Status: replaced by liquid formulation.

Organizations involved:

MedImmune Vaccines, Inc. – Manuf.

MedImmune, Inc. – R&D; Tech.; World mark.; Parent

AstraZeneca plc –Parent

Henry Schein, Inc. – USA mark.

Wyeth Pharmaceuticals – World mark.; Former

Aviron, Inc. – R&D; Tech.; Former

National Institute of Allergy and Infectious Diseases (NIAID), NIH – R&D; Tech.

University of Michigan – R&D; Tech.

Medeva Pharma, Ltd. – Manuf.; Former

Becton Dickinson & Co. – Manuf. other

Packaging Coordinators, Inc. – Manuf. other

CSL Ltd. – Asia mark.

Cross ref.: See the Influenza Virus Vaccine Products entry (#470) in the Vaccine Products section, and the entry below for CAIV-T, a newer non-frozen/refrigerator-stable version of FluMist which recently replaced this original frozen formulation.

MedImmune switched to manufacture of the new CAIV-T formulation of this product in early 2007 (see the entry below), to have this new vaccine available for the 2007/8 influenza season.

Description: Influenza Virus Vaccine, Live, Intranasal or FluMist is an aqueous nasal spray trivalent formulation of natural recombinant (reassortment; not gene spliced) cold-adapted temperature-sensitive attenuated nonpathogenic live influenza viruses having immunogenic viral coat proteins (hemagglutinin and neuraminidase) from representative virulent epidemic wild-type influenza strains and an influenza virus core with six attenuating gene mutations. The gene mutations result in influenza strains that are: a) cold-adapted (ca), i.e., they replicate efficiently at 25°C, a temperature that is restrictive for replication of many wild-type influenza viruses; (b) temperature-sensitive (ts), i.e., they are highly restricted in replication at 37 °C (Type B strains) and 39 °C (Type A strains), temperatures (at or above human core body temperature) at which many wild-type influenza viruses grow efficiently; and (c) attenuated (att) so as not to produce classical influenza-like illness. The modified viruses’ cold adaptation and temperature sensitivity allow the viruses to replicate (for manufacture) at room temperature and in the nasal passages and upper respiratory tract (cooler than core body temperature), while the viruses do not replicate or replicate poorly at higher core body temperature in the lower respiratory tract (thus, not causing disease).

FluMist is administered by intranasal large particle mist (60 µm average diameter droplets; 0.25 mL into each nostril). FluMist contains approximately 107 TCID50 of each of the selected influenza virus strains per 0.5 mL dose in a diluent of normal allantoic fluid (NAF; from chicken eggs) also containing sucrose-phosphate-glutamate (SPG). FluMist contains no thimerosal (mercury-based antimicrobial preservative), unlike all other marketed influenza vaccines.

The modified influenza virus strains are generated by a natural reassortment (recombination) process, not modern high-tech recombinant methods, e.g., involving use of restriction enzymes, co-expression of a marker gene to allow selection of desired recombinant organisms, etc.. Reassortment relies on the natural ability of the segmented influenza virus RNA genome, which contains RNA polymerases that lack sequence proofreading/editing functions, to recombine when different strains replicate in culture. This process mimics natural reassortment/recombination in animals, particularly pigs and humans, which ultimately results in influenza virus antigenic drift and periodic generation of new pathogenic strains. The reassortants are then screened and viruses with the desired phenotypes (and gene sequences) are isolated. For each of the three strains in FluMist, the six internal gene segments responsible for the cold adaptation (ca), temperature sensitivity (ts), and attenuated (att) phenotypes are derived from the Master Donor Virus (MDV), and the two gene segments that encode the immunogenic influenza virus surface proteins, hemagglutinin (HA) and neuraminidase (NA), are derived from Master Seed Viruses (MSVs) derived from wild-type influenza viruses recommended by the CDC and FDA for inclusion in each year’s vaccine formulation. Thus, the three viruses contained in FluMist maintain the replication characteristics and phenotypic properties of the MDVs but express the primary immunogens, HA and NA, of the three representative wild-type influenza virus A and/or B strains that are expected to circulate during the upcoming influenza season.

Like conventional injected vaccines containing inactivated virus, the virus reassortants are manufactured (cultured) in specific pathogen-free (SPF) chicken eggs using the three virus strains with NA and HA antigens representative of the main influenza A and/or B strains expected to be epidemic in the upcoming flu season. The current first-generation product, FluMist, must be stored frozen. A second generation liquid product. CAIV-T, requiring only refrigeration is in development (see entry below).

FluMist is supplied as a single-use, pre-filled intranasal spray device in 10-sprayer packages. Each pre-filled FluMist sprayer contains a single 0.5 mL dose and is delivered as a fine mist. The spray device has a teflon tip with a one way valve that produces a large-particle aerosol that is deposited in the nose and nasopharynx. The tip of the sprayer is inserted just inside the nose and the plunger is depressed to spray the first half of the dose. The dose-divider clip is then removed from the plunger of the sprayer to administer the second half of the dose into the other nostril. In actual use, approximately half of the dose from a FluMist sprayer (0.25 mL) is administered into each nostril while the recipient is in an upright position.

FluMist is stored frozen at -15 °C (5 °F) prior to use. FluMist is thawed immediately prior to administration by holding the sprayer in the palm of the hand. Alternatively, FluMist may be thawed in a refrigerator and stored at 2-8 °C (36-46 °F) for no more than 24 hours prior to use.

Nomenclature: Influenza Vaccine, live rDNA, frozen [BIO]; FluMist [TR]; Influenza Virus Vaccine Live, Intranasal [FDA]; Influenza Virus Vaccine, Trivalent A & B Live, Cold Adapted [FDA; used prior to approval]

Biological.: The recombinant cold-adapted/temperature-sensitive influenza virus strains have a viral coat presenting influenza virus hemagglutinin (HA) and neuraminidase (NA) immunogenic epitopes from a virulent influenza strain along with an attenuated influenza virus core. The HA and NA RNA sequences of an attenuated “master donor” virus (MDV) are replaced with HA and NA RNA sequences from epidemic wild-type influenza strains. Temperature sensitivity is conferred to the MDV by modification of the polymerase Basic Protein 2 (PB2) gene, which encodes a 759 amino acid polypeptide that is one of the three proteins comprising the RNA-dependent polymerase complex of influenza virus. Viral RNA replication is dependent on PB2 (along with PB1, PA, and NP). The three polymerase proteins, PB1, PB2, and PA, form a trimolecular complex in the nuclei of infected cells.

