Pandemic Influenza Vaccine Development sanofi pasteur R

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Pandemic Influenza Vaccine Developmentsanofi
pasteur RD, 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

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Strategies for the Development of aPandemic
Influenza Vaccine

• Short term (lt 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 RD into new
  vaccine approaches, including cell culture
  technology

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Sanofi Pasteurs 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
Challenge by an Alum-Adjuvanted H5N1 Vaccine in
Cynomolgus 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)
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Virology Results PCR
H5N1- specific TaqMan PCR in pharyngeal swabs
H5N1- specific TaqMan PCR in lungs
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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. 3671657-1664

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Assessments

• Safety
• D0-7 and D21-28 solicited AEs recorded
• Erythema, Swelling, Induration, Ecchymosis gt0cm,
  Pain
• Fever (oral gt37.5C), 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 18)
• Seroneutralization (SN) assay (LLOD 12)
• Statistics
• Descriptive analysis on intent-to-treat population

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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 gt38C
• No severe injection site pain

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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)
• Seroconversionseroprotection
• Presentation of results
• Most relevant assessment criteria
• Distribution of titers i.e., various
  seroconversion thresholds
• Fold-rises

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Immunogenicity Reverse cumulative HI titer
distribution (horse erythrocytes)
D21
D42
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Immunogenicity Reverse cumulative
Seroneutralization (SN) titer distribution
D42
D21
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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 30µgAl induced response in gt60 of
  subjects HI titer gt32 gt2-fold rise in SN titer
• Encouraging immune response seen with lower
  dosages
• gt40 of subjects seropositive (HI test) after two
  doses of 7.5µg, 15µg or 15µgAl
• Adjuvant effect is seen with 30µg HA after the
  2nd dose

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Next Steps sanofi pasteur, France

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

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Sanofi Pasteurs Pandemic Preparedness United
States

• In response to the US Government RFP
• May 2004 production of 8000 doses of a
  monovalent H5N1 vaccine for clinical trials
  sponsored by the NIAID
• September 2004 contract awarded for the supply
  of 2 million doses H5N1 vaccine from industrial
  scale batches
• November 2004 contract awarded to establish and
  maintain flocks of egg-laying hens for the
  manufacture of vaccine at full capacity on a
  year-round basis
• April 2005 contract awarded for the development
  of a cell culture vaccine
• September 2005 H5N1 vaccine stockpile
• Implementation of large scale production

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Sanofi Pasteurs Pandemic Preparedness U.S.A.
A/Vietnam (H5N1) clinical doses (NIH/HHSN266200400
031E) ? Protective dose 90 µg HA/1 ml dose

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

• 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

• 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/Indonesia (H5N1 clade 2) clinical
doses (HHSO100200600023C)
Development
Stockpiling
Contingency
High-Dose H5 clinical doses 30 µg/0.1 ml
intradermal (HHSO100200500004C)
A/Mallard/Netherlands (H7N7) clinical
doses (HHSO100200600023C)

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

Adjuvanted H5 clinical doses Dose-ranging study
of alum adjuvanted vaccine (HHSO100200600021C mod
2)
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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/placeb
  o
• 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

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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