Transcript Document

Japanese Encephalitis Purified Inactivated
Virus Vaccine
- Second generation Cell Culture Vaccine
1
Synopsis
• Objective
• Epidemiology
• Currently available vaccines-Comparison
• BE’s Development program
• Product Profile
• Clinical Program
• Conclusion
20-Jul-15
2
Objective

Developing a novel JE Vaccine that is:  As immunogenic as currently available, mouse brain derived vaccines
 Has a better safety profile

Accelerated development by in-licensing
a already licensed
technology from partnership with Intercell-Vienna

To gain IAPCOI recommendation for use in India and other
endemic regions for prevention of JE virus infection
20-Jul-15
3
Epidemiological data
20-Jul-15
4
Comparison between different JE vaccines
(Mouse brain, Live (PHK) and Vero cell based )
Strain
Substrate
Formulation
Licensed
Inactivated
(Biken)
Live attenuated
(Chinese)
Nakayama, Beijing-1
Mouse brain
SA14-14-2
Primary hamster kidney
(PHK) cells
Lyophilized
Lyophilized
1954 – Japan
1993 – US
Worldwide: traveller vaccine
Geographic
SE Asia – childhood
use
Administration Subcutaneous
0.5 mL-children
Dosage
1.0 mL-adults
Booster
Efficacy
Protection
Safety
20-Jul-15
At one year & every 3 years
91% – 2 dose
Antibody levels > or = 1:10
Rare cases of urticaria,
angioedema, dyspnea, acute
encaphalo-myelitis
1988 – China
China, India
Inactivated
Intercell and Bio E)
IXIARO/ JEEV
SA14-14-2
Vero Cells (Monkey Kidney
cells
Liquid
Licensed* in USA, Australia,
Canada & many other
countries
Traveller vaccine
Subcutaneous
0.5 mL-children
1.0 mL-adults
IM
0.25 mL-children (in progress)
0.5 mL-adults
At 6 years
80% – 1 dose
97.5% – 2 dose
Antibody levels > or = 1:10
Few serious adverse event
reported
Studies on going
96 % – 2 dose in adult
95.7% -2 dose in children
Antibody levels > or = 1:10
lower rate of Adverse Events.
5
Vaccine – Live Versus Killed
Inactivated
Live attenuated
• These were the easiest preparations to use.
• Prepared from attenuated strains
• The preparation are simply inactivated.
• They multiply in the human host and provide
• The microbe structure is intact but the replicative
continuous antigenic stimulation.
Potential safety problems
• Under attenuation
• Mutation leading to reversion to virulence
• Preparation instability
• Contaminating viruses in cultured cells
• Heat liability
• Should not be given to immunocompromized or
pregnant patients
function is destroyed.
• Preparation of killed vaccines may take the route of
heat or chemicals.
• - Appropriate for use in all populations, including
immunocompromised
Potential safety problems
• Incomplete inactivation
• Increased risk of allergic reactions due to large
amounts of antigen involved
Feature
Live
Inactivated
Dose
Low
High
No. of dose
Single ( mostly used as 2 doses)
Two or more
Need for Adjuvant
No
Yes
Duration of immunity
long
Short
Antibody Response
IgG
IgA, IgG
CMI
Good
Poor
Reversion to Virulence
Possible
Not possible
20-Jul-15
6
Introduction of JE Vaccine (JeeV™)
- Through Partnership

To Achieve accelerated development & Introduction of vaccine: 
Biological E Ltd. partnered in 2005 with Intercell Biomedical Ltd, Scotland, UK
for the technology transfer, marketing & distribution of its Japanese
Encephalitis Vaccine.

