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Pandemic Influenza Vaccine DevelopmentPandemic Influenza Vaccine Development
sanofi pasteur R&D, France
Frederick R. Vogel, Ph.D.
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IntroductionIntroduction
Strategies for the Development of a Pandemic
Influenza Vaccine
Pandemic Influenza Preparednesssanofi pasteur France
Preclinical Results (sanofi pasteur, Erasmus MC)
Clinical Results (sanofi pasteur)
sanofi pasteur United States
Clinical Results (NIAID)
Conclusions
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Strategies for the Development of aStrategies for the Development of a
Pandemic Influenza VaccinePandemic Influenza Vaccine
Short term (< 3 years): to develop as quickly as
possible pandemic vaccines based on existing
technology (Split vaccine/ egg-based technology)
Medium / long term: to improve the performance of
influenza vaccines and encourage R&D into new
vaccine approaches, including cell culture
technology
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Sanofi Pasteur’s Pandemic Preparedness: FranceSanofi Pasteur’s Pandemic Preparedness: France
Research program initiated in 2002
NIAID research grant: Production and testing of egg- and cell-based H5N1 and H7N1 vaccine strains
FLUPAN (EC) contract:
Cell-based H7N1 vaccine production in PER.C6 cells (Crucell NV)
FLUPAN Phase 1 clinical study began in Norway in September 2006
Pilot scale egg-based production of H5N1 vaccines since 2004
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Preclinical: Immunogenicity and Protection from Preclinical: Immunogenicity and Protection from Challenge by an Alum-Adjuvanted H5N1 Vaccine in Challenge by an Alum-Adjuvanted H5N1 Vaccine in
Cynomolgus MacaquesCynomolgus Macaques
C. Ruat1 – C. Caillet1 – J. Simon3 – I. Legastelois1 – F. Pistoor3 – R. Fouchier3 – A. Bidaut2 - A. Osterhaus3
1: sanofi pasteur 2: sanofi-aventis 3: Erasmus MC
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Immunogenicity Results: HI titers (chicken rbcs)Immunogenicity Results: HI titers (chicken rbcs)
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Virology Results: PCRVirology Results: PCR
H5N1- specific TaqMan PCR in lungsH5N1- specific TaqMan PCR in
pharyngeal swabs
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Summary - PreclinicalSummary - Preclinical
An inactivated H5N1 pandemic flu vaccine, at a dose level of 30 µg HA adjuvanted with aluminum hydroxide (600 µg Al) was immunogenic in monkeys.
Immunization with the alum-adjuvanted H5N1 did not induce disease exacerbation when monkeys were challenged with parental viral strain.
Virus titration revealed that the animals receiving the aluminium hydroxide-adjuvanted vaccine were protected from viral challenge.
Protection was also observed with the unadjuvanted vaccine.
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Clinical: H5N1 sanofi pasteur FranceClinical: H5N1 sanofi pasteur France
Design
Randomised, open, multicenter study conducted in France
300 healthy adults, 50/group; 18-40 years old
Six vaccine formulations:
7.5, 15 or 30 µg of hemagglutinin (HA) with or without
aluminium hydroxide adjuvant (Ad)
Two i.m. vaccinations (deltoid), 21 days apart
Objectives
Immunogenicity after each vaccination
Safety profile: within 21 days following each injection
Designed for EU Core Pandemic Dossier
Lancet 2006. 367:1657-1664
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AssessmentsAssessments
SafetyD0-7 and D21-28: solicited AEs recorded
Erythema, Swelling, Induration, Ecchymosis >0cm, Pain Fever (oral >37.5°C), Headache, Malaise, Myalgia, Shivering
D0-42: SAEs and unsolicited AEs recorded
ImmunogenicityD0, 21, D42 assayed by UK HPA (M. Zambon)
Haemagglutination inhibition (HI) using horse erythrocytes (LLOD 1:8)
Seroneutralization (SN) assay (LLOD 1:2)
Statistics Descriptive analysis on intent-to-treat population
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Clinical: ResultsClinical: Results
Population300 subjects completed up to D42
No drop-outs, lost to follow-up or withdrawals
Mean age per group: 24 – 26 years
Male/female per group: 0.8 - 1.9
SafetyNo SAEs D0-42
No fever with oral temp >38°C
No severe injection site pain
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Immunogenicity ResultsImmunogenicity Results
