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Pandemic vaccines: development status
Martine Denis
Beijing
Jan 29, 2007
Pandemic vaccine development: an usual framework
Typical diseases justifying
vaccine development
* Well defined pathogen
* Established burden of
disease
* Clear needs in terms of
vaccine indication and
logistics of administration
Pandemic vaccine development: an usual framework
Typical diseases justifying
vaccine development
* Well defined pathogen
Pandemic influenza
* Unknown / unpredictable
influenza virus
* Established burden of
disease
* Disease inexistent as of today,
but could be severe and
affect all pop. worldwide
 Political / economical
considerations
* Clear needs in terms of
vaccine indication and
logistics of administration
* Variable / poorly defined
vaccination strategies
(e.g. stockpiling…)
* Several lessons from the past
(e.g. Spanish flu, swine flu…)
The H5N1 threat
• Epidemiology data:
– Global spread of H5N1 infection in birds and increasing number
of human cases
– H5N1 virus mutating in a way that may make it more infectious
to humans
– Only 2 amino acid changes in the receptor-binding pocket of H5
would yield a virus that efficiently recognizes receptors on
human cells
 The next pandemic may be imminent
Mills et al. PLOS Medicine 2006;3(6):e135
Garten et al. Atlanta: International Conference on Emerging Infectious Diseases; 2006
Harvey et al. J.Virol. 2004;78(1):502-7
The H5N1 threat
• First immunogenicity data:
– Unadjuvanted split inactivated H5N1 vaccine poorly
immunogenic in humans
H5 dose (µg)
% subjects w. titer  1 :40
90
54
45
43
15
22
7.5
9
NEJM 2006; 354:1343-51
The H5N1 threat
• Epidemiology data:
– The next pandemic may be imminent
• First immunogenicity data:
– Unadjuvanted H5N1 vaccine poorly immunogenic
 DEVELOPMENT OF NEW PANDEMIC VACCINES = CRITICAL
 H5N1 used as prototype pandemic strain
Pandemic vaccine development objectives
• A pandemic vaccine:
– Should be producible in volumes matching needs
– Should be safe
– Should be approved by regulatory authorities in
reasonable timeframe
Pandemic vaccine technologicals options
Egg-based
manufacturing
Cell-based
manufacturing
Inactivated
vaccines
Live
vaccines
DNA vaccines;
recombinant
proteins
Pandemic vaccines: clinical development status
Phase II
Phase I
Berna
Virosomes
Med
Immune
LAV
CSL
Whole/
Al
SP
Split /
Al
Baxter
Whole/
Al
Merck
M2
Source: IFPMA R&D table Oct 06
Berna
Whole/
Al
CSL
Split /
Al
Phase III Filed
Japan
Whole /
Al
GSK
Whole/
Al
GSK
Split/
AS
Novartis
Surf Ag/
MF59
Pandemic vaccines and regulatory file submissions
• Regulatory file submission = key step in vaccine
development
– Vaccine composition defined
– Vaccine presentation defined
– Preclinical and clinical data available to support
vaccine safety and immunogenicity
– Manufacturing process defined
– Manufacturing facilities available
Immunogenicity of whole / Alum H5N1 vaccine
Seroprotection rate HI (%)
Adults aged 18-60 years, post dose 2
100
90
80
70
60
50
40
30
20
10
0
CHMP criteria
placebo
1·25 µg
2·5 μg
5 μg
10 μg
H5 dose
Jiangtao Lin, et al. www.thelancet.com
DOI:10.1016/S0140-6736(06)69340-9
Low doses of H5 induce
low levels of antibodies
Immunogenicity of GSK whole / Alum H5N1 vaccine
Adults aged 18-60 years, post dose 2
100
H5N1 3.8
µg
H5N1 3.8 µg
SP with 95% CI
75
H5N1 7.5
H5N1 7.5 µg
H5N1 15 µg
H5N1 15 µg
H5N1 27
H5N1 27 µg
CHMP criteria
50
25
0
Before vaccination
Saenger IVW Vienna Oct 2006
Post second dose
15µg H5 required to pass all
3 CHMP registration criteria
Immunogenicity of split / Alum H5N1 vaccine
Adults aged 18-40 years, post dose 2
90
Seroconversion
GMT
80
70
60
50
40
30
20
10
0
7.5 ug
7.5 ug/Al
15 ug
15 ug/Al
30 ug
30 ug/Al
Treatment (twice at 21 d interval)
Bresson J-L, et al. www.thelancet.com
DOI:10.1016/S0140-6736(06)68656-X
Alum provides modest enhancement
of the antibody response
Immunogenicity of GSK low dose AS adjuvanted H5N1 vaccine
Seroprotection Rate HI (%)
100
75
3.8µg H5
7.5µg H5
15µg H5
30µg H5
Upon formulation with AS,
3.8µg H5 enough to pass all
3 CHMP registration criteria
CHMP criteria
70
50
3.8µg H5 AS
7.5µg H5 AS
15µg H5 AS
30µg H5 AS
25
0
Before vaccination
Borkowski IVW Vienna Oct 2006
Post first dose
Post second dose
106750/NCT:00309634
• Low dose H5N1 vaccine feasible upon
combination with potent adjuvant
–Seasonal: 45µg
12-fold capacity increase
–Pandemic: 3.8µg
• Suitable pandemic vaccine composition
identified
Pandemic vaccine: available too late?
