TritanrixHepB and TritanrixHepBHib vaccines

1
Tetra pentavalent vaccines
and future trends
2
Development history
1923 diphtheria 1926 pertussis 1927
tetanus 1935 yellow fever 1936
influenza 1955 polio Salk 1957
DTPw 1958 polio Sabin
3
Development history
1980s
1982 plasma-derived HBsAg 1986 first r-DNA
HepB vaccine HBsAg produced in yeast 1988
first unconjugated Hib (PRP vaccine)
4
r-DNA hepatitis B vaccine principle
5
HepB component base profile

• registered launched since 1986
• HBsAg expressed in yeast cells (Saccharomyces
  cerevisiae)
• 11 purification steps
• significantly exceeds the WHO specifications
• protein content of 98 (at least 8 more HBsAg)
• DNA content 2.5 pcgs or lower (at least 40 times
  purer)
• immunogenicity (gt95 SP protective efficacy)
• stable for 1 week at 45C /gt 1 month at 37C no
  freezing
• gt750 million doses used during the last 25 years

6
Development history
1992 PRP conjugates (PRP-D, PRP-CRM, PRP-T,
PRP-OMP, adjuvanted conj.) in liquid or
lyophilised form 1996 DTPw-HepB 1998
DTPw-HepB/Hib liquid tetravalent Hib
pentavalent
1990s
7
Conjugate PS vaccines
8
Paediatric meningitis (1996-2000)
Welcome Trust Study, Queens Hospital Blantyre
Malawi
9
DTPw-HepB (tetra) formulation



inactivated B.pertussis
yeast derived HBsAg
D toxoid
T toxoid

• ready for use liquid vaccine
• in 10 dose vials
• overfill to be discarded
• storage at 2C to 8C
• no freezing!

10
DTPw-HepB/Hib formulation



inactivated B.pertussis
D toxoid
T toxoid
yeast derived HBsAg
conjugation lyophilisation
Hib-PS
DTP-HepBHib
11
DTP-HepB/Hib QC/QA processes
12
Release process
13
Production capacity

• tetra/penta EMEA approved
• largely used in government programmes around the
  world including (GAVI, PAHO, ..)
• from the 90s till 2002, 83 mio doses used in 66
  countries
• demandgtcapacity

now gt50 mio doses annually
14
Vaccine cold chain
15
Vaccine damage due to freezing
certain vaccines are more at risk from loss of
potency due to freezing than to heat exposure
most sensitive

• HepB
• DTP-HepB
• DTP-HepB/Hib
• DTP
• DT
• Td
• TT

-0.5C freezing point
least sensitive
freezing can totally and irreversibly damage the
efficacy of these vaccines and increase the risk
of side effects
Too cold cold chain
16
Vaccine damage due to freezing
freezing of vaccines can occur when vials are
exposed to freezing temperatures during

• transport in cold boxes with conditioned ice
  packs
• improperly managed transport as air cargo
• storage or transport in areas with low ambient
  temperatures
• storage in cold rooms or refrigerators
  (especially ice-lined and domestic
  refrigerators) that are set at inappropriately
  low temperatures or have non-uniform
  temperatures within, e.g. cold spots near the
  freezer compartment

Too cold cold chain
17
Place vaccines correctly
not in the lowest 20 cms of ILRs (ice lined
refrigerators)
do not place DTP, TT, DT, dT, HepB, and liquid
Hib within 20 cms of the base of these
models idem for DTP-HepB and reconstituted
DTP-HepB/Hib vaccines put gt6" thick blocks of
styrofoam insulation to cover the bottom of these
models to prevent the possibility of people
putting the freeze-sensitive vaccines there
Too cold cold chain
18
Cryosensitivity/thermostability
release titer
exposure to heat or to freezing
potency loss during shelf-life
expiry titer
minimum
shelf-life
19
What went wrong?
cost, image, stress ... unprotected infants?
12
10
transit storage
vaccine transferred to national EPI stores
vaccine arrives at airport
8
clearing agent stores
6
national EPI storage
4
2
0
48
21
75
192
210
138
165
237
102
-2
20
DTP3 rates define the uptake of ...
the combined DTP-HepB or DTP-HepB/Hib vaccines
21
Vaccination schedule?
or variation thereof?
age
vaccine
birth
BCG OPV0 (HB0)
6 weeks
DTP-HepBHib1 OPV1
10 weeks
DTP-HepBHib2 OPV2
14 weeks
DTP-HepBHib3 OPV3
9 months
measles (YF)
22
Any interferences?

• reactogenicity?
• immunogenicity?
• PE? long-term PE?
• boosters?

• liquid/lyophilised?
• preservative or not?
• stability? shelf-life?
• manufacturing, supply?

