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EV71 Vaccine Development
Weining Meng
June 9th , 2016
• Epidemic of EV71-associated HFMD
• Development of Sinovac’s EV71 Vaccine, Inlive
• Phase III Trial Design and Outcome
• Industrialization of EV71 Vaccine
• Summary
Outline
EV71-Hand Food Mouth Disease Epidemic
1998, Taiwan, 129106 cases,including 405 critical
cases and 78 deaths, 91% of deaths are children
aged less than 5 years old.
1975,in Bulgaria, 750 children cases, including 149
cases of acute flaccid paralysis and 44 deaths
1997, Malaysia, 2628 cases,average age of 30
deaths is 1.5 years old.
EV71 Epidemic In China
2007-2015,
In total 14 millions HFMD reported,with more than
3,350 fatal cases
《Hand, foot, and mouth disease in China, 2008–12:An epidemiological study》
EV71 EV71 EV71
Total Serious Death
Mild cases:45% are EV71 Serious cases:80% are EV71 Fatal cases:90% are EV71
Serious HFMD epidemic in China;
EV71 inducing main serious and fatal cases;
Vaccine against EV71 is the answer.
83344
488955
1155525
1795336 1638743
2198438
1855547
2819581
2014999
17
126
353
888
506 569
263
508
124
0
100
200
300
400
500
600
700
800
900
1000
2007 2008 2009 2010 2011 2012 2013 2014 2015
0
500000
1000000
1500000
2000000
2500000
3000000
发病数 死亡数
HFMD Reported Cases and Fatal Cases 2007-2015
Reported Cases
Fatal Cases
2008 2009 2010 2011 2012 2013 2014 2015
Preclinical Studies Applied
For Clinical Trials
Clinical Trials
PhaseⅠ PhaseⅡ Phase Ⅲ
2011.05●2011.11●
2013.03●
Commercial Plant
Construction
Applied for Approval
★ 2010.12
Clinical Trial Application Approved
★ 2013.05
Applied for Production Approval
★ 2014.11
CFDA Experts Review
★ 2015.12.30 Approval
GM
P
Insp
ect
ion
Development Milestones
Characters of InliveTM
Vero Cell, cell factory cultivation technology;
H07 strain, C4 genotype, isolated by China CDC;
Inactivation with formaldehyde
Al(OH)3 as adjuvant
100 u/200u/400 u, 2 doses/3 doses regimen
Pre-clinical Studies of Sinovac EV71 Vaccine
Safety
Acute toxicity test
Local stimulation test
Allergy test
Repeated doses toxicity study (rat, cynomolgus monkey)
Immunogenicity
Mice (immune dosage, ED50)
Rats (immunization schedule, longevity of serologic responses)
Protection efficacy (neonatal mice)
Animal model was developed by the University of Sydney
Passive protection model
Female mice 0 day 1 week 2 week 3 week 4 week
Mate & prime boost Give birth
New born mice
MP-26M
EV71 vaccine
Challenge new born mice With 5 days old
Clinical seprated human EV71 strain —Unlethal
Mouse adapted strain MP-26M
Continues passage in brains of one-day-old
BALB/c mice Lethal
Establishment of Animal Model-Neonatal Mice
Inoculation for the mother mice with antigen from 50u-800u at day 0 and 14 could
cause 100% protection for the baby mice which were challenged MP-26M virus at 5 days
after birth.
Cross protection to different genotype has been approved in this animal model
Formalin-inactivated vaccine provokes cross-protective immunity in a mouse model of human entervirus 71 infection, Vaccine 29 2011
EV71 Vaccine Clinical Trails
Phase I
• Objective:Safety, Immunogenicity
• Subjects:Babies, children, and Adult
• Dose:100U、200U、400U
Phase II
• Objective:Immunogenicity, safety
• Subjects:6-35 months babies
• Dose:100U、200U、400U
168 subjects
540 subjects
广西
Phase III
• Objective:Protective effective
• Subjects:6-35 months babies
• Dose:400U
Phase III
• Objective:consistency
• Subjective:6 months-5 years children
• Dose:400U
10077 subjects
1400 subjects
江苏
Multi-center, randomized, double-blinded, placebo-controlled
Immunization Schedule: Day 0, 28
Dosage: 400U/dose
Investigator Jiangsu CDC
Lab Tests Technician
Virus isolation, PCR: National Institutes for Viral Disease Control & Prevention, China CDC
Serum Tests: National Institutes for Food and Drug Control (NIFDC)
Statistician The Fourth Military Medical University
Sponsor Sinovac Biotech Co., Ltd.