Influenza A viruses have a single-stranded negative-sense RNA genome composed of eight segments that encode three polymerase proteins (PB1, PB2, PA); four membrane-associated proteins [hemagglutinin (HA); neuraminidase (NA), membrane (M) protein, M2 protein]; nucleocapsid protein (NP); nonstructural protein (NS1); nuclear export protein (NEP); and PB1-PB2 protein (for influenza A viruses). Influenza B viruses are similarly composed, except the NA gene also encodes another protein, NB, and the M gene does not encode M2 protein. Protective immunity, both humoral and cellular, in humans is primarily associated with the HA and NA proteins, and vaccines must be adapted to include HA and NA identical or sufficiently similar to (cross-reactive with) the HA and NA antigens of pathogenic strains in circulation each influenza season. The segmentation of or compartmentalization of the influenza virus genome permits the exchange of viral genes (segments) between viruses infecting the same cell (co-infection). This reassortment or recombination does not occur between influenza A and B type viruses, so two Master Donor Viruses (MDVs) are needed for reassortment vaccines–one to attenuate influenza A H1N1 and H3H2 viruses and one for influenza B viruses.

The two FluMist MDVs developed decades ago (Maassab, et al.) used influenza A/AA/6/60 (H2N2) cold adapted (ca) for influenza A-type strain attenuation and influenza B/AA/1/66 ca for influenza B-type strain attenuation. Influenza A/AA/6/60 (H2N2) ca MDVwas originally generated by adaptation to cold temperatures by multiple passages (repeated culturing cycles) of influenza A/AA/6/60 (H2N2) at progressively lower temperatures in primary chicken kidney cle (PCKC) cells for 23 passages, plaquing at 25˚C for passages 24-30, and three amplifications in embryonated egg culture (E). This provided the type A MDV –influenza A/AA/6/60 ca (PCKC30, E3) with ts (temperature sensitivity), ca (cold adapted), and att (attenuation in ferrets) phenotypes. This MDV has four to five genes that independently contribute to attenuation, two ts mutations (PB1 and PB2), and 2-3 non-ts mutations (PA, NP, M), which contribute to cold adaptation (ca). Influenza B/AA/1/66 ca was similarly generated (Maassab, et al.) by adaptation to colder temperatures by six passages in PCKC, seven plaque passages in PCKC at 25˚C and three amplifications in eggs, providing the influenza B-type MDV – influenza B/AA/1/66 ca (PCKC13, E3), similarly expressing ts, ca, and att phenotypes. These two MDVs have been used to generate trivalent, cold adapted influenza vaccine (CAIV-T) vaccines with 6/2 segment reassortments that have been studied and tested in humans for over 25 years.

Attenuated influenza virus vaccine strains are developed by co-infecting host cells with a live recombinant influenza variant, i.e., the master donor containing temperature-sensitive and other attenuating mutations, and a target epidemic wild-type virus strain. Reassortant viruses are harvested and screened for the presence of the desired mutations, i.e., viruses with genomes containing attenuating mutation(s) but retaining the viral envelope of the wild-type strains, including wild-type hemagglutinin (HA) and neuraminidase (NA) epitopes. Reassortants containing the wild-type HA and/or NA proteins are selected using antibodies against these surface epitopes from the wild-type donor virus. Resultant viral progeny retaining the master donor core with viral coat from the wild-type epidemic influenza strains are used for vaccine preparation. Updated vaccine strains, e.g., reflecting each year’s recommended strains, can be produced by modification of the viral coat components of the recombinant viruses to include the viral coat (including HA and NA antigens) from that year’s expected epidemic strains.

The genetic stability of FluMist viruses has been examined in four clinical studies. FluMist vaccine viruses were shown genetically stable and retained their cold-adapted, temperature-sensitive, and attenuated phenotype during replication in young children. Limited sequence alterations occurred in the vaccine strains. An average of 2 nucleotide differences/genome in the approximately 14 kilobase viral genome were detected among the clinical virus isolates. If attenuating mutations were limited to one or two nucleotide changes, the virus composition could ultimately “revert” or back mutate in the host and regain its original pathogenic phenotype. However, successive passage (repeated culturing) of virus at increasingly lower temperatures has resulted in the “cold-adapted” reassortant viruses with multiple mutations that have been shown to be genetically stable, with the HA and NA RNA sequences of the attenuated master donor virus replaced with HA and NA RNA sequences from circulating influenza strains. The temperature sensitive (ts) mutants of influenza, e.g., ts1A2, do not replicate in the lower respiratory tract of infected animals and often replicate in the upper respiratory tract to a lower level than wild-type virus. The ts1A2 strain contains temperature sensitive lesions in both PB1 and PB2 genes.

See “Principles Underlying the Development and Use of Live Attenuated Cold-Adapted Influenza A and B Virus Vaccines,” by B.R. Murphy (NIAID) and K. Coelingh (MedImmune), Viral Immunology, 15(2), p. 295-323.

Companies.: Development of attenuated influenza virus for intranasal vaccines began before modern recombinant DNA methods were available. Dr. H.F. Maassab, University of Michigan, and collaborators developed methods for attenuating influenza A virus for live intranasal vaccines starting in the early 1970s, e.g., see Maassab, et al., Fed. Proc., 30:413, 1971; and Proc. Soc. Exp. Biol. and Med., 139:768, March 1972. This involved producing temperature-sensitive mutants by culturing virus at low temperature. Temperature-sensitivity and attenuating mutations were transferred from the attenuated strain to wild-type virus by genetic reassortment, i.e., natural recombination involving co-culture of the attenuated and wild-type viruses. Live attenuated influenza viruses were developed and tested in clinical trials conducted by the National Institute of Allergy and Infectious Diseases (NIAID), NIH, starting in 1975, well before Wyeth (or later Aviron) began commercial development.

Wyeth-Ayerst, now Wyeth, was the original commercial developer of FluMist-like reassortant virus vaccines from 1991-1993 in collaboration with the National Institute of Allergy and Infection Diseases (NIAID), National Institutes of Health. Wyeth took a license from NIH in 1989, with NIAID/NIH conducting trials at the time. But the company abandoned this effort. The Chemo-Sero-Therapeutic Research Institute (Kaketsuken) licensed certain rights to the vaccine in 1993 from NIH, and was developing the vaccine in Japan but, like Lederle/Wyeth, it returned the rights to the NIAID (in 1996). As described more fully below, Aviron (later MedImmune, into which Aviron later merged) continued commercial development and marketing of FluMist in collaboration with Wyeth, but Wyeth returned all rights to MedImmune in April 2004 after the dismal launch of FluMist in the 2003-2004 flue season. MedImmune will continue to manufacture and market FluMist, with manufacturing levels and sales expected to be comparable to those of the 2003-2004, while concentrating on development of CAIV-T (refrigerator-stable formulation), with this expected to enter the market for the 2007-2008 flu season.