BE received the technical knowhow
vaccine through technology transfer.
from Intercell for manufacturing JE
Technology transfer involves use of same Raw material, standard manufacturing and analytical
procedures, scale of production, specification for in process, final bulk and finished product and
acceptance criteria between sites (Biological E and Intercell)
20-Jul-15
7
JE Vaccine (JeeV™) - Profile

Second generation vaccine based on attenuated JEV strain SA14-14-2;
 Vaccine produced on Vero cells, purified, inactivated and alum
adjuvanted -a classical, well-proven approach to vaccine development

No gelatin stabilizers

Thimerosal-free formulation

2-dose immunization schedule

Liquid format to be supplied in Glass vials
20-Jul-15
8
JE vaccine(JeeV™) – Batch Description
Batch Parameters
Capacity
Batch size
180 roller bottles
Average yield / batch
30 Liters
No. of batches manufactured till date
12
No. of filled lots
07 +03
No. Batches released by NRA
07+ 03
Product presentation
In Glass Vial ( each vial contains 0.5 mL of
Vaccine
(without preservative)
Immunizing Dose
20-Jul-15
Adult :0.5 mL i.e. one dose per vial
Pediatric: - 0.25 mL i.e. two dose per vial
9
JE Vaccine(JeeV™) – Pre-Clinical studies
A repeat dose toxicity study was conducted in rats to evaluate safety and
immunogenicity of JE-PIV vaccine candidate.
• Study was performed at
• Three dose level (3mg, 6mg and 12 mg )
• Three (1,14, 28 day) dose schedule
Observation/ Outcome
• Clinical observations: - No mortality and major clinical signs observed.
• No Major differences in Hematology, serum biochemistry, organ weights, and
gross pathology between treated and control group were seen on day 29 and
day 43.
• Anti-JEV neutralizing antibodies were found in Sera of all animals in PRNT
assay
In conclusion repeated exposure of JE Vaccine (BE) exerted no toxic effect
in Rats and was found to be immunogenic.
20-Jul-15
10
Immunogenicity – JEEV specific PRNT50
IMMUNOLOGICAL INDICATOR OF EFFICACY
» Efficacy trials of a new JE vaccine not feasible because of
ethical issues related to availability of existing JEV vaccines
» Licensure of IXIARO based on immunogenicity criteria (noninferiority versus JE-VAX)
» Indicator of Efficacy: PRNT50 ≥ 1:10 (Serum dilution giving a
50% reduction in a Plaque Reduction Neutralization Test)
» WHO Expert Panel accepts PRNT50 ≥ 1:10 as protective
(Hombach 2005)
Hombach et al
2005. Vaccine
23; 2005:
5205-5211
11
20-Jul-15
* Placebo
vaccine:
Phosphatebuffered saline
solution with
0.1% Al(OH)3
1 Tauber E,
Lancet 2007;
370: 1847-53
2 Tauber E,
Journal of
Infectious
Diseases 2008;
198: 493-9
3 Schuller E,
Vaccine 2008;
12; 26(34):
4382-6
4 Schuller E,
Vaccine 2009;
27 (15): 218893
5 DubischarKastner et al,
Vaccine 2010;
28: 5197–5202
6 Kaltenboeck
A, Vaccine
2009; 27: 44834489
7 Eder S,
Vaccine 2011;
29: 2607–2612
20-Jul-15
JE vaccine - Different Clinical studies at Intercell(ICB) –
Overview of Clinical Program
» 5,557 subjects exposed to IXIARO(Intercell) clinical Trials
(for licensure in US,EU and Australia)
IXIARO
(N)
Control
(N)
428
437
Trial
Objective
IC51-3011
Pivotal Immunogenicity vs JE-VAX®
IC51-3022
Pivotal Safety vs Placebo* control vaccine
2,012
663
IC51-3033