Data and Safety Monitoring Board (DSMB): 5 members
Phase III-Clinical Trial Design
National & Jiangsu Provincial HFMD Epidemic Surveillance Data
HFMD Epidemiological Data of 6 counties in Jiangsu (2010)
EV71 Incidence of 6-35Months old Infants ranged 400-2000/100,000
Hypothesis 2: Incidence in the placebo group would be 800/100,000
Hypothesis 1: Vaccine Protection Rate would be 80%
Sample Size:
10,000
Experimental Vaccine Group
5000
Placebo (Control) Group
5000
Surveillance Period: 1 Year
Phase III-Hypotheses & Sample Size Calculation
2012 2013 2014
1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3
Primary Endpoint Efficacy
Secondary Endpoint Safety
Surveillance (1st Year)
Surveillance (2nd Year)
D0 D56 M8 M14 M26
Secondary Endpoint Immunogenicity Immune Persistency
Blood Sampling
Day0 28
Age Experimental Control Total
6-11 Months 1250 1250 2500
12-23 Months 2500 2500 5000
24-35 Months 1250 1250 2500
Total 5000 5000 10000
Immunogenicity Subgroup
Total: 1200
400 subjects from each of the 3 centers
Phase III-Subjects Grouping & Surveillance Design
Reported by subjects’ parents
Clinical symptoms + PCR results ↓
Preliminary diagnosis
Clinically Suspicious Cases
Collect Throat & Anal Swabs
Fluorescence-based Quantitative PCR within 24 hrs
EV Negative Cases
CA16 Positive Cases
Other EV Positive Cases
EV71 Positive Cases
Follow-up Visit within 48 hrs Collect throat & anal swabs, stool &
blood samples for re-check
DSMB Review Symptoms, duration, PCR
results (Virus isolation,
neutralizing antibody test)
Confirmed Cases
Outpatients Information from
Medical Institution Case
Detected
Sampling & Tests
Phase III-Monitoring & Diagnosis of Cases
Primary
Protection rate against EV71-associated disease (80%)
48 EV71-associated HFMD or Herpangina during 1 year of monitoring period
Secondary
Safety Day 0 – 56: incidences of solicited & unsolicited AE Day 57 – Month 14: incidence of SAE
Immunogenicity (Immunogenicity subgroup) In experimental group & control group at day 56: anti-EV71 neutralizing antibody positive rate, GMT, GMI
Immune persistency (Immunogenicity subgroup) In experimental group & control group at M8 & M14: anti-EV71neutralizing antibody positive rate, GMT, GMI
Exploratory Explore the immunological surrogate of protection
Phase III-Endpoints Design
12446 volunteers been screened
2369 were excluded
10077 enrolled & randomly assigned into experimental or control group
Safety Analysis Set: 5044 5044 received 1st dose 4719 received 2nd dose
Safety Analysis Set: 5033 5033 received 1st dose
4711 received 2nd dose
Surveillance & primary efficacy analysis (intention-to-treat/full analysis set, FAS) 5028
Efficacy analysis: per-protocol Set (PPS) 4587
132 discontinued the study
Surveillance & primary efficacy analysis (intention-to-treat/full analysis set, FAS) 5041
132 discontinued the study
325 did not receive 2nd dose
322 did not receive 2nd dose
5 discontinued
Efficacy analysis: per-protocol Set (PPS) 4578
3 discontinued Experimental Group
Control Group
Phase III-Subjects
EV71 Positive Case
119
EV71-associated
99
Other EV71
Positive Cases
20
PCR
Virus isolation
Neutralizing antibody
DSMB Review &
Confirmation
EV71-associated
herpangina cases
4
EV71-associated
HFMD 95
Total
10077 subjects
EV71-associated hospitalized
HFMD
24
EV71-associated severe HFMD
8
Phase III-Surveillance Results (FAS)
Case Classification
FAS
Case Number Incidence Density (%,95%CI) Protection Rate
(%,95%CI) P-value
Experimental Control Experimental Control
EV71 Positive Cases 13 106 0.261 2.175 88.0
(78.6,93.2) <0.0001
EV71-associated diseases
5 94 0.101 1.929 94.8
(87.2,97.9) <0.0001
EV71-associated HFMD 5 90 0.101 1.847 94.6
(86.6,97.8) <0.0001
EV71-associated hospitalized HFMD
0 24 0.000 0.493 100.0
(83.7,100.0) <0.0001
EV71-associated severe HFMD
0 8 0.000 0.164 100.0
(42.6,100.0) 0.0036
Incidence Density Rate (IDR)=(Case Number/Person-year)×100% Protection Rate = (Control Group IDR – Experimental IDR)/ Control Group IDR ×100%
Person-Year: Experimental: 4973.2 Control: 4873.0
The Protection Efficacy of the vaccine reached the designed primary endpoint(80% for the 1st Year Surveillance)
Phase III-Efficacy Results (FAS) 1st Year
EV71 Vaccine-Efficacy
Protection rate for EV71 infection: 94.8%
Protection for hospitalized cases and serious cases:100.0%
5
94
0
10
20
30
40
50
60
70
80
90
100
疫苗组 对照组
病例数 病例数
Effectiveness for EV71 Infection
0
24
0
10
20
30
40
50
60
70
80
90
100
疫苗组 对照组
Protection rate:100.0%
Effectiveness for hospitalized cases
病例数
Protection rate:94.8%
vaccine Control vaccine Control
Efficacy, Safety, and Immunogenicity of an Enterovirus 71 Vaccine in China, The New England Journal of Medicine, 2014
No. of Cases No. of Cases
EV71 Vaccine-Immunogenicity
56 days after vaccination,Neutralizing antibody positive rate 98.79%、GMT 165.79,
8 months and 14 months after vaccination, high level of antibody
Good immunogenicity and immune persistence.