Aviron, Inc. assumed development of FluMist, and entered into a Collaborative Research and Development Agreement (CRADA) with NIAID for clinical trials in 1995. Aviron was acquired by MedImmune, Inc. in January 2002, and became MedImmune Vaccines, Inc. MedImmune was acquired by AstraZeneca plc in April 2007.

MedImmune Vaccines, Inc., Mountain View, CA (CBER/FDA est. no. 1652), manufactures components of FluMist, including live influenza virus strains, within its own facilities at a site acquired from Evans Vaccines Ltd. (later a subsidiary of PowderJect, FDA CBER est. no. 1262, in Speke, U.K., near Liverpool. Final filling and packaging of the product is performed by MedImmune within the facilities of Packaging Coordinators, Inc. (Philadelphia, PA). Medeva Pharma Ltd. (also known as Evans Vaccines) had manufactured vaccines used in many of FluMist’s earlier clinical trials.

Wyeth-Ayerst, then a subsidiary of American Home Products Corp. (AHP), now Wyeth), was originally Aviron’s, then MedImmune’s, partner in the development and marketing of FluMist. In Jan. 1999, Aviron signed a worldwide agreement with Wyeth Lederle Vaccines for the development, manufacturing, distribution, marketing, promotion, and sale of FluMist. MedImmune and Wyeth co-promote FluMist in the U.S. Wyeth held exclusive marketing rights to FluMist outside of the U.S. (excluding Korea, Australia, New Zealand and some South Pacific countries). Wyeth was to distribute FluMist and record all product sales. MedImmune received approximately 50% of FluMist revenues. These payments were higher in the U.S. than internationally. Aviron/MedImmune received cash payments of $15 million for the initial licensing, $15 million upon acceptance of the BLA by FDA, and $20 million upon FDA approval. Wyeth also paid Aviron/MedImmune for other development and regulatory milestones. Wyeth held marketing rights for an initial term of seven years from the first commercial sale of FluMist in the U.S., and an initial term of eight years from the first commercial sale of FluMist outside the U.S., with an option to extend its rights both in the U.S. and internationally for an additional four years. Extending both U.S. and international rights would trigger payments to MedImmune in excess of $140 million. The original agreement included a commitment by Wyeth to provide up to $40 million in financing for Aviron, a portion of which was contingent upon regulatory approval and the remaining part to come from purchase of future securities offerings. The total potential value for the license fees, milestones, financing support, and term extension options that Aviron/MedImmune could receive from Wyeth exceeded $400 million. Aviron/MedImmune also received on the order of 50% of product revenues from Wyeth, in the form of transfer payments and royalties which increase at higher sales levels. MedImmune was responsible for manufacture of the first-generation frozen formulation (FluMist). Both MedImmune and Wyeth each had rights to manufacture the second-generation liquid product then in development.

MedImmune has licensed CSL Ltd. exclusive development and marketing rights in Korea, Australia, New Zealand, and certain South Pacific countries.

Aviron’s/MedImmune’s original partner for contractor manufacture of bulk reassortant viruses and NAF diluent during much of FluMist’s development had been Medeva Pharma, Ltd., which became Evans Vaccines Ltd. (subsidiary of PowderJect Pharmaceuticals plc), which was acquired by Chiron Corp. (Chiron Vaccines), which merged into Novartis AG in late 2005. Until MedImmune established its own facilities at the Speke site, leased (from Chiron/Evans/PowderJect), Chiron/Evans/PowderJect had been the only vaccine manufacturer in the U.K., and manufactures its own conventional influenza vaccine for the U.S. market. Medeva was acquired by Celltech plc, and Celltech subsequently divested the company to PowderJect Pharmaceuticals plc, which was acquired by Chiron, which was acquired by Novartis. Medeva began manufacturing FluMist at Speke for use in clinical trials in 1995. Formal collaboration between Medeva and Aviron for manufacture of FluMist began in 1997. Medeva received $1 million upon execution of their manufacturing agreement, was to receive specified payments for supplying vaccine components on a price-per-dose basis, and was to receive up to $40 million from a combination of milestone payments, facility usage fees and other payments over the course of the agreement. Medeva would also receive additional milestone payments for meeting quantity-based production targets in the later years of the contract.

In Oct. 2000, after the PowderJect acquisition of Medeva, the manufacturing arrangement between Medeva (then Evans) and Aviron (now MedImmune) for bulk production of monovalent vaccines and normal allantoic fluid (NAF) diluent was renegotiated, and Aviron/MedImmune obtained full control over bulk manufacture of its product. A dedicated leased production unit within Evans’ facility was leased to Aviron, which staffed it with its own employees (many transferred from Medeva). This agreement runs through June 2006. Aviron made initial payments to Evans/PowderJect totaling $15 million, and was to pay $4 million annually for five years. PowderJect also receives performance-based milestone payments of up to $3 million over the period of the agreement and company stock. PowderJect expected that revenues under this new agreement would be higher than under the original agreement. MedImmune (after acquisition of Aviron) also acquired the remaining 24 years of a 25-year lease from Celltech Group plc of ~8 acres of land in Speke, U.K., and has used an existing 45,000 square foot structure on this property to build a new FluMist/CAIV-T manufacturing facility.

MedImmune’s Speke facilities include a leased bulk manufacturing facility that used for manufacture of FluMist by MedImmune (and originally by Evans/Medeva for manufacture of injectable influenza vaccine); and a new influenza vaccine manufacturing facility built by MedImmune and approved by FDA for FluMist manufacture in late 2005, with manufacturing starting in 2006. The preexisting leased bulk production plant in Speke can produce up to 18-20 million bulk doses per season. The new plant has a capacity of up to 15 million bulk doses per month or about 90 million doses per influenza manufacturing season, with 10-times the square footage of the existing facility and has larger testing and storage facilities. Construction and validation of MedImmune facility were substantially completed in spring 2005. Until regulatory approval of this new bulk facility, MedImmune continued bulk production of FluMist at the nearby leased facility. The new facility could also be used to produce vaccine year round in the event of an influenza pandemic. The square footage of the new facility is 10 times larger than MedImmune’s existing bulk manufacturing facility in Speke. The facility uses a new filtration process, which is expected to provide greater sterility assurance during bulk production. MedImmune’s existing blend/fill/finish vaccine production facility in Philadelphia, PA, within Packaging Coordinators, Inc., has undergone improvements and modifications to increase finished product capacity to about 35 million doses per influenza season.