23
DTPw-HepB reactogenicity
of doses with symptoms Cody et al. Pediatrics
1981 68 (5) 650-660 Gustafsson, Olin et al.
N. Engl. J. Med. 1996 334 (6) 349-355
24
Any reactogenicity versus Grade 3
25
Comparative reactogenicity
n 400, Mexico, Brazil, Panama, Venezuela, Dom.
Rep.
Santos JI 2nd World Congress Ped Inf Dis Nov 99
Manila
26
DTPw-HepB vaccine reactogenicity
.. no significant difference in the ratio of
doses followed by a symptom between DTPw and
DTPw-HepB vaccines the study demonstrated
that the addition of Hib to DTPw-HepB did not
adversely alter the reactogenicity nor the
immunogenicity of the established DTPw-HepB
vaccine
Diez-Delgado J et al. Vaccine 1997, Vol 15 Nr
12/13, pp. 1418-22 Santos J.I. 2nd World Congress
Ped Inf Dis Nov99, Manila
27
DTPw-HepB vaccine reactogenicity
during the first trimester, vaccination
coverage in children lt1 year old was 88 for the
complete schedule, and 87 for DTP over 800
000 doses have now been administered
preliminary information from 32 state
immunization programs and from the passive
surveillance system of adverse events associated
with vaccine application, suggest that the
pentavalent vaccine is well accepted by both
parents and health workers furthermore, the
reactogenicity of the combined vaccine is similar
to that observed with DTP alone
EPI newsletter 1999, XXI (4) 8
28
Field feed-back
in some African programs there is a perception
of better tolerability worthwile documenting
29
Field acceptance of the vaccine

• 5 in one message olympic festival/new vaccine
  introduction
• 31.7 got first DTP in combo form 93.5
  completed series
• drop out rate of only 5.83 compared to overall
  drop-outrate of 30
• 64.1 parents aware of penta lt20 knew about
  HepB/Hib
• what about older siblings!
• media
• 7 month-follow-up
• 83 penta3 valid coverage79.4 OPV3 68 me

30
Post-marketing surveillance
October 26,1999
including SAE
31
Comparative immunogenicity
n 400, Mexico, Brazil, Panama, Venezuela, Dom.
Rep.
Santos JI 2nd World Congress Ped Inf Dis Nov 99
Manila
32
Protective efficacy against pertussis

• prospective, blinded household contact study
• vaccine efficacy of97.6 better than DTPa
  comparator
• PE reactogenicity into perspective

Schmitt, HJ et al. JAMA, 1996 275 37-41
33
DTPw-HepB anti-HBs response
100
SP
94.9
93.2
schedule 3, 4, 5
GMTs in mIU / ml
66.1
post II III 25 186 95
588
separateHepB DTPw
combinedDTPw-HepB
post III (m6)
post II (m5)
Prikazsky, DTPw-HBV-038
34
DTPw-HepB/Hib anti-HBs response
Bock HL Vaccines today protecting the future
March 1998, KL Malaysia
35
Chiang Rai field trial - Thailand

• no difference in safety and reactogenicity
  profile
• immunogenicity
• faster protection resulted in a lower carrier
  rate

36
Need for boosters or not?

• scientific data do not support the need for
  hepatitis B booster vaccinations (ACIP, ACIP
  Canada, VHPB, WHO), provided the vaccine has
  adequately primed those vaccinated and induced a
  solid immune memory
• as Hib diseases mostly strike infants children
  lt5 years of age boosters after that age are not
  required depending on the countries a booster
  dose is sometimes given during the second year of
  life after a 3-dose priming schedule within the
  GAVI frame priority is given to priming a maximum
  of infants at 6,10 and 14 weeks of age

37
Benefits of combined vaccines
? coverage
? acceptance
?HB/Hib casesprevented
far fewerinjections
DTPHepB/Hib
higher seroprotection rates for HepB gt80 after
2nd dose excellent anti-PRP levels vis DTPa
38
Combined vaccines in perspective
combined vaccines will simplify the
administration of an increasing number of
antigens against major childhood diseases in the
regular immunization schedule, by decreasing the
number of injections, visits to health care
providers and discomfort for children and
parents it has been demonstrated that the
indirect costs of fully immunizing a child are by
far larger than the costs of the vaccines
themselves the use of combined vaccines will
result in reduced costs in the logistics of
delivering immunisation services and surveillance
of three different vaccines these benefits
should increase compliance and thereby
immunisation coverage
EPI newsletter 1999, XXI (4) 8
39
DTPw-HepB vs separate vaccines
EGYPT
1.7 Mio Births
MALAYSIA
0.5 Mio Births
BRAZIL
3.1 Mio Births
Intermediate to high endemicity countries for HBV
infection
40
HepB combined vs. separate approach
Egypt as an example savings in time, wastage
logistics per year

• parameter
• DTPw wastage
• n inj. lt 1yr
• programme costs
• needles used
• nurses time for service delivery

combined
change
separate
20.8 3 (4) 32 mio6.5 mio 5 min
25 6 54 mio 11 mio 10 min
- 4.2 - 50 - 33 - 40 - 40 - 50

Combined Vaccines for the Worlds Children
P. Van Damme, Barcelona, 1999
41
HepB combined vs. separate approach
Egypt as an example cost/savings of logistics per
year
Combined Vaccines for the Worlds Children
P. Van Damme, Barcelona, 1999
42
HepB combined vs. separate approach
Egypt/Brazil as examples clinical economic
results/year
incremental benefits - lifetime
separate
combined
/100 000 births

n chronic carriers
33
26
7 averted
2 800
1 274
1 526
direct medical costs
352 94
235 294
117 647 savings
15 mio
4.7 mio
10 mio
P. Van Damme, Barcelona, 1999
Combined Vaccines for the Worlds Children
43
HepB combined vs. separate approach
44
Combined vaccine evolution
Public Health / PublicDTP/OPV based
IPV? MMR? varicella? Pneumococci? rotaviruses? hep
atitis A? HPV, HSV?
DTP-HepB DTP-HepB/Hib DTP-HepB/Hib Men
C DTP-HepB/Hib Men A, C DTP-HepB/Hib Men A,
C, W, Y, B
the big 3 HIV, TB, malaria
45
An ounce of prevention .....
is worth a pound of cure ... but first do no
harm!