vaccination policy, vaccine development and manufacturing...
TRANSCRIPT
Vaccination policy, vaccine development and manufacturing in
JapanYoichiro Kino, Ph.D
Executive Managing DirectorKaketsuken
Background of KAKETSUKEN• Organization Name
– The Chemo-Sero-Therapeutic Research Institute(known as KAKETSUKEN, the abbreviation of its Japanese name)
• Type of Organization– Japanese General Incorporated Foundation
• Founding– founded in Kumamoto, Japan in December 1945
• Employees– 1,826 people
• Mission– Contribute to human health and the prevention and treatment
of illness and infectious diseases through the development and supply of biomedical products
2014/-/- Kaketsuken 2
Today’s talk• Japanese Vaccination Law• Japanese vaccination policy• History of vaccine development in Japan• Vaccine manufactures in Japan• Vaccine development and national lot release system• Vaccine gap• Vaccine Industry Vision• Case studies
– Cell culture JE– DPT-sIPV– Pandemic Influenza
• Vaccines in the future
Japanese Vaccination Law
• To contribute to the maintenance of health of the people by implementation of vaccination and other public health countermeasures in order to prevent the spread and occurrence of infectious diseases
• Also intended to provide rapid compensation for health damages caused by vaccination
Japanese vaccination policy• Routine vaccination
– Category A• Vaccines for important infectious diseases• Strong recommendation aiming at social immunity• vaccinations are all free of charge
– Category B• Vaccines for individual protection• Partial reimbursement of vaccination cost
• Voluntary vaccination– Voluntary vaccination is not free and costs vary
depending on the shot
Routine vaccinations
Cate
gory
ADTaP-IPV
Measles,Rubella
JE
TB
Hib
PCV
HPVCa
tego
ry B
Influenza>65
High risk
Voluntary vaccines• Live
–Varicella–Mumps–Rota–Yellow fever
• Inactivated–Hep B–Hep A–Rabies–Pneumo 23
Current vaccination schedule
Products Available from Japanese Manufacturers
--●--Smallpox--●--Gas gangrene AT
●Botulinus AT--●--Mamushi AT--●--Habu AT--- - ●Rabies-●---Varicella--M-M-R II●●Mumps-●M-M-R II●●MR (Measls+Rubella)--●--
--●--
●●●●●Tetanus●●●●●DT ●●●●●DPT -●●--DPT- IPV-●●--CC- J. E.●●●-●Flu
DenkaBikenKAKETSUKENTakedaKitasatoDSProduct
HB (Recombinant)Hep A
Products from foreign manufacturers
Products MSD Sanofi Pfizer GSKHep B ○
Pneumo ○ ○Hib ○
Rota ○ ○HPV ○ ○IPV ○
Yellow Fever ○
National lot release systemNon-clinical
Studies
Clinical Studies
CMC/Efficacy/Safety
New DrugApplication MRBP
VaccineProduction
In-houseTesting
NationalControlTesting
LotRelease
NIID
History of vaccine development in Japan
Missing10 years
VVZV
DTaP
Vaccine Gap
• The missing 10 years led to the “Vaccine Gap”– The following important vaccines were not used in
Japan• Rota, Hib, Pneumo, HPV, IPV
• To close the gap, the WHLW established the Vaccine Industry Vision in 2007
Vaccine Industrial VisionAction Plans