On April 26, 2004, after the dismal launch of FluMist, Wyeth returned to MedImmune all rights to FluMist, CAIV-T and other cold-adapted influenza vaccines. Wyeth received an upfront payment from MedImmune, and will receive unspecified milestone payments and royalties for its involvement in FluMist and cold-adapted vaccines development. MedImmune expects the severance of ties with Wyeth will cost the company $105 million in 2004. MedImmune wrote off a $73 million loss; acquired a Wyeth distribution center in Louisville, KY, all clinical trials data and some manufacturing materials; and Wyeth provides some manufacturing services during a transition period expected to last through much of 2004. With its gaining of full rights to FluMist and CAIV-T, MedImmune announced it would continue to manufacture and market FluMist, with sales expected to be comparable to 2003-2004 season sales, while concentrating on development of CAIV-T, which it expects to be available for the 2007-2008 flu season. MedImmune also paid $30 million to acquire in-process research and development. A month earlier, Wyeth announced it was closing its Marietta, PA, vaccine manufacturing facility, which had been producing clinical supplies of CAIV-T (a task which MedImmune will assume).

In June 2004, MedImmune selected Henry Schein, Inc. (including its Caligor Medical and General Injectables & Vaccines (GIV) subsidiaries) to be the exclusive U.S. distributor of FluMist for the 2004-5 flu season. MedImmune will oversee all sales and marketing activities with special emphasis on pediatricians and pharmacies. In addition to selling FluMist (to pharmacies and physicians at $23.50/dose), Henry Schein will respond to customer product inquiries, process returns, and promote the product through marketing initiatives to primary care physicians.

MedImmune has a supply agreement with Becton Dickinson and Co. for supply of its AccuSpray nasal spray delivery system for use with FluMist, with provisions to expand production capacity to 50 million units annually.

Specific pathogen-free (SPF) eggs for viral culture are obtained from Specific Pathogen-Free Avian Supply, a division of Charles River Laboratories, Inc.

In May 2006, MedImmune received a $169 million, 5-year grant from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, to develop expanded manufacturing capacity for cell culture manufacture of its influenza vaccines (primarily CAIV-T; see entry below). This, along with company support, will fund conversion of a current company plant in Frederick, MD, for manufacture of 150 million doses in six months.

In June 2007, MedImmune, was awarded a $55.1 million contract from the U.S. Department of Health and Human Services (DHHS) to retrofit its U.S.-based (original Aviron plant in CA) vaccine manufacturing facilities to produce pandemic influenza vaccines using FluMist influenza vaccine technology. Under the cost-sharing portion of the contract, MedImmune will contribute approximately $14 million to the retrofitting. The upgrading of these facilities will “provide warm-base manufacturing operations to help the government rapidly respond to vaccine manufacturing needs in the event of a pandemic,” i.e., facilitate rapid domestic manufacture of FluMist containing pandemic (e.g, influenza H5N1) infleunza strains, if needed

In April 2007, AstraZeneca plc acquired MedImmune for over $15 billion.     

Manufacture: The Master Donor Viruses (MDVs) used (influenza virus A/Ann Arbor/6/60 and B/Ann Arbor/1/66) for FluMist were originally developed by Maassab et al. using serial passage at sequentially lower temperatures in specific pathogen-free (SPF) primary chick kidney cells. See Maassab, et al., Adaptation and Growth Characteristics of Influenza Virus at 25˚C, Nature, Feb. 11, 1960, p 612-614, and Maassab, et a.., Biologic and Immunologic Characteristics of Cold-Adapted Influenza Virus, Journal of Immunology, Vol. 102, No. 3, 1969, pages 728-732. During this process, the MDVs acquired mutations in six gene segments encoding internal viral proteins. These mutations conferred cold adaptation (ca), temperature sensitivity (ts), and nonpathogenic attenuated (att) phenotypes. The resulting Master Virus Seed (MVS) strains are reassortant viruses containing six genes of the cold-adapted (ca), temperature-sensitive (ts) attenuated Master Donor Virus (MDV) and two genes, the HA and NA genes, from the selected wild-type isolate, and are referred to as 6:2 reassortants. Maximal attenuation of the MVS is achieved when all six internal genes from the MDV are present. However, individual genes confer significant attenuating properties. Therefore, it is theoretically possible that a mutation (reversion to pathogenic wild-type) in one or more of the genes would not result in pathogenic virus.

Each year, after the CDC’s and FDA’s annual selection of the influenza virus strains to be included in the subsequent season’s vaccine, the master virus seeds (MVSs) are created for large scale production. Each of the three MVSs contained in FluMist is produced annually by genetic reassortment of a wild-type influenza virus (selected as a target for vaccines the upcoming flu season) and a Master Donor Virus (MDV), i.e., the wild-type and attenuated MDV viruses undergo natural genetic recombination (their RNA sequences recombine) as they both replicate in culture. This first step is conducted at MedImmune Vaccine’s Mountain View, CA, facility, and generally takes 4-12 weeks. The cold-adapted MVSs may be cultured using large-scale in vitro methods. This may facilitate quicker scale-up and manufacture of larger quantities of seed virus for subsequent egg inoculation.

The modified influenza virus strains are each cultured in chicken hen eggs, much the same as other influenza vaccines (See the Influenza Vaccine Products entry, #470). Each of the three reassortant viruses is inoculated into specific pathogen-free (SPF) eggs that are incubated to allow for virus replication. The allantoic fluid of the eggs containing high virus titers is harvested, clarified by centrifugation, and stabilized with a buffer containing sucrose, potassium phosphate, and monosodium glutamate (SPG). These steps are performed at the company’s leased facility in Speke, England (on the site of Evans Vaccines). The vaccine’s diluent, which is normal allantoic fluid (“NAF”), is also produced in bulk at this facility. The harvested bulk vaccine strains and NAF are frozen and shipped to Aviron’s leased Philadelphia, PA, facility within Packaging Coordinators, Inc.

The bulk quantities of the vaccine strains from the three strains are then blended and diluted (using NAF) to produce trivalent bulk vaccine. The bulk vaccine is then filled into intranasal spray devices, labeled, and frozen stored at <15 °C.

Gentamicin sulfate is added early in the manufacturing process to prepare reassortant viruses, at which time residual gentamicin is present at a calculated concentration of approximately 1 µg/mL. Later steps of the manufacturing process do not use gentamicin, so that with subsequent dilution the residual concentration in the final product is <0.015 µg/mL (limit of detection of the assay).

Each lot of viral harvest is tested for attenuation in ferrets and is also tested extensively by a battery of in vitro and in vivo methods for the presence of adventitious agents. Attenuation (nonpathogenicity) can be tested in animals, but the current animal models, primarily the ferret model, are imperfect for predicting events in humans.

Each MVS safety profile is evaluated in a clinical trial in adults to provide additional safety data prior to release of the trivalent vaccine. The trial design ensures that the MVS vaccine virus has sufficient attenuation in humans, as demonstrated by low incidence of fever over 101˚F (oral). In clinical trials with FluMist in adults, the rate of fever in vaccine and placebo recipients has been similar, e.g., about 0.6%. Similar rates of fever in MVS and placebo recipients are expected in trials evaluating each new MVS, provided there is no significant loss of attenuation. Performing these clinical trials is part of CBER lot release requirements for all new modified MVSs (until more experience has been gained with FluMist).

