1. Pandemic (H1N1) 2009 Influenza Vaccine Manufacturing Considerations Vaccines and Related Biological Products Advisory Committee (7/23/2009) Jerry P. Weir, Ph.D., Director Division of Viral Products/OVRR/CBER/FDA

2. Emergence of the Pandemic (H1N1) 2009 Virus and Vaccine Recommendation On May 26 2009, WHO released a recommendation for development of vaccines against the pandemic (H1N1) 2009 virus “The majority of the novel influenza A (H1N1) isolates are antigenically and genetically related to the A/California/7/2009 (H1N1)v virus. Should vaccines be prepared against the novel influenza A (H1N1) virus, it is therefore recommended that vaccines contain the following: - An A/California/7/2009 (H1N1)v -like virus”

3. Reference Strains for Pandemic (H1N1) 2009 Vaccine Development Currently available reference strains Classical reassortants - NYMC X-179A & CSL IVR-153 RG reassortants - A/Texas/05/2009-IDCDC-RG15, A/California/07/2009-NIBRG121) and A/California/04/2009 (H1N1)v-PR8-CBER-RG2 The ferret safety testing for X-179A, IVR-153, RG15 and NIBRG121 has been completed. Tests on other reassortants not needed per WHO guidance Reassortants for LAIV produced by manufacturers All reference strains are A/California/7/2009 (H1N1) –like Both classical and reverse genetic reassortants are acceptable for vaccine production

4. Virus Yields from Pandemic (H1N1) 2009 Reference Strains Development work has indicated that existing reference strains have an expected yield of around 30% of H1N1 seasonal vaccine strains Potential reduction in current global vaccine production capacity estimates Manufacturers have expressed a need for better yielding vaccine strains Additional reassortants in preparation, some being derived from other wild type strains (e.g., A/England/195/2009, A/New York/18/2009) Reference strains under development are A/California/7/2009 (H1N1) –like No expectation that significantly better yields will result If higher yielding strains are found, additional clinical trials likely not to be needed

5. Potency Reagents for Pandemic (H1N1) 2009 Influenza Inactivated Vaccines Potency of inactivated influenza vaccines (μg/dose of hemagglutinin (HA) determined by SRID and standardized using reagents supplied by regulatory agencies Reference antiserum is strain-specific Production begins when the new HA is prepared for immunization; high titer antiserum requires multiple injections Pandemic (H1N1) 2009 HA for injection difficult to isolate Reference antigen is inactivated whole virus to which an HA value is determined by the collaborating WHO Essential Reference Laboratories (CBER, NIBSC, TGA, NIID) Production is at industrial scale and requires manufacturers to be in production using a candidate vaccine reference strain

6. Timelines for Availability of Pandemic (H1N1) 2009 Potency Reagents Reference antiserum available from NIBSC (UK) and sent to other WHO ERLs (CBER, TGA, NIID) early July Reference antigen available from TGA (Australia) and sent to other ECLs (NIBSC, CBER, NIID) early July Calibration and assignment of antigen value for the initial reference antigen ongoing Target date – end of July Can be used to evaluate clinical trial material Reference antigen for US manufacturers end of July Will be bridged to TGA antigen by SRID in-house and with small set of collaborating laboratories (not WHO ECL network) Preparation of reference antiserum for US manufacturers underway Specificity and optimization being evaluated

7. Availability of Pandemic (H1N1) 2009 Potency Reagents and the Initiation of Clinical Trials Due to the urgency of the pandemic situation, formulation of vaccine for clinical trials is needed before potency reagent calibration is finalized Flexible approach is being taken to allow the use of alternative methods (e.g., HPLC) for potency determination of initial vaccine lots used in clinical trials Manufacturers will test all vaccine lots by SRID when reference standards become available Vaccine lots will undergo usual testing and lot release procedures

8. Summary Emergence of Pandemic (H1N1) 2009 influenza virus has presented numerous challenges for vaccine manufacturing Some challenges expected as a result of extensive pandemic preparedness planning (e.g., switchover and scale-up; development of reference strains and reagents, biocontainment procedures) Some challenges unique to the Pandemic (H1N1) 2009 influenza virus (e.g., low yields even after reassortant, difficulty in isolation of HA for antiserum production) Extraordinary interaction and cooperation among manufacturers, public health agencies and national regulatory authorities to address difficulties encountered