UK model: Epidemic peaks in ~50 days
from the first case (~90-120 days after
initial outbreak)
(Ferguson et al. Nature 2006, April 26)
Pandemic vaccine: available too late?
UK model: Epidemic peaks in ~50 days
from the first case (~90-120 days after
initial outbreak)
(Ferguson et al. Nature 2006, April 26)
Manufaturing
the first lot of
vaccine takes
approximately
3 months
Weeks after the pandemic vaccine strain is made available to GSK
1
Prep’n of Seeds
Process optimization
Bulk manufacture
QC of bulks
Fill and finish
QC and release
2
3
4
5
6
7
8
9
10
11
12
Stockpiling with a pre-pandemic vaccine:
a proactive approach
• A stockpile offers potential for earlier protection
• A pre-pandemic vaccine:
– Should be producible in volumes matching needs
– Should be safe
– Should be approved by regulatory authorities in reasonable
timeframe
– Should induce immunity against drift influenza strains
– Should have a multi-year shelf life
Pre-pandemic vaccine: technological options to induce
immune cross-reactivity
AS
ADJUVANTS
MF59
Whole virus
Alternative
antigens
M2 proteins
GSK AS adjuvanted vaccine cross-protects ferrets in
heterologous H3N2 challenge
IN challenge (Wyoming)
Virus titer (log TCID50/ml)
6
GSK FLU
GSK FLU + AS
Day 2 post challenge
P <0.001
5
4
3
Vaccination
(Panama)
2
1
D+38
D+43
D+44
D+45
D+47
Time
The AS adjuvant is key to induction
of cross-protection in the ferret model
Baras IVW Vienna Oct 2006
Immune cross-reactivity with whole / Alum H5N1 vaccine
Vaccine strain: Vietnam/1203/04 (clade 1)
Testing: microneutralization against
Indonesia/05/05 (clade 2)
N.B. preliminary data
Dose 3.75mcg Al
7.5mcg Al
7.5mcg plain
Day
0
5.9%
5.9%
0%
21
17.6%
17.6%
40.9%
42
35.3%
58.8%
72.7%
Fair levels of cross-neutralization
detected between strains as distant
as Vietnam and Indonesia
Baxter Vaccines IVW Vienna Oct 2006
Pandemic Preparedness Options
World-wide H5N1 Pandemic
Phase 3
Phase 4
Phase 5 Phase 6 : PANDEMIC
Time
1st
dose
Only planning for
manufacturing
during pandemic
2nd
Protection
dose
3-4 weeks
1st
dose
Manufacturing of
prepandemic
vaccine
2nd
dose
Protection
6 months
Manufacturing of
prepandemic
vaccine
1st
dose
2nd
dose
3-4 weeks
Cross
Protection
“3rd”
dose
Direct
Protection
months or years
Pre-Pandemic Vaccine
Pandemic Vacc.
Pandemic / pre-pandemic vaccine development:
a long journey
• A vaccine for pregnant women? Infants?
Immunocompromised?...etc
• Duration of immunity to drift strains? Breadth of
immunity to drift strains?
• How to combine pre-pandemic and pandemic vaccines?
Number of doses? Interval between doses?...etc
• ???
CONCLUSIONS
• Significant progress over the past months: H5N1
pandemic and pre-pandemic vaccine feasibility
established
• Several regulatory files submitted (pandemic and prepandemic); one positive opinion granted by EMEA
• Partnership between manufacturers and health
authorities is key