1. a 1 Smallpox Vaccine Downselection National Vaccine Advisory Committee February 4, 2003

2. a 2 Joint HHS / DoD Working Group NVACDSB Georges PeterGeorge Poste Robert DaumDorothy Margolskee Stephen BlackJohn Dingerdissen Richard WhitleyRebecca Devine

3. a 3 Acambis smallpox vaccines Vaccine:ACAM1000ACAM2000 Awarded:September 2000November 2001 Terms:20 yr contract Produce stockpile continuous production. in shortest possible Produce ASAP timeframe Doses:54m (originally 40m)155m Partner:NoBaxter CDC contract 1CDC contract 2

4. a 4 Two contracts, two vaccines

5. Passage history

6. a 6 Cloning rationale >Dryvax® a swarm of virus subpopulations >DNA genome, clonal vaccine will have stable genotype and phenotype >Consistency of manufacture >Removal of adventitious passenger viruses

7. a 7 Comparative evaluation of ACAM1000 and Dryvax® ?Lower  -IFN BP Hrm gene expressionHuman cells SameReplication, plaque morphology Cell culture Same In progress Hind III Restriction map Sequence Genome Same Lower Same Lower Same or higher Same vs. Dryvax® Gene expression (microarray)Human (ex vivo) Neurovirulence Dermovirulence Antibody responses Monkey DermovirulenceRabbit Neurovirulence Replication in brain tissue Antibody, T cell responses Protection vs. challenge Mouse ParameterModel

8. a 8 Pharmacology-toxicology summary >ACAM1000 and ACAM2000 have an acceptable preclinical safety and immunogenicity profile >Both vaccines resemble Dryvax® in their biological characteristics >ACAM1000 and ACAM2000 have similar biological characteristics

9. a 9 Regulatory status 14 ‘Rolling BLA’ 21 Aug 02IND BB-IND #10268 ACAM2000 R&D initiated 1Dec01 2322 Jan 02IND BB-IND #10253 78 Jan 02Master File BB-MF #10227 ACAM1000 R&D initiated 1Oct00 No. amendments Original submission DocumentProduct

10. Clinical trials Q1 2 3 4 Q1 2 3 4 Phase 1 N=100 Phase 2 dose (naïve) N=350 Phase 2 dose (vaccinated) N=350 Phase 3 N=4000 Phase 1 N=100 Phase 2 dose (naïve) N=350 Phase 2 dose (vaccinated) N=350 Phase 3 N=4000 Phase 2 immunology N=90 ACAM1000 ACAM2000 ACAM1000/ 2000 2002 2003

11. Manufacturing overview Cell expansion Seed virusInfection Cell harvest Cell disruption (Microfluidizer) Benzonase digestion Ultrafiltration Diafiltration Dilute to desired potency Fill, lyophilize ACAM1000 P8 ACAM2000 P9

12. a 1212 Current status of manufacture (as of 6-Dec-02) YesNoDeliverable to NPS Licensable productClinical trial material Regulatory status No. doses No. lots 1,200 L bioreactor10 layer NCFsScale FinalPilotProcess ACAM2000ACAM1000

13. a 1313 ACAM2000 product flow

14. a 1414 Current status of manufacture (as of 6-Dec-02) YesNoDeliverable to NPS Licensable productClinical trial material Regulatory status No. doses No. lots 1,200 L bioreactor10 layer NCFsScale FinalPilotProcess ACAM2000ACAM1000

15. a 1515 ACAM1000 scale-up status >Limited to PD on cell expansion with no virus work until ACAM2000 manufacture completed in Jan03 >MRC-5 cells grown at 50L scale with adequate cell density >Successful bead-bead transfer 50L  50L >Planned: scale up 50L  500L >PD on cell harvest from microcarriers in progress >Some equipment (centrifuge, cell separator) not yet in place

16. a 1616 Summary >ACAM1000 and 2000 are equivalent in their preclinical and clinical activities >ACAM1000 and 2000 are similar to Dryvax® in their biological characteristics

17. a 1717 Summary >ACAM2000 is far ahead of ACAM1000 with respect to development and manufacturing –ACAM2000 –bulk fermentation completed –manufactured at scale (~8 m doses finished product/week) –155 m doses kitted/delivered May03 –ACAM1000 –No bulk fermentation until a) completion of ACAM2000 purification and b) ACAM1000 process development for production at scale (Apr03) –54 m doses kitted/delivered Oct03

18. a 1818 Summary >ACAM2000 has minimal risk –ACAM2000 –bulk fermentation completed –GMP production of finished product (multiple lots) –Clinical proof of principle established with lot produced at scale –ACAM1000 –Cell expansion scale up not yet achieved –Virus yields at scale uncertain –No GMP production at scale –Clinical proof of principle established with small-scale pilot lot

19. Options for completion of 155 + 54 m (209 m) doses Option 1 Option 2 Feb04 Jun04 Jun03Apr03 Dec03 Oct03 Apr04

20. Continuous production of ACAM2000 Feb04

21. Risks and benefits Option 1 (ACAM2000) >Bulk vaccine completed >Seamless completion of 54 m additional doses using existing process >Minimal risk >Validation essentially complete >No change-over at Canton and CBL >One Phase III trial ($40 m) >Full stockpile licensed product at least 4 mo. earlier Option 2 (ACAM1000+2000) >No bulk manufactured >MRC-5 scale-up not yet accomplished >Process development required for virus production at scale >Risk of delays >New validation program >Change-over at Canton and CBL >Two Phase II trials ($80 m) >Full stockpile licensed product at least 4 mo. later