MedImmune had capacity for manufacture of 6 million doses for the 2003-2004 flu season, expected to produce this amount for this first marketing season, and expected to increase capacity in subsequent years.

FDA class: Biologic BLA

indications: [annual BLA supplements for manufacture of new formulations for each influenza season are not included]

Date =200030617; BLA; Indications: = for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age

Date = 20031231; BLA supplement; Indication = approval of storage in a frost-free freezer without using the provided FluMist FreezeBox (for vaccine purchased after this date)

Date = 20041002; BLA supplement; Indication = storage of FluMist vaccine in conventional frost-free freezers without use of company-supplied a “FreezeBox” (freezer insert) for the for the current 2004-2005 flu season

Date = 20050318; BLA supplement; Indication = approval of changes to the previously approved 2004-2005 labeling (package insert)

Date = 20051227; BLA supplement; Indication = approval of manufacture at new facilities in Speke, U.K.

Date = 20060706: BLA supplement; Indication =approval of use of reverse genetics (plasmid rescue) to produce seasonal strains

Date = 20070105; BLA supplement; Indication = convert from the frozen formulation to a liquid formulation [Note, this and other FluMist approvals carry over to the current liquid formulation of FluMist (see entry below).

indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 4/2005]:

FOR NASAL ADMINISTRATION ONLY

FluMist is indicated for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age.

FluMist is not indicated for immunization of individuals less than 5 years of age, or 50 years of age and older, or for therapy of influenza, nor will it protect against infections and illness caused by infectious agents other than influenza A or B viruses.

Status: Aviron submitted its original Product License Application (PLA)/Establishment License Application (ELA) to the FDA on June 30, 1998. However, in Sept. 1998, the FDA issued a non-fileable (refusal-to-file) letter which raised questions about manufacturing and lot-to-lot consistency of the vaccine (then manufactured by Medeva). Aviron subsequently had to delay its FDA filing for about a year, missing out on potentially marketing the product during the 2000-2001 flu season Compliance issues included inadequate validation of utility systems in the manufacturing facilities (not with basic manufacturing aspects of the vaccine). These issues were resolved.

Aviron (re)filed its BLA for FluMist on Oct. 31, 2000, and it was accepted for review on Dec. 29, 2000. The filing was for prevention of influenza in healthy children and healthy adults (no restrictions to high-risk groups). With efficacy and safety demonstrated in multiple clinical trials, it was hoped that FDA would act quickly, perhaps granting FluMist approval in time to be launched for the 2001-2002 influenza season. FDA issued “complete response” letters requesting further information, to which MedImmune replied in August 2001 and July 2002.

This BLA requested approval for use in the age range from 12 months to 64 years of age. The proposed age range was revised on March 15, 2002 to 19 months to 64 years of age, and on November 1, 2002 was revised to 5 years through 64 years of age. The original BLA also sought approval for travelers to areas with circulating influenza viruses, but this was removed.

On Dec. 17, 2002, the FDA’s Vaccines and Related Biological Products Advisory Committee recommended approval to prevent influenza in healthy children, adolescents and adults ages 5 through 49 (but not in those below age five or ages 50-64, the main groups at risk and targeted for influenza vaccination). The panel voted in favor of the product’s safety in the 50-64-year age group, but indicated that data on efficacy in the 50-to-64-year age group were inadequate. Prior to the committee meeting, MedImmune had modified its BLA to remove use in patients age 50 and under, removing many safety concerns and problems likely to further hold up approval. The modified BLA requested two dosing regimens : for the first influenza vaccine use in children 60 months through 8 years, two 0.5 ml doses given at least one month apart; for those previously immunized against influenza and for individuals 9 years through 64 years of age, one 0.5 mL dose.

On Jan. 30, 2003, MedImmune received a “complete response” letter that requested no additional trials and asked only five questions. MedImmune quickly responded. Approval appears likely by or in the second quarter of 2003 for use in persons age 5-49. In Feb. 2003, the company reported that it expects that it will take at least two years to complete trials supporting extension of the age range to include elderly (>64 years of age) persons.

Full FDA approval, with expected limitations on use based on age (current indications:), was granted on June 17, 2003; approval time = ~3.8 years).

FluMist has not been approved in the European Union or other countries, i.e, it is only approved in the U.S.

In Sept. 2005, MedImmune submitted a supplemental Biologics License Application (sBLA) to the FDA for approval to use CAIV-T, its refrigerator- stable liquid formulation of FluMist, in preventing influenza in healthy individuals 5 to 49 years of age. CAIV-T is treated by this book as a different product than FluMist. See the entry below for CAIV-T.

In Oct. 2004, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention’s (CDC), voted to include FluMist in the federal government’s Vaccines for Children (VFC) program as an alternative to the injectable flu vaccine beginning with the 2005-2006 influenza season. Healthy children ages 5 to 18 years who meet the eligibility requirements of the VFC program (enrolled in Medicaid) may receive FluMist at no cost next season. However, with CDC and federal vaccine programs short of funds (budget reductions), CDC may be expected to favor purchase of conventional injected vaccine for the VFC and other federal vaccine programs.

On Dec. 27, 2005, FDA granted approval for manufacture of FluMist at MedImmune’s newly-constructed Speke, U.K., site. Because FluMist is sold only in the U.S., the facility does not require British regulatory approvals (other than for export). This facility will manufacture CAIV-T after its approval and it replaces FluMist.

On July 6, 2006, FDA approved a sBLA allowing the use of reverse genetics technology to construct new vaccine strains to produce FluMist (Influenza Virus Vaccine Live, Intranasal) and CAIV-T (see entry below). This now applies primarily to the new liquid formulation of FluMist (see entry below), This will enable MedImmune to replace cumbersome seasonal vaccine strain development methods that were created in the 1960s with modern reverse genetics technology. This is expected to be used/useful to accelerate the availability FluMist/CAIV-T in case of an influenza pandemic, and has been used for the development of seed virus used for manufacture of influenza virus H5N1 (pandemic influenza; bird flu) vaccines the company currently has in early trials.

Tech. transfer: In 1991, Wyeth-Ayerst Pharmaceuticals, then a subsidiary of American Home Products Corp., licensed recombinant cold adapted live intranasal influenza vaccine technology from the National Institute of Allergy and Infectious Diseases (NIAID; Bethesda, MD), National Institutes of Health (NIH). The company sponsored some clinical trials, but relinquished its rights back to NIH in 1993.