• Promote translational activities from basic research to clinical development
• Promote strategic alliances among relevant companies, including foreign companies, and establish an internationally competitive vaccine production basis
• Assistance for vaccine development and establishment of production facilities for non-profitable emergency use vaccines
• Improvement of regulatory systems for new vaccine approvals• Improvement of adjustment systems for stable vaccine supply
Action Plan Results• Some foreign companies made alliances or
collaboration with domestic companies– Daiichi and GSK, Biken and Merck, Kaketsuken and
GSK, Takea and Novartis
• Some Japanese drug companies went into vaccine research– Takeda, Daiichi, Astellas, Tanabe
• Several guidelines have been established– Pre-clinical, clinical, and prototype pandemic vaccine
Action plan resultsYear Vaccine Company
2008 Hib Sanofi
2009 Vero derived JE Biken
2009 HPV GSK
2010 PCV7 Pfizer
2011 Vero JE Kaketsuken
2011 HPV Merck
2011 Rota Merck, GSK
2012 Salk IPV Sanofi
2012 DTaP-Sabin IPV Kaketsuken, Biken
2013 PCV13 Pfizer
2014 FCC Pandemic influenza Kaketsuken, Takeda
Case studies
• Vero cell derived Japanese encephalitis vaccine
• DTaP + Sabin IPV• Cell culture H5N1 pandemic
influenza vaccine
Vero cell JE (ENCEVAC)• Date of approval: Jan. 17, 2011• Non-proprietary name:
Freeze-dried cell culture-derived inactivatedJapanese Encephalitis vaccine
• Strain: Beijing strain• Indication:3 year old or older / 0.5 mL (4μg/dose )Under 3 years old / 0.25mL (2μg/dose)
• Formulation: Lyophilized• Shelf life: 3 years (under refrigeration)
•Administration (3 injections for Pediatric use): Primary immunization The usual primary series consists of two doses given by subcutaneous
injection at an interval of 1~4 weeks.Booster immunization The usual booster dose is given by subcutaneous injection one year after
primary immunization.
Numbers of Patients andDeaths from JE in Japan
0
1000
2000
3000
4000
5000
600019
4619
5019
5419
5819
6219
6619
7019
7419
7819
8219
8619
9019
94
Patie
nts an
d Dea
ths
0
10000
20000
30000
40000
50000
60000
Liter
PatientDeath
Vaccine production
Year
Before Vaccination
Issues with MouseBrain-Derived JE Vaccine
Stable securement of enormous numbers of mice used for the vaccine production
Possible risk of contamination with unidentified mouse-derived pathogens
Adverse events due to residual mouse brain proteins
Incineration of a huge amount of residual mouse bodies
Not animal friendly
Vero Cell (ATCC CCL-81)
Fermentation of Vero Cell
Vero Cell (ATCC CCL-81)
Manufacturing Facility
Column chromatography(Sulfate Cellulofine)
Bulk vaccine
Ultra centrifugation(Sucrose density gradient )
Inactivation usingFormalin
Concentration byUltra filtration
Harvest culturefluid
Virus inoculation(Beijing-1)
Manufacturing process(Vero cell derived)
Vero Cell(ATCC CCL-81)
Ultra centrifugation(Sucrose density gradient )
2500L Fermenter
MB-JEV CC-JEV
Electron Microscope
100nm100nm