Long-term Safety and Immunogenicity Follow-up
2,283
181
975
82
IC51-3044
Immune Response Kinetics
374
0
IC51-3055
Long-term Persistence of Immunity and Effect of a
Booster Dose
356
0
IC51-3086
Concomitant Vaccination - HAVRIX®
127
65
IC51-3117
Persistence of Immunity after Booster Dose
198
0
IC51-323
phase-III safety and immunogenicity study (3-18yrs)
1409
458
12
JE Vaccine(JeeV™) –Phase 1 clinical study
• In 2010 BE conducted phase-I clinical study in adults to demonstrate safety of the vaccine
manufactured at our facility in Hyderabad
•
Clinical study was performed on Healthy subjects with the vaccine manufactured at BE
Title
A single center open label phase-I study to evaluate the safety and reactogenicity of BE’s
inactivated JE vaccine in ≥18 to <49 year old healthy adult male subjects.
Study
Subjects enrolled
Study Site (s)
Schedule
Dose
Duration
Phase I (Adult)
20 healthy male;  18 to < 49 years
Single; D.Y.Patil Hospital, Pune, India
2 dose (0.5 mL); Day 0 and 28
6mcg /0.5 mL
56 days
Conclusions
 JE vaccine, given intramuscularly [6µg/0.5mL dose] to healthy adult male volunteers
 Vaccine well tolerated at all administration times, and had an impressive low reactogenicity profile.
 Study provided evidence of both safety and reactogenicity of this vaccine administered in healthy adults in
two dose schedule (0 and 28th day).
 This study cleared the path for administering vaccine to the target population of children between ≥1 to <3
years of age.
13
20-Jul-15
Phase II- Clinical study
DOSE CONFIRMATION
Study Conclusions
 JE vaccine (IC51) showed an appealing safety and
Population
• 60 healthy children ≥1 to<3 years of age
• 1 Site in M.S.Ramaiah Hospital, Bangalore, India
Treatment Groups
• IC51- 0.5 mL: 2 Injections, Days 0/28, i.m.
• IC51 0.25 mL: 2 Injections, Days 0/28, i.m.
• JenceVacTM: 0.5 mL, 3 Injections, Days 0/7/28, sc
Schedule
immunogenicity profile at 6 and 3 mcg dose.
 Similar
safety and immunogenicity
treatment arms
 The neutralizing antibody response
results
all
three
 at day 28 was 65.2%, 71.4%, & 63.6%
 at day 56 was 95.7%, 95.2% & 90.9%.
 Both IC51 groups appeared to have a lower rate of Adverse
IC51 0.5 mL, DAYS 0/28, i.m.
24 subjects
IC51 0.25 mL, DAYS 0/28, i.m.
24 subjects
JenceVac TM: 0.5 mL, DAYS 0/7/28, s.c.
12 subjects
GMT and SCR Day 56
Safety Day 56
20-Jul-15
Pediatric (IC)- at BE
Events compared to JenceVacTM.
Study provided support to use of the 3 mcg – dose in
children below 3 years of age for further development of
the vaccine pediatric programs
14
JE Vaccine(JeeV™) – Overview Phase II/III
A multicentric open label randomized controlled phase-II/III study to evaluate
safety and immunogenicity of JE vaccine in Healthy ≥1 to <3 year old Indian
children.
Sample size: -
456 subjects in 2:1 ratio ( 304:152)
Study centre: -
N=57 / centre x 8 centres
Test Vaccine: -
BE’s JE-PIV (JEEV®)
Comparator Vaccine: -
GCC Korea mouse brain inactivated vaccine
Immunization Schedule: -
JEEV® - two injections D 0 and 28
Comparator – three injections D 0,7 and 28
SCR of Control: -
90.9% in ≥1 to <3 yr old healthy children
Expected SCR of JEEV®: -
90% in ≥1 to <3 yr old healthy children.
Power & Dropout allocation:
90% ; 15%
20-Jul-15
15
JE Phase-II/III Study – Objectives
