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Each 0.5 mL dose is formulated to contain 10 6.5-7.5 TCID 50 (median tissue culture infectious dose) of live attenuated influenza virus reassortants of the strains recommended by the U.S. Public Health Service (USPHS) for the 2005-2006 season: A/New Caledonia/20/99 (H1N1), A/California/7/2004 (H3N2), and B/Jiangsu/10/2003 (B/Shanghai/361/2002like) [1]. These strains are (a) antigenically representative of influenza viruses that may circulate in humans during the 2005-2006 influenza season; (b) cold-adapted (ca) (i.e., they replicate efficiently at 25°C, a temperature that is restrictive for replication of many wildtype viruses); (c) temperature-sensitive (ts) (i.e., they are restricted in replication at 37°C (Type B strains) or 39°C (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently); and (d) attenuated (att) so as not to produce classic influenza-like illness in the ferret model of human influenza infection. The cumulative effect of the antigenic properties and the ca, ts, and att phenotype is that the attenuated vaccine viruses nasopharynx to replicate in the induce protective

• Influenza Vaccine Information Center
Novartis has successfully completed production of the first batch of the Influenza A(H1N1) vaccine using the wild virus strain. We are also close to completing manufacture of the first vaccine batch using the reassortant seed — the modified virus provided by the US Centers for Disease Control and Prevention (CDC) to vaccine manufacturers in May — at our state of the art cell-culture production facility in Marburg, Germany. Based on the success with the wild type strain production, Novartis expects to be able to achieve rapid manufacture and scale up of A(H1N1) vaccine production using cell-based and the reassortant seed. We are using both cell-based vaccine

production in Marburg, which is faster, and our egg-based manufacturing in Liverpool, UK and Siena, Italy to increase the likelihood of the greatest possible supply. Novartis continues to work alongside the World Health Organization (WHO), US CDC, Pan American Health Organizations (PAHO), and other government agencies worldwide, as well as the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on developing a strong and effective response to the A(H1N1) flu pandemic. The health and welfare of people, including Novartis associates and their families, is of paramount importance. Novartis, in line with its efforts for pandemic preparedness and ensuring business continuity, has put in place actions to ensure the protection associates in the affected areas. of its

immunity. Each of the three influenza virus strains contained in FluMist is a genetic reassortant of a Master Donor Virus (MDV) and a wild-type influenza virus. The MDVs (A/Ann Arbor/6/60 and B/Ann Arbor/1/66) were developed by serial passage at sequentially lower temperatures in specific pathogen-free (SPF) primary chick kidney cells [2]. During this process, the MDVs acquired the ca, ts and att phenotype and multiple mutations in the gene segments that encode viral proteins other than the surface glycoproteins. The individual contribution of the genetic sequences of the six non-glycoprotein MDV genes ("internal gene segments") to the ca, ts, and att phenotype is not completely understood. However, for the Type A MDV, at least five genetic loci in

Influenza Virus




Intranasal (FluMist®) is a live trivalent nasally administered vaccine intended for active immunization for the prevention of influenza.

three different internal gene segments contribute to the ts and att phenotype. For the Type B MDV, at least three genetic loci in two different internal gene segments contribute to both the ts and att properties; two additional genetic loci in a third gene segment also contribute to

the att property. No evidence of reversion has been observed in the recovered vaccine strains that have been tested (135 of possible 250 recovered isolates) (see TRANSMISSION ) [3, 4]. For each of the three strains in FluMist, the six internal gene segments responsible for ca , ts , and att phenotypes are derived from the MDV, and the two segments that encode the two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are derived from the corresponding antigenically relevant wild-type influenza viruses that have been recommended by the USPHS for inclusion in the annual vaccine formulation. Thus, the three viruses contained in FluMist maintain the replication characteristics and phenotypic properties of the MDV and express the HA and NA of wild-type viruses that are related to strains expected to circulate during the 2005-2006 influenza season. Viral harvests used in the production of FluMist are produced by inoculating each of the three reassortant viruses into specific pathogen-free (SPF) eggs that are incubated to allow for vaccine allantoic virus replication. The fluid of these eggs is





approximately 1 µg/mL. Later steps of the manufacturing process do not use gentamicin, resulting in a diluted residual concentration in the final product of <0.015 µg/mL (limit of detection of the assay). FluMist does not contain any preservatives. Each pre-filled FluMist sprayer contains a single 0.5 mL dose. The tip attached to the sprayer is equipped with a one-way valve that produces a fine mist that is primarily deposited in the nose and nasopharynx. When thawed for administration, FluMist is a colorless to pale yellow liquid and is clear to slightly cloudy (see DOSAGE AND ADMINISTRATION ).

Manufactured and Marketed by: MedImmune Vaccines, Inc.

Gaithersburg, MD 20878 MedImmune Vaccines, Inc. A SUBSIDIARY OF MEDIMMUNE, INC.

harvested, clarified by centrifugation, and stabilized with buffer containing sucrose, potassium phosphate, and monosodium glutamate (0.47 mg/dose). Each lot of viral harvest is tested for ca, ts, and att and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. Viral harvests from the three strains (H1N1, H3N2, and B) are subsequently blended and diluted as required to desired potency with allantoic fluid derived from uninfected SPF eggs and/or diluted stabilizing buffer (same composition as above) to produce trivalent bulk vaccine. The bulk vaccine is then filled directly into individual sprayers for nasal administration. These sprayers are labeled and stored at </= -15°C. Gentamicin sulfate is added early in the manufacturing process during preparation of reassortant viruses at