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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