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