0
20
40
60
80
100
120
140
160
180
GM
T
对照组
疫苗组
Pre-vaccination
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
阳性率
对照组
疫苗组
Positive R
ate
Control
Vaccine
Control
Vaccine
Pre-vaccination
Efficacy, Safety, and Immunogenicity of an Enterovirus 71 Vaccine in China, The New England Journal of Medicine, 2014
0.00 0.00 0.00 0.00 0.00
2.66
0.24 0.08 0.22 0.10 0.04 0.02 0.06 0.02 0.02 0.00 0.02
2.42 0.40 0.12 0.26 0.16 0.08
0.00 0
3
6
9
12
15
触痛 红斑 硬结 肿胀 瘙痒 发热 腹泻 食欲下降 恶心呕吐 烦躁 疲倦乏力 变态反应
局部不良反应 全身不良反应
试验组 N=5044 安慰剂组 N=5033
Incidence of each Grade 3 AE symptom(%)
Pain Redness Induration Swelling Itching Fever Diarrhea Loss Of Appetite Nausea Irritability Fatigue Allergy
Local AE Systemic AE
Experimental Control
5.5 6.7 5.6 3.2 2.1
34.7
12.6 8.4 8.2 7.4 3.4 1.4 5.3 6.7 5.9 2.9 2.2
35.1
12.4 8.6 7.6 6.9 3.5 1.3
0
20
40
60
80
100
触痛 红斑 硬结 肿胀 瘙痒 发热 腹泻 食欲下降 恶心呕吐 烦躁 疲倦乏力 变态反应
局部不良反应 全身不良反应
试验组 N=5044 安慰剂组 N=5033
Incidence of each AE symptom(%) AE Incidence: Experimental(5044):51.7% Control(5033):52.8% not statistically significant (p=0.2905)
Pain Redness Induration Swelling Itching Fever Diarrhea Loss Of Appetite Nausea Irritability Fatigue Allergy Local AE Systemic AE Experimental Control
Phase III-Safety Results
No significant different between vaccine group and placebo group
Objective: to evaluate the lot-to-lot consistency, immunogenicity and safety of this EV71 vaccine candidate
Design: randomized, double-blinded, placebo-controlled
Sample size: 1400 (4 groups with 350 subject per group)
Immunization Schedule: Day0, 28
Immunogenicity indicator: neutralizing antibody level (Day 0, 56)
Safety indicator: systemic AE, local AE, SAE
GMT Logarithmic difference (95% CI)
Criteria Conclusion
Lot 1 vs. Lot 2 0.04 (-0.04~0.12)
-0.176~0.176
Equivalent
Lot 1 vs. Lot 3 0.02(-0.06~0.10) Equivalent
Lot 2 vs. Lot 3 -0.02(-0.10~0.06) Equivalent
Demonstrated Lot-to-lot Consistency
Phase III-Lot to Lot Consistency
Production 19000 m2
4F Ready for use
3F QC Labs
EV71 Bulk 20 million does/year
2F Formulation
Filling & Packaging 100 million doses/year
1F Cold Room 1.8 million vials
Utilities
Others
4000 m2
2F Animal Lab
1F Biobank
Office 9000 m2
Industrialization Total :29,021 ㎡
Built-up area:32,322 ㎡
Quality Control Center
23
EV71 Workshop
Capacity of 20 million does per year
Large scale cells/virus cultivation
• Completed an integral development process of EV71
vaccine
– Pre-clinical trial (protection animal model)
– Clinical trials (94.8% protection rate)
• Built up vaccine production capacity of >20 million
doses/year
• Believe will play a significant role for HFMD control in
China
• Seek collaboration with other organization for HFMD
control in other countries
• Hope WHO could involve more in HFMD control
Summary