEI

1

European Regulatory Authorities´ Perspective and View on

Proving Safety and Immunogenicity of Combined Vaccines - General Aspects -

- Recent experiences -


2

Multivalent Vaccines Available in the EU (I)

• DTPw/a - based– DTPa-IPV– DTPa/Hib– DTPa-IPV/Hib– DTPw-IPV/Hib– DTPa-IPV-HepB– DTPa-IPV-HepB/Hib– DTPa-IPV-HepB-Hib

Community-MA since October 2000


3

Multivalent Vaccines Available in the EU (II)

– DTPa-IPV-HepB/Hib (Infanrix - Hexa; Glaxo SmithKline)

• Pharmaceutical Form: Powder and suspension for suspension for injection

– DTPa-IPV-HepB-Hib (Hexavac; Aventis Pasteur MSD)

• Pharmaceutical Form: Suspension for injection in pre-filled syringe


4

Simplifying Vaccination Schedules (I)

PrimaryImmunisation

(1st and 2nd yearof life)

Type of Vaccine No. ofImmunizations

DTP 4

Hib 4

IPV 4

HepB 4

Total 16


5

Simplifying Vaccination Schedules (II)

PrimaryImmunisation



DTPa/w-IPV/Hib 4

HepB 4

Total 8


6

Simplifying Vaccination Schedules (III)

PrimaryImmunisation



DTPa-IPV-HepB/Hib

4

Pneumococcalvaccine

4

Total 8


7

Towards a harmonised vaccination schedule for primary immunisations of infants and young children in the

EU?

Simplifying Vaccination Schedules (IV)


8

Other Advantages Provided by Combined Vaccines

• Increased compliance

• Increased vaccine coverage

• Improved vaccination documentation

• Reduced overall costs of vaccination campaigns

• Reduced storage requirements


9

Potential Quality Concerns Identified During Dossier Evaluation

• Cumulative stability of vaccine intermediates– seed lots

– live or inactivated harvests from bacterial or viral cultures

– purified harvests consisting of toxins, toxoids, polysaccharides, bacterial or viral suspensions

– purified antigens

– conjugated polysaccharides

– final bulk vaccine

– vaccine in the final closed container stored at low temperature awaiting labelling


10

Intermediate 1

DaysWeeks

MonthsYears

Intermediate 2

DaysWeeks

MonthsYears

Intermediate 3

DaysWeeks

MonthsYears

Intermediate 4

DaysWeeks

MonthsYears

Intermediate 5Days

WeeksMonthsYears

Final Bulk

DaysWeeks

MonthsYears

Finished Product

Years


11

Possible Impact of the Age of an Intermediate on the Stability (Potency) of the ActiveSubstance made from it (I)

Stability Profile ofan Intermediate

(Potency)

Isolated Intermediate

Active Substance Made from thisIntermediate in the Finished Product

StabilityProfile I

StabilityProfile II

Stability ProfileIII

Time


12

Cumulative Stability of Vaccine Intermediates (I)

• Hexavalent vaccines contain 9 or 10 different antigens:– D- component 1– Pa- components 2 or 3– T- component 1– IPV- component 3– Hib component 1– HepB component 1

x 2,3 or 4


13

Cumulative Stability of Vaccine Intermediates (II)

• CPMP/BWP/4310/00 Concept Paper on the Development of a CPMP Points to Consider on Stability and Traceability Requirements for Vaccine Intermediates


14

Potential Efficacy Concerns Identified During Dossier Evaluation (I)

• Combining antigens to formulate a multivalent vaccine is more than just mixing– Changes may occur in the immunogenicity due

to interference of vaccine antigens– Reliable potency testing may become

increasingly complicated– Do the established surrogates/correlates for

protection need reconsideration?


15

• Epidemiological aspects– Altered pathogen circulation

• Modified strains due to the use of acellular Pertussis components

• Invasive Hib- disease may be prevented but pathogen circulation is still ongoing due to persistent infections (carrier status)

Potential Efficacy Concerns Identified During Dossier Evaluation (II)


16

The Hib Valence

• Are reduced anti- PRP titers before booster immunisation a risk for children in their first and second year of life (I)?– Do we need a redefinition of the cut off levels

(1.0 µg/ml and 0.15 µg/ml)?– What type and quality of immune response is

triggered by conjugated Hib vaccines?– Is there always an anamnestic immune response

in very small children at risk even if there are no detectable anti Hib titers before the booster?


17

Are reduced anti- PRP titres before booster immunisation a risk for children in their first and second year of life (II)?

• The ethnic factor (Sweden)

• The different vaccination schedules (UK)


18

The Acellular Pertussis Valence (I)

• Does the number of pertussis antigens determine the clinical efficacy of acellular pertussis vaccines?

• Are acellular pertussis vaccines inferior to whole cell pertussis vaccines?

• Are anti Pa antibodies surrogates of protection? • Do levels of anti Pa titres correlate with sufficient

or insufficient protection from disease?


19

The Acellular Pertussis Valence (II)

• Is the genetic polymorphism of circulating B. pertussis strains driven by acellular pertussis vaccines with only one or two components?

• Does this have an epidemiological impact?

• Are acellular pertussis vaccines responsible for re-emerging pertussis disease?


20

Long term persistence of Hepatitis B immune protection

• Three dose schedule (no booster, early booster - 3, 5, 11/12 months -)

• Four dose schedule (booster vaccination in the second year of life)


21

Safety Aspects

• Fever > 39°C

• Inconsolable crying

• Severe local reactions

• Allergic oedema as a serious adverse reaction


22

Follow- up Measures

• Long- term stability testing program focussing on the age of the intermediates used

• Sampling and testing under the auspices of the EDQM?


23

Post - Marketing Studies

• Long- term epidemiological surveillance studies to monitor effectiveness of the hexavalent vaccines as well as distribution and circulation of the natural pathogens

• Large controlled safety studies to compare the reactogenicity profile of the hexavalent vaccines compared to the vaccine generation used before


24

Pharmacovigilance Aspects

• Pharmacovigilance data from spontaneous reporting will define the rare adverse drug reaction profile of hexavalent vaccines. These rare effects need to be carefully evaluated to eventually amend the SPC and PIL accordingly.

Documents

19th VHPB meeting on "combined hepatitis B vaccines", Malta 22- 23.10.01, Dr. M. Pfleiderer, PEI 1 European Regulatory Authorities´ Perspective and View