Immunogenicity
PPS CC-JEV(A)(4g/dose)
CC-JEV(B) (8g/dose)
MB-JEV(17g/dose)
After 2nd
vaccination100%(143/143)
100%(141/141)
94.5%(138/146)
After 3rd
vaccination100%(143/143)
100%(140/140)
100%(146/146)
Seroconversion rate
PPS CC-JEV(A)(4g/dose)
CC-JEV(B) (8g/dose)
MB-JEV(17g/dose)
After 2nd
vaccination 2.58 2.78 2.04After 3rd
vaccination 3.87 3.96 3.43
Antibody geometric mean titer
ENCEVAC
Local Reactions over three injections (≥5%)
ReactionCC-JEV(A)(4g/dose)
CC-JEV(B) (8g/dose)
MB-JEV(17g/dose)
n % 95% CI n % 95% CI n % 95% CI
Erythema 27 16.6 11.2-23.2 39 24.8 18.3-
32.4 33 20.8 14.7-27.9
Swelling 11 6.7 3.4-11.8 13 8.3 4.5-
13.7 13 8.2 4.4-13.6
Induration 3 1.8 0.4-5.3 8 5.1 2.2-
9.8 4 2.5 0.7-6.3
Itching 1 0.6 0.0-3.4 2 1.3 0.2-
4.5 13 8.2 4.4-13.6
ENCEVAC
Systemic Reactions over three injections (≥5%)
ReactionsCC-JEV(A)
(4g/dose)CC-JEV(B)
(8g/dose)MB-JEV
(17g/dose)n % 95% CI n % 95% CI n % 95% CI
Fever 35 21.5 15.4-28.6 44 28.0 21.2-
35.7 23 14.5 9.4-20.9
Coughing 13 8.0 4.3-13.3 9 5.7 2.7-
10.6 11 6.9 3.5-12.0
Nasaldrainage 11 6.7 3.4-
11.8 11 7.0 3.5-12.2 8 5.0 2.2-
9.7
Rash 9 5.5 2.6-10.2 4 2.5 0.7-
6.4 4 2.5 0.7-6.3
Diarrhea 6 3.7 1.4-7.8 6 3.8 1.4-
8.1 8 5.0 2.2-9.7
Headache 4 2.5 0.7-6.2 4 2.5 0.7-
6.4 8 5.0 2.2-9.7
ENCEVAC
DTaP-Sabin IPVQuatrovac
Collaboration among JPRI, Bikenand Kaketsuken
Biken JPRI KKT
sIPV Trivalent Bulk
DTaP DTaP
DTaP-sIPVDTaP-sIPV Clinical Development
DPaT-sIPV production
Final bulk
Final product (Quatrovac)
AdjuvantedBulk
Diphtheria
Culture
Purification
DT
DT Bulk
Inactivation
Adjuvant
Tetanus
Culture
Purification
TT
TT Bulk
Adjuvant
AdjuvantedBulk
Inactivation
Polio virus
Culture
Purification
Purified polio
MonovalentBulk
Trivalent Bulk
Inactivation
Pertussis
Culture
Purification
FHA BuldPT Bulk
Purified pertussis bulk
PT FHA
Inactivation ホルマリン処理
Kaketsuken JPRI
Phase III clinical study design
Study Design Randomized, double-blinded, and controlled study
Subject Healthy infants and children(3 to <74 months of age)
Number of Subjects DTaP-sIPV: 221Active control: 121
Study Vaccine Test vaccine: DTaP-sIPV (1.5:50:50 DU/dose)Control vaccine: DTaP, OPV
0
100
200
300
0
5
10
15
20
Immunogenicity Ge
omet
ric M
ean
Antib
ody
Tite
rs
0
5
10
15
20
0
100
200
300
Diphtheria Tetanus PT FHA
DTaP-sIPV(primary immunization)
DTaP-sIPV(booster immunization)
DTaP(primary immunization)
DTaP(booster immunization)
18.0
11.9
5.44.36
1.72 0.982 1.32 1.2739.0 39.2
62.0 77.5
196 187
255
305
DTaP-sIPV DTaP DTaP-sIPV DTaP DTaP-sIPV DTaP DTaP-sIPV DTaP
(Comparison of GMTs of DTap antigens)
Antibody to polioGMT (log2)
Type 1 Type 2 Type 3
DTap-IPV
OPV
APre Post
PrimaryPreBooster
PostBooster
Pre Post Primary
PreBooster
PostBooster
Pre Post Primary
PreBooster
PostBooster
Protection
Safety
0
20
40
60
80
100R
ate
of V
acc
ine
-re
late
dA
dve
rse
Eve
nts
(%) DTaP-sIPV
DTaP
74.5
86.4
40.1
60.0 59.9
71.2
38.9 40.8
9.7 7.2
A similar safety profile was confirmed in the Kaketsuken trial.