In Feb. 1995, Aviron entered into a materials and technology transfer agreement with the University of Michigan. Aviron received exclusive worldwide rights related to the cold-adapted influenza vaccines and proprietary master donor strains (MDSs) of influenza viruses developed by Dr. H.F. Maassab. The university received warrants to purchase company stock. With the acquisition of Aviron by MedImmune, these rights were exchanged for warrants to purchase 419,250 shares of MedImmune common stock, plus an additional 5,150 shares upon FluMist approval. The university does not receive royalties.

In March 1995, Aviron entered into a Collaborative Research and Development Agreement (CRADA) with NIAID to conduct clinical trials with FluMist. In June 2000, Aviron extended the CRADA through June 2003. As a part of this agreement, Aviron obtained exclusive rights to data generated from previous clinical trials conducted by NIH and Wyeth.

Aviron nonexclusively licensed recombinant influenza virus attenuating technology from NIAID, NIH, in September 1994, particularly NIAID inventions involving the introduction of temperature-sensitive polymerase basic protein (PB1 and PB2) gene mutations into influenza virus genome transcripts and transfer of these into wild-type strains. Licensed inventions included those by Dr. B. Murphy, et al., NIAID, involving methods for the introduction of attenuating mutations in the PB2 gene of influenza A virus, e.g., U.S. patent application 08/481,631, filed June 7, 1995. Mutations for temperature-sensitivity are introduced by site-directed mutagenesis at specific sites into cDNA copies of the influenza PB2 gene. An RNA transcript of the mutant PB2 gene is recovered into infectious influenza A virus using a host range restricted helper virus. The attenuating mutant PB2 gene can be transferred into new variants of wild influenza A virus, enabling rapid attenuation of epidemic virus strains for vaccine use. Modifications of this method enable controlled introduction of mutations into influenza A virus polymerase basic protein 1 (PB1) genes; polymerase acidic protein (PA) genes; nuclear protein (NP) genes; membrane protein (M) genes; and non-structural protein (NS) genes.

U.S. patent 3,992,522, “Temperature-sensitive recombinant mutant viruses and a process for producing same,” by R.M. Chanock and B.R. Murphy (both with NIAID), granted November 16, 1976, is assigned to the National Institutes of Health. This describes development of temperature sensitive (ts) recombinant (recombination from co-culture of strains in host cells) influenza viruses by chemical mutation, involving culture of virus in the presence of 5-fluorouracil (5-FU).

Aviron (MedImmune) has received U.S. patents including 5,690,937 and 6,090,391. These concern methods for mutating influenza virus PB2 genes for temperature sensitivity. The patents describe substitution of nonnative amino acid residues for native tryptophan residues that affect cap binding activity of PB2, e.g., in the region spanning amino acid residues 537 through 575 of PB2 protein.

MedImmune, Inc. has licensed patents and effectively controls “reverse genetics” (plasmid rescue) technology for generating influenza vaccine strains from pathogenic strains. This involves converting the RNA virus to its corresponding DNA sequence, deleting genes associated with pathogenicity, and converting the DNA back to an RNA virus clone, e.g., for large-scale egg culture and vaccine manufacture. This approach may provide a rapid method for generating culturable virus strains retaining their original HA, NA and other other epitopes. This technology has not yet been tested in clinical trials, although there has been some discussion that this method might be needed in case of a serious influenza pandemic. When used to produce pandemic influenza vaccine seeds, reverse genetics has the added benefit of enabling removal of potentially pathogenic portions of the virus. For pandemic vaccines, reverse genetics does not require vaccine manufacturers to work directly with the infectious pandemic strain, rather only segments of its genome. This technology is now being used by most companies manufacturing and the U.S. government in their development of pandemic vaccines, and other companies manufacturing pandemic influenza vaccines using reverse genetics will have to take licenses from MedImmune, which the company has already indicated will be readily accessible. MedImmune has already given the World Health Organization (WHO, UN) a nonexclusive license to develop and distribute reverse genetics-based vaccines in a pandemic situation; and may eventually apply this technology to annual reformulation of FluMist/CAIV-T.

In Dec. 2005, MedImmune further extended its reverse genetics portfolio by acquiring exclusive worldwide rights to certain intellectual property owned by Mount Sinai School of Medicine for reverse genetics, including U.S. patents 6,544,785 and 6,649,372. Mount Sinai received an upfront fee, and will receive milestone payments and royalties on future product sales. With this MedImmune owns or has exclusively licensed intellectual property concerning influenza virus reverse genetics including the Mount Sinai School of Medicine Plasmid Rescue Portfolio (WO 01/04333); MedImmune Fundamental Reverse Genetics Portfolio (WO 91/03552); Wisconsin Alumni Research Foundation (WARF) Plasmid Rescue Portfolio (WO 00/60050); and St. Jude Children’s Research Hospital Dual Promoter Plasmid Rescue Portfolio (WO 01/83794).

MedImmune has granted use of its reverse genetics technology to U.S. and international health authorities for clinical research, and offers commercial licenses to vaccine manufacturers developing pandemic influenza vaccines.

Trials: FluMist has been evaluated in 20 clinical trials in which a total of 20,228 participants received 28,979 doses. These trials included 16,260 healthy children 1-17 years of age and 3,805 healthy adults 18-64 years of age who received at least one dose of vaccine. Second and third annual doses were given to 3,003 adults and 642 children, respectively. In randomized, placebo-controlled trials, 8,339 healthy children and 3,314 healthy adults received vaccine.

Also, more than 9,000 persons of all ages received reassortant vaccine components in Wyeth- and NIH-sponsored trials prior to Aviron licensing the vaccine technology in 1995. Clinical trials with cold adapted intranasal influenza vaccines began in 1976. Overall, in placebo-controlled challenge trials, cold adapted strains demonstrated safety with 66%-100% protection against systemic illness and 17%-100% protection against infection (with safety and efficacy comparable to conventional injected vaccines). These vaccines induced strong immune responses, including local mucosal immunity in the nasal passages, after simple administration as a nasal spray.

Results from a Phase III study performed by the Live Attenuated Influenza Virus Vaccine in Healthy Adults Trial Group were published in the July 14, 2000, issue of the Journal of the American Medical Association (JAMA). The study demonstrated efficacy using FluMist for prevention of influenza in healthy adults. Vaccine recipients experienced statistically significant reductions in illness-associated days lost from work, health care provider visits, and use of prescription antibiotics and nonprescription medications. This double-blind, placebo-controlled trial enrolled 4,561 working adults (aged 18-65) at 13 sites in the U.S. during the 1997-1998 flu season (September 1997-March 1998). Approximately two-thirds of the subjects received a single dose of the vaccine and the rest received placebo. Illness, as determined by multiple definitions, was reduced among vaccine recipients. This included 22.9% less days of febrile illness, 27.3% less days of severe febrile illness, and 24.8% less days of febrile upper respiratory tract illness. Vaccine recipients experienced 28.4% fewer work days missed due to febrile upper respiratory illness, and a 40.9% reduction in health care provider visits. Vaccine recipients also experienced a 45.2% reduction in days of prescription antibiotic use, and 28.0% fewer days of use of non-prescription medications due to upper respiratory illness. During peak outbreak periods, vaccine and placebo recipients experienced comparable levels of febrile illness, but severe febrile illness was reduced in vaccine recipients. Most of the subjects in the trial administered the vaccine on their own, demonstrating its ease of use. The efficacy rates for prevention of illness in adults in this and other trials using FluMist are similar to those reported for conventional inactivated injected influenza virus vaccines. The investigators concluded that the vaccine was safe and effective in adults.