Primary Objectives
As the study is clinical Phase 2/3 study part
1 of the study was Phase 2 and part 2 of the
study was Phase 3
Secondary Objectives [Phase III (part-2)]
 To compare proportion of subjects  Sero-conversion (PRNT50 ≥ 1:10) at day 28
 Achieving 4-fold rise in anti-JEV N antibody
titres at Day 28 and Day 56.
A) Phase II (part-1)
• To assess safety and reactogenicity of
JEEV® after first dose
administration
(3mg/0.25mL) in 35% of healthy ≥1 to <3
year old children at day 7
 To
compare
GMTs
for
anti-JEV
neutralizing antibody titres of JEEV® with
that of a licensed vaccine (control) at day
28 and day 56
 To assess the safety and tolerability of
•
B) Phase III (part-2)
• To demonstrate non-inferiority of JEEV®
with a licensed JE vaccine (control) in
terms of difference in proportion of
subjects
achieving
sero-conversion
(PRNT50 ≥ 1:10) at day 56.
20-Jul-15
JEEV® in comparison with a licensed
vaccine (control) for a period of 56 days
after the first vaccination.
 To assess possible clinically significant
changes in safety parameters in both
vaccine groups.
16
SCRs at Screening, Day 28 & Day 56
20-Jul-15
17
GMTs at Screening, Day 28 & Day 56
GMT= Geometric Mean Titer
20-Jul-15
18
Overview of Related Adverse Events
Related Adverse Events
20-Jul-15
Un-related Adverse Events
19
JE Vaccine JeeV™ – Overview Phase IV Study
(BECT019)
An Open label multi-centric parallel randomized phase-IV non-inferiority
study to evaluate the immunogenicity and safety of BE’s Inactivated vero
cell based Japanese Encephalitis Vaccine in ≥18 to ≤49 year old adult
subjects in a two dose schedule in comparison with a licensed vero-cell
culture derived Inactivated JE vaccine.
Sample size:
162 subjects in 2:1 ratio (108:54)
Study centre:
N=54 / centre x 3 centres
Test Vaccine:
JEEV™ Vaccine (BE)
Comparator Vaccine:
IXIARO® Vaccine (Intercell)
20-Jul-15
20
SCR at Baseline, Day 28 & Day 56 (ITT)
Component
JEEV
IXIARO
n1
n2
p-value
LCL
UCL
Remarks
Proportions
(PP)
99.07%
98.15%
108
54
0.6149
-2.68%
4.53%
Non-inferiority
Demonstrated
21
NI & Geometric Mean Fold Rise in Titres
Availability of Clinical Data in ≥2M to <18 years old children and adolescents
» Data from a nested dose-finding run-in phase in children aged ≥3 - <12 years
confirmed the use of full adult dose (6µg/0.5mL) for children ≥3 years of age,
adolescents and adults (Sub group n=200; 1:1) (Intercell Philippines study)
» A Large pivotal phase-III safety and immunogenicity study in ≥2M to <18 years
was completed in Philippines in March, 2012 (Intercell).
 Three study centers with N=1869 total enrolment
 An Open Label, Randomized, Active controlled, Phase 3 Study
 Targeted Age group was ≥2 months to <18 years
20-Jul-15
23
IC51-323 – Safety & Immunogenicity Summary
Efficacy Conclusions:
• The vaccine was highly immunogenic in both the doses (3µg/0.25mL & 6µg/0.5mL)
tested in Pediatric & adolescent population.
• The most appropriate IC51 dose for children ≥3 to <12 yrs was determined to be
0.5mL based on the safety profile and statistically significant higher GMT compared
to 0.25mL dose.
• SCR >99% of children receiving age appropriate dose.
• SCRs ranged between 100% - 85.5% depending on age by dose group.
