European Regulatory Authorities´
Perspective and View on Proving
Safety and Immunogenicity of
Combined Vaccines - General
Aspects - Recent experiences 19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
1
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
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Simplifying Vaccination
Schedules (I)
Primary
Immunisation
(1st and 2nd year
of life)
Type of Vaccine
No. of
Immunizations
DTP
4
Hib
4
IPV
4
HepB
4
Total
16
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Simplifying Vaccination
Schedules (II)
Primary
Immunisation
(1st and 2nd year
of life)
Type of Vaccine
No. of
Immunizations
DTPa/w-IPV/Hib
4
HepB
4
Total
8
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Simplifying Vaccination
Schedules (III)
Primary
Immunisation
(1st and 2nd year
of life)
Type of Vaccine
No. of
Immunizations
DTPa-IPVHepB/Hib
Pneumococcal
vaccine
4
Total
4
8
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Simplifying Vaccination
Schedules (IV)
Towards a harmonised vaccination
schedule for primary immunisations
of infants and young children in the
EU?
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Other Advantages Provided by
Combined Vaccines
•
•
•
•
Increased compliance
Increased vaccine coverage
Improved vaccination documentation
Reduced overall costs of vaccination
campaigns
• Reduced storage requirements
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Intermediate
1
Days
Weeks
Months
Years
Intermediate
2
Days
Weeks
Months
Years
Intermediate
3
Days
Weeks
Months
Years
Intermediate
4
Days
Weeks
Months
Years
Intermediate 5
Days
Weeks
Months
Years
Final Bulk
Days
Weeks
Months
Years
Finished
Product
Years
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Possible Impact of the Age of an Intermediate on the Stability (Potency) of the Active
Substance made from it (I)
Stability
Profile I
Stability Profile of
an Intermediate
(Potency)
Stability
Profile II
Isolated Intermediate
Active Substance Made from this
Intermediate in the Finished Product
Stability Profile
III
Time
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Cumulative Stability of Vaccine
Intermediates (I)
• Hexavalent vaccines contain 9 or 10
different antigens:
–
–
–
–
–
–
D- component
Pa- components
T- component
IPV- component
Hib component
HepB component
1
2 or 3
1
x 2,3 or 4
3
1
1
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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?
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Potential Efficacy Concerns Identified
During Dossier Evaluation (II)
• 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)
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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?
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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)
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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?
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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?
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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)
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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Safety Aspects
• Fever > 39°C
• Inconsolable crying
• Severe local reactions
• Allergic oedema as a serious adverse
reaction
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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?
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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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.
19th VHPB meeting on "combined
hepatitis B vaccines", Malta 22-
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