PopulationNaïve pre-vaccination antibody below LLOD, given value of LLOD/2(one positive subject by HI & SN, one borderline by SN only)
Seroconversion=seroprotection
Presentation of resultsMost relevant assessment criteria
Distribution of titers i.e., various seroconversion thresholds
Fold-rises
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Immunogenicity: Reverse cumulative HI titer distribution Immunogenicity: Reverse cumulative HI titer distribution (horse (horse erythrocytes)erythrocytes)
0102030405060708090
100
8 16 32 64 128 256 512 1024HI Titre
%
D42
0102030405060708090
100
8 16 32 64 128 256 512 1024HI Titre
%
D21
7.5µg7.5µg+Al
15µg15µg+Al
30 µg30µg+Al
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0102030405060708090
100
20 40 80 160 320 640SN Titre
%
0102030405060708090
100
20 40 80 160 320 640SN Titre
%
Immunogenicity: Reverse cumulative Seroneutralization Immunogenicity: Reverse cumulative Seroneutralization (SN) titer distribution(SN) titer distribution
7.5µg7.5µg+Al
15µg15µg+Al
30 µg30µg+Al
D21
D42
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Clinical: Key FindingsClinical: Key Findings
H5N1 vaccine is safe and well tolerated
HI and SN results show similar trends
Two doses needed to optimize immune response
Two doses of 30µg+Al induced response in >60% of
subjects: HI titer >32 & >2-fold rise in SN titer
Encouraging immune response seen with lower dosages
>40% of subjects seropositive (HI test) after two doses of:
7.5µg, 15µg or 15µg+Al
Adjuvant effect is seen with 30µg HA after the 2nd dose
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Phase II safety and immunogenicity clinical study
conducted in 2006
Core mock-up dossier preparation and potential
rolling submission
Next Steps: sanofi pasteur, FranceNext Steps: sanofi pasteur, France
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Sanofi Pasteur’s Pandemic Preparedness: U.S.A.Sanofi Pasteur’s Pandemic Preparedness: U.S.A.
A/Vietnam (H5N1) clinical doses
(NIH/HHSN266200400031E) Protective dose: 90 µg
HA/1 ml dose
Acquisition of H5N1 Vaccine (2005)
Build pre-pandemic vaccine stockpile with current strain
(HHS/HHSO100200500004C)1.2m 90 µg doses for DoD3000 30 µg/0.1 ml doses for NIH
A/Mallard/Netherlands (H7N7) clinical doses(HHSO100200600023C)
A/Indonesia (H5N1 clade 2) clinical doses
(HHSO100200600023C)
Acquisition of H5N1 Vaccine (2006 & 2007)
Build pre-pandemic vaccine stockpile with current strain
(HHS/HHSO100200700026I)
Cell-based Preparedness
• Accelerate development of cell-based vaccine
(CDC/HHS200-2005-11758)
Egg-based Preparedness
• Annual clinical doses• Year-round egg supply(CDC/200-2004-10431,
HHSO100200600023C)
High-Dose H5 clinical doses
30 µg/0.1 ml intradermal(HHSO100200500004C)
Adjuvanted H5 clinical dosesDose-ranging study of alum adjuvanted vaccine(HHSO100200600021C mod 2)
Development
Stockpiling
Contingency
H5N1 Vaccine Services
Build 2 million dose pre-pandemic stockpile
(CDC/200-2004-09881, HHSO100200600021C)
90 µg HA/ml, 5 dose vialNIH hyperimmune studyCDC employee protection
2004 2005 20072006
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First clinical study (phase I)
451 healthy adults (18-64 years), 2 injections three weeks apart
Dosage: 90, 45, 15, 7.5ug of hemagglutinin/placebo
Conclusion: A two-dose regimen of 90 µg of subvirion H5N1 vaccine does not cause severe side effects and, in the majority of recipients, generates neutralizing antibody responses typically associated with protection against influenza
N. Engl. J.Med. 2006. 354: 1343-1351
Second clinical study (phase II)Results of aluminum hydroxide adjuvanted H5N1 vaccine trial to be presented by NIAID at the WHO meeting in February 2007
H5N1 Clinical Results: sanofi pasteur US (NIAID)H5N1 Clinical Results: sanofi pasteur US (NIAID)
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For all actors, including public health agencies and vaccine
manufacturers, pandemic influenza vaccine development
poses a challenge and requires strong cooperation
Financial support by national authorities, permanent dialog
and interaction between public health authorities and vaccine
companies, associated with active collaboration with
academic research institutions and biotech companies are
needed to meet such challenge
ConclusionsConclusions