• GMTs higher in younger children and in ≥12 to <18 yrs. were comparable to levels
typically seen in adults.
• Pre-existing JEV antibodies appear to lead a better persistence of antibodies at
month 7.
Safety Conclusions:
1. All reported AEs up to Day 56 were similar across age groups. No related SAEs
were reported.
2. Solicited local AEs – Pain, itching, tenderness, Hardening, swelling & redness.
3. Solicited systemic AEs – Irritability, nausea, vomiting, diarrhoea, flu-like symptoms,
excessive fatigue, muscle pain, rash, Headache, loss of appetite, fever. (bold=most
frequently reported)
4. The vaccine was found to be safe and well tolerated in ≥2M to <18 yrs.
20-Jul-15
24
SUMMARY -JE Clinical Studies at BE
BECT007 (BE-IC)
IC51 Phase-II
Study
BECT013
JEEV Phase-1
Study
BECT018
JEEV Phase-2/3
Study
Ped. dose confirmation
Adult Safety (FIA*)
Safety & Non-inferiority
1
1
8 (57/site)
Study Status
Completed
Completed
Ongoing
Comparator
JenceVac™ (Shanta)
Nil
GCC-JE Vaccine
Sample Size
N=60 (2:2:1) (24:24:12)
N=20 (single arm)
N=456 (2:1) (304:152)
IC51 - 3µg/0.25mL (Gr-1) IC51
- 6µg/0.5mL (Gr.-2)
JenceVac™ - 0.5mL(Gr-3)
JEEV™ 6µg/0.5mL (0 & 28D)
JEEV™ 3µg/0.25mL (Gr-1)
GCC-JE=0.5mL(Gr-2)
≥1 to <3 yrs
≥18 to <49 yrs
≥1 to <3 yrs
3µg/0.25mL=95.7% (200.9)
6µg/0.5mL=95.2% (218.1)
NA
92.42%
Jencevac=90.9% (230.3)
NA
98.58
3µg is preferred dose
Safety established
Safety and non inferiority
established
Particulars
Type of Study
No. of Study Sites
Dose
IC51/JEEV = i.m. (0,28)
GCC-JE = s.c. (0,7,28)
Target Group
SPR of test Vaccine
SPR of Control
Vaccine
Results
FIA*=First In Adult
20-Jul-15
25
SUMMARY -JE Clinical Studies at BE
BECT019 –
JE Phase-IV Adult NI Study
BECT021 JE Phase-IV Adult Safety &
Tolerability Study
Type of Study
Open Label Phase-IV adult
non-Inferiority Study
Open label Phase-IV Adult Safety & Tolerability
Study
Target Group
Adults of either gender - ≥18 to ≤49 yrs
Adults of either gender - ≥18 to ≤49 yrs
Sample Size
162
(2:1) (108:54)
[SPR 96.4%-T Vs. 96.4%-C]
432
(Assumption-58.9% of subjects with at least 1
TEAE based on IC51-302 results
3 (54/site)
8 (54/site)
Feb, 2012 to April, 2012
Yet to start
IXIARO® Vaccine
Single arm – No comparator
JEEV® 6µg/0.5mL (Gr-1) i.m.
IXIARO® 6µg/0.5mL (Gr-2) i.m.
JEEV® 6µg/0.5mL i.m.
Particulars
No. of Study Sites
Study Duration
Comparator
Dose
Blood Sample; Lab Tests
End Point/Outcome
Duration of Study
Status
20-Jul-15
2 times (at 0 & 56D) for Hematology,
Biochemistry & Urinalysis;
3 times for PRNT
SCRs [PRNT50 (1:10)]
GMTs, 4-fold, NI, All AEs
56 Days (-4/+7 Time Window);
No. of Visits-4
Completed
(CSR Released on 15th Sept, 2012)
Only Vital signs & AE tracking
All AEs, SAEs, TEAEs & Vitals
56 Days (-4/+7 Time Window);
No. of Visits-4
Ongoing
26
Conclusion
• Jeev® is Purified, in-activated, safe and efficacious
vaccine manufactured in India by using proven cell
culture technology platform.
• Technology
transfer using USFDA and
approved technology/product.
EMEA
• Large data base supporting safety/efficacy in human
population globally including endemic regions.
20-Jul-15
27
We seek your recommendation for Use
of Inactivated JE Vaccines as well in
making our country proud for an unmet medical need of this vaccine for
endemic region!!!
20-Jul-15
28
29