Dr. R.B. Belshe, St. Louis University Health Sciences Center, and collaborators reported in the February 2000 issue of the Journal of Pediatrics that FluMist protected children during 1997-1998 flu season clinical testing against an unexpected strain of influenza A virus in circulation that season, i.e., an antigenic variant strain for which the vaccine had not been designed to provide protection. This double-blind, placebo-controlled trial enrolled 1,358 children between ages two and seven years old. The vaccine was 86% effective for protection against the unexpected A/Sydney/97-like viruses that emerged and became the predominant circulating influenza A type H3N3 viruses in 1997/1998. The vaccine provided a level of protective efficacy equivalent to that of natural influenza virus infection (86%). Among the only 15 cases of influenza A/Sydney cases in the 917 FluMist recipients, these children had significantly milder symptoms, including shorter duration of fever, fewer middle-ear infections, and no lower respiratory tract disease, compared to the 51 A/Sydney cases in placebo recipients. None of the FluMist-vaccinated children developed infections with the three strains contained in that year’s trivalent FluMist formulation (100% efficacy).

Depending on the infecting and challenge virus strains, natural influenza infection can provide protection for 4-7 years. The length of protection provided by FluMist has not yet been determined. Completed trials do not support conclusions about the efficacy of the live vaccine vs. conventional inactivated vaccines against antigenic variant viruses. Aviron completed a “bridging study” demonstrating comparability of bulk vaccine then manufactured by Medeva in the U.K. and formulated and packaged at its U.S. facilities to vaccine fully manufactured by Medeva (used in earlier clinical trials). Overall, the protective efficacy (in the upcoming flu season) of FluMist is comparable to that of injected vaccines.

In spring 2004, with Wyeth dropping involvement with FluMist and CAIV-T, MedImmune reported it planned three new trials in the next two years – a pediatric safety trial in about 7,000 6-71 month old infants during the 2004-2005 flu season; a Phase III trial comparing CAIV-T with conventional injected vaccine during the 2004-2005 flu season; and a Phase III trial in subjects 50-64 years old during the 2005-2006 flu season. Before returning FluMist rights, Wyeth had conducted five studies of CAIV-T in a total of 5,500 patients.

In spring 2004, with Wyeth dropping involvement with FluMist and CAIV-T, MedImmune reported it planned three new trials in the next two years – a pediatric safety trial in about 7,000 6-71 month old infants during the 2004-2005 flu season; a Phase III trial comparing CAIV-T with conventional injected vaccine during the 2004-2005 flu season; and a Phase III trial in subjects 50-64 years old during the 2005-2006 flu season. Before returning FluMist rights, Wyeth had conducted five studies of CAIV-T in a total of 5,500 patients.

In the Dec. 7, 2005 issue of the Journal of the American Medical Association, a study confirmed the relative safety of FluMist in its approved populations. As of Aug. 16, 2005, the FDA’s/CDC’s Vaccine Adverse Event Reporting System (VAERS) had recorded 460 adverse event reports for FluMist vaccinations starting Aug. 2003. Of the events listed, 40 were considered serious, including breathing problems in asthma patients (for whom the vaccine is contraindicated). No fatalities were reported, but there were seven reports of possible anaphylaxis (a severe allergic reaction), two reports of Guillain-Barre syndrome (a temporary inflammation of the nerves), one report of Bell’s palsy (paralysis of the facial muscles), and eight reports of asthma exacerbation among individuals who had a prior history of asthma. It was not clear if all of these reactions were due to the vaccination. The prior year’s vaccine shortage may have led some doctors to administer the vaccine to risky patients. Overall, 73 of the cases involved individuals who should not have received the vaccine, which was only recommended to healthy individuals five to 49 years of age.

In the Dec. 13, 2006, edition of the New England Journal of Medicine, results were published from a study in over 15,000 children showing that school-based influenza vaccination programs may be an effective and feasible strategy to help lessen the impact of seasonal influenza on households and communities. Households with children who attended schools with vaccination programs (intervention schools) reported significantly fewer flu-like symptoms than households with children who attended schools without such programs (control schools). All vaccinated children in the study received FluMist. The study showed significant clinical benefit from school-based immunization of healthy children using FluMist.

In May 2007, MedImmune reported additional results from a previous study showing that use of FluMist in daycare and school settings may help reduce the burden of seasonal influenza. Economic analyses applied to outcomes observed in previously completed clinical studies suggest that influenza vaccination (FluMist) may provide a beneficial cost savings to the community at large. Results from a previously published placebo-controlled, two-season trial involving children aged 6 months to 36 months attending daycare centers showed that those children receiving FluMist experienced significantly fewer cases of influenza-like illness (ILI) (Vesikari, T, et.al., Pediatrics, 2006). Data from a community-based study involving 15,000 children in 28 schools across four states (Maryland, Texas, Minnesota and Washington) showed that households of the 11 schools where children received FluMist reported statistically significant reductions in ILI, child doctors’ office visits, medications and work/school absenteeism in the peak flu week as compared to the households of the 17 control schools where no influenza vaccinations were provided. In the first year of the study, vaccination provided savings of approximately $5.47 per child, while in the second year of the study, the projected savings increased to almost $144 per child. The significantly higher savings projected in the second year were due in part to the a higher rate of influenza infection among the study population. From the societal perspective, FluMist immunization of young children in daycare or school settings seems to make economic sense. By reducing influenza attack rates, there is less burden on the healthcare system and fewer days missed from school and work. Additional data were reported from a study showing that increased vaccination rates may help prevent late-season influenza B outbreaks.

Medical: The vaccine is administered using a novel spray syringe (from Becton Dickinson and Co.) which releases a large particle aerosol spray into the nasal passages and upper respiratory tract. This intranasal administration of the live attenuated viruses generally induces an asymptomatic infection capable of inducing potent humoral (antibody), local mucosal immunity (IgA antibodies), and cellular immune responses (cytotoxic T lymphocytes; CTLs) upon later exposure to wild-type influenza virus (with similar, cross-reactive HA and/or NA epitopes).