Conclusions
• DTaP-sIPV vaccine• has similar safety profile to the DTaP vaccine• induced significant neutralizing antibody response
to both Sabin and wild type strains• did not interfere the immunogenicity of the DTaP
components• has been used for a routine immunization without
any trouble in Japan since November, 2012• This is the first approved vaccine containing Sabin
IPV in the world
Cell culture pandemic influenza vaccine
Cell Culture - Pandemic Vaccine Development Project
MDCK33016suspension
SF+suspensionCell MDCK
AdherentEB66
suspensionMDCK
AdherentVero
Adherent
MF59plainAdjuvant AlumAS03 Alum plain
SubunitrHAAntigen Whole virionSubunit Whole
virionWhole virion
VietnamVirus strain IndonesiaIndonesia Indonesia Indonesia
NovartisUMNAstellasCampany Biken Kaketsuken
GSKKitasato
DiichisankyoTakedaBaxter
-DevelopmentStage WithdrawnLicensed Licensed Lisenced
Production Capacity
(within 0.5Y)>50M doses>80M doses >80M doses >50M doses
2nd Subsidy(Million US$)
240240 300 240
1st Subsidy(Billion \) 3.1 3.5 2.63.3
37
KD-295Mixing at the time of use
What is KD-295?
H5N1 A/Indonesia/5/2005 strain
Attenuation(Reverse genetics method)
PR8-IBCDC-RG2 strain
CultureEB66 cells
Inactivation and Purification
HA split(KD-295 antigen)
Adjuvant (AS03)
38
EB66® cells
Embryo collection
ES cells
ImmortalGenetically stable
EB66 cells
Growth in suspensionSerum-free mediumScaleable
Property of Valneva (former Vivalis)
A strain of ducks, specifically selected for its excellent sanitary status and historical traceability, was used to produce eggs in a defined controlled environment. Embryos were then isolated from these freshly led eggs and embryonic stem (ES) cells were specifically extracted from the embryos and expanded in the laboratory. Then, the EB66 cell line has been derived from such duck ES cells using a proprietary process.
EggsDucks
39
Garçon et al. Understanding Modern Vaccines, Perspectives in vaccinology, Vol 1, Elsevier 2011; chapter 4: p89-113
AS03 Adjuvant System in Pre- and Pandemic Flu vaccinesAS03
SqualeneVitamin E: ɑ-tocopherol+ = AS03
Structure: oil in water (emulsion)
Density: close to 1 (water)
Viscosity close to water
Surfactant: Polysorbate 80
Water+ +
40
Conclusion
Immunogenicity
All groups exceeded CHMP criteria after 2 doses
Marked increase of neutralizing antibody after 2 doses was confirmed
Cross-immunity was confirmed
Safety
No incidence of serious adverse events or immune-mediated diseases
Based on frequency and intensity of adverse events, the reactgenicityand safety data obtained up to Day 201 suggest an acceptable safety profile.
Pandemic vaccine production facilities
Vaccination committeeThe MHLW has established a new vaccination and
vaccine committee under the Health Science Council in Apr, 2013Immunization Basic Policy Sub-committeeAdverse Reaction Sub-committeeR & D and Production & Distribution Sub-committeeMR based combined vaccine; MMRVDTaP-IPV based combined vaccine; DTaP-IPV-Hib-Hep BMore efficatious influenza vaccineNoro virus vaccineRSV VaccineVaccine for herpes zoster
Summary• Japan has not always been a leader in vaccine
development• Missing 10 years (1996-2005) led to a “Vaccine
Gap”• The vaccine Industry Vision filled the gap,
however, some new vaccines are still imported • In addition to the development of novel
vaccines, domestic production of all important vaccines is necessary
Collaboration Between Mahidol University and Kaketsuken for The Development of a Novel
Dengue Vaccine
• Kaketsuken entered into a material and technology transfer agreement with Mahidol University in October 2011, for the University’s novel live attenuated dengue vaccine strains and related technology
• After favorable results from a candidate vaccine and preliminary studies, Kaketsuken is planning to enter pre-clinical studies soon