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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