Market: Total FluMist sales reported by MedImmune were $21 million in 2005, and $18.6 million in 2004. See the CAIV-T FluMist entry below for 2006 sales ($only $36 million) and marketing information. Other revenue, primarily royalties and milestone payments, were $3.1 million in 2004; and $47.4 million in 2003 (from royalties and milestones payments from Wyeth).

FluMist, even though more expensive than injectable vaccines, compared to most other biopharmaceuticals, is still a relatively inexpensive, more commodity-type product. Analysts with Friedman, Billlings and Ramsey (FBR) consider FluMist (and CAIV-T) to be a low profit margin product, with profits less than 50% of sales. FBR reports regarding MedImmune, “FluMist is a drag on gross margins, reducing margins from roughly 75% to 68%-69%.”

MedImmune developed FluMist in collaboration with Wyeth, which held marketing rights, but Wyeth withdrew in April 2004 after a dismal launch during the 2003-2004 flu season. MedImmune is continuing to market FluMist, but not as aggressively, e.g., without large advertising expenses, as with its first year on the market with Wyeth.

Upon its acquisition of Aviron, MedImmune had set end-user sales goals of $500 million within three years of FluMist’s launch, and $1 billion within five years. MedImmune originally projected total FluMist revenue (product sales and other revenue from milestones and royalties) would be $120-$140 million in the 2003-4 flu season. SG Cowan had projected 2003-4 sales of FluMist would be $75 million and 2004-5 sales to be $160 million (based on approval only for those ages 5-49). However, such rapid attainment of these sales levels turned out to be overly optimistic (to put it mildly).

Upon approval, MedImmune reported that it expected to manufacture 6 million doses for the 2003-4 flu season. As evidence of its confidence in FluMist, Wyeth halted manufacture and sales of its conventional injected vaccine, FluShield (see #480).

FluMist was launched on Sept. 2, 2003, with its approval restricted to healthy persons ages 5-49, including much of the general population. Wyeth initiated a massive $25 million U.S. public relations/advertising campaign to support the U.S. launch of FluMist. An advertising agency conducted a $40 million direct-to-consumer ad campaign for Wyeth. This was an unprecedented marketing expenditure for a vaccine product. Historically, the combined U.S. promotional expenditures for influenza vaccines have been about $2 million/year. MedImmune/Wyeth encouraged large employers to purchase vaccine and sponsor “FluMist days” for employees to receive the vaccine. Also, pharmacies in the 38 states allowing pharmacists to administer vaccines were encouraged to stock and administer FluMist.

However, the market launch of FluMist (2003-4 flu season; essentially all sales in 2003 calendar year) was a disaster. MedImmune delivered about 4.1 million doses of vaccine to Wyeth in 2003. Confronting lagging sales and with some physicians/clinics marking the price above the ~$46 dollars that MedImmune/Wyeth expected most consumers to be be charged, consumers were offered a $25 mail-in rebate in Nov. 2003 to promote sales. In mid-Dec. 2003, the price of FluMist for public vaccination programs was reduced to $20. In late Jan. 2004, CDC reported only 61,360 doses were sold under this program (while Wyeth reported 69,200). None of these actions significantly boosted sales, despite favorable conditions, includling well-publicized shortages of conventional injected vaccine by December, an influenza A strain circulating that was resistant to that year’s strain selection, early onset of influenza outbreaks in the U.S., and continued direct-to-consumer advertising. Discounted prices might have boosted sales, if they had been offered before or early in the flu season, e.g., in early fall.

For the 2003/4 flu season, Wyeth distributed only about 830,000 doses of FluMist during the 2003-4 season (by Dec. 31, 2003), far lower than its original projection of 4 million doses. On Jan. 21, 2004, MedImmune offered 250,000 doses for free to the Centers for Disease Control and Prevention (CDC) for distribution to public sector vaccination programs. However, only 40,000 were requested and distributed to state health departments.

In Feb. 2004, with the 2003/4 vaccine sales season over, MedImmune reported that 80% of doses manufactured (about 3 million doses) for the product launch (2003-4 flu season) were unsold and would be destroyed. MedImmune reported $46 million in FluMist revenue in 2003, with all of this involving milestone and other payments from Wyeth unrelated to sales (i.e., the company reported no income from FluMist). MedImmune projected eventual total sales, after return of unused vaccine, of ~$30 million, with revised total FluMist-related income (full 2003-2004 flu season) projected at $76 million (in $55-85 million range), well below the company’s original $120-$140 million projection.

In March 2004, MedImmune revised its guidance to the investment community. FluMist was projected not to produce significant revenue for the company for at least three more years, and the company was now concentrating on development of CAIV-T, its second generation liquid product requiring refrigeration (not continuous frozen storage). After the close of 1st quarter 2004, MedImmune reported that it expected 2004 FluMist related revenue of $45-$55 million (down from prior projection of $55-$85 million, with this being a revised projection from $120-$140 million). Although the company considered dropping FluMist altogether, the company is committed to further development, particularly CAIV-T, and projected eventual $500-$800 million/year in sales. Approval of CAIV-T was projected by 2007 (for the 2007-2008 flu season). In the meantime, the company would only manufacture a “relatively small number” of doses of frozen FluMist vaccine in coming years, i.e., about the same number of doses annually as during the 2003-2004 launch season. The company also continued clinical studies to gain approval of FluMist for infants/younger children and the older/elderly cohorts (below age five and over age 50). MedImmune now viewed FluMist as “a pre-launch product until the refrigerator-stable formulation is ready. We’re looking to establish it [CAIV-T] as a superior pediatric vaccine.”

With sales not expected to increase significantly for several years, e.g., until the introduction of a refrigerated formulation, Wyeth had no way to retrieve its considerable investment in FluMist. The CEO of MedImmune had remarked that it was “illogical” for Wyeth to continue to co-market the vaccine.

For the 2004/2005 flu season, MedImmune announced prices for FluMist were $16.00 wholesale per non-returnable dose or $23.50 wholesale per returnable dose -- a decrease drop of ~50% from the 2003-2004 season. Most purchasers probably paid the higher price, allowing them to return any unsold stock at the end of the season. [Officially, the 2004 Average Wholesale Price (AWP) was $552.00 for 10 dosage devices, and the Direct Cost (Manufacturer’s discount price) was $460.00 for 10 (Red Book, 2004)]. During the 2003/4 flu season (product launch), Flumist generally cost consumers about $46/dose, about 2-3 times the cost of a conventional injected influenza vaccine (costing many as little as $10-$15). Many consumers paid much more for FluMist. MedImmune expecting to sell about 450,000 doses of FluMist.

For the 2004/2005 flu season, at the encouragement of federal officials concerned about an