Pandemic Influenza Vaccine Development sanofi pasteur R&D, France

Frederick R. Vogel, Ph.D.

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Introduction

Strategies for the Development of a Pandemic Influenza Vaccine Pandemic Influenza Preparedness sanofi pasteur France

Preclinical Results (sanofi pasteur, Erasmus MC) Clinical Results (sanofi pasteur)

sanofi pasteur United States

Clinical Results (NIAID)

Conclusions 2

Strategies for the Development of a Pandemic 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 3

Sanofi 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

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cells (Crucell NV) FLUPAN Phase 1 clinical study began in Norway in September 2006 Pilot scale egg-based production of H5N1 vaccines since 2004 4

Preclinical: Immunogenicity and Protection from Challenge by an Alum-Adjuvanted H5N1 Vaccine in Cynomolgus Macaques C. Ruat 1 – C. Caillet 1 – J. Simon 3 – I. Legastelois1 – F. Pistoor 3 – R. Fouchier3 – A. Bidaut 2 - A. Osterhaus 3 1: sanofi pasteur 2: sanofi-aventis 3: Erasmus MC 5

Immunogenicity Results: HI titers (chicken rbcs) 6

Virology Results: PCR H5N1- specific TaqMan PCR in pharyngeal swabs H5N1- specific TaqMan PCR in lungs 7

Summary - 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 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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Assessments

Safety D0-7 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 Immunogenicity D0, 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 10

Clinical: Results

Population 300 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

Safety No SAEs D0-42 No fever with oral temp >38 °C No severe injection site pain 11

Immunogenicity Results

Population Naïve 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 results Most relevant assessment criteria Distribution of titers i.e., various seroconversion thresholds Fold-rises 12

Immunogenicity: Reverse cumulative HI titer distribution (horse erythrocytes) %

100 40 30 20 10 0 90 80 70 60 50

%

100 90 80 70 60 50 40 30 20 10 0 8 7.5µg 7.5µg+Al 16 15µg 15µg+Al 30 µg 30µg+Al 32 64 128 256 512 1024

HI Titre

D21 8 16 32 64 128 256 512 1024

HI Titre

D42

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%

100 90 80 70 60 50 40 30 20 10 0 20

Immunogenicity: Reverse cumulative Seroneutralization (SN) titer distribution %

100 90 80 70 60 50 40 30 20 10 0 7.5µg 7.5µg+Al 15µg 15µg+Al 30 µg 30µg+Al 40 80

SN Titre

160 320 20 640 D21 40 80

SN Titre

160 320 640 D42

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Clinical: 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 15

Next Steps: sanofi pasteur, France

Phase II safety and immunogenicity clinical study conducted in 2006 Core mock-up dossier preparation and potential rolling submission 16

Sanofi Pasteur’s Pandemic Preparedness: U.S.A.

Development Stockpiling Contingency A/Vietnam (H5N1) clinical doses (NIH/HHSN266200400031E)

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Protective dose: 90 µg HA/1 ml dose H5N1 Vaccine Services

Build 2 million dose pre pandemic stockpile (CDC/200-2004-09881, HHSO100200600021C)  90 µg HA/ml, 5 dose vial  NIH hyperimmune study  CDC employee protection

Egg-based Preparedness

• Annual clinical doses • Year-round egg supply (CDC/200-2004-10431, HHSO100200600023C)

2004 2005 Cell-based Preparedness

• Accelerate development of cell-based vaccine (CDC/HHS200-2005-11758)

Acquisition of H5N1 Vaccine (2005)

Build pre-pandemic vaccine  stockpile with current strain (HHS/HHSO100200500004C) 1.2m 90 µg doses for DoD  3000 30 µg/0.1 ml doses for NIH

A/Mallard/Netherlands (H7N7) clinical doses

(HHSO100200600023C)

Adjuvanted H5 clinical doses

Dose-ranging study of alum adjuvanted vaccine (HHSO100200600021C mod 2)

2006 Acquisition of H5N1 Vaccine (2006 & 2007)

Build pre-pandemic vaccine stockpile with current strain (HHS/HHSO100200700026I)

A/Indonesia (H5N1 clade 2) clinical doses

(HHSO100200600023C)

High-Dose H5 clinical doses

30 µg/0.1 ml intradermal (HHSO100200500004C)

2007 18

H5N1 Clinical Results: sanofi pasteur US (NIAID)

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 19

Conclusions

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 20