Pandemic (H1N1) 2009 Influenza VaccineManufacturing Considerations

Vaccines and Related Biological Products Advisory Committee (7/23/2009) Jerry P. Weir, Ph.D., Director

Division of Viral Products/OVRR/CBER/FDA

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”

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

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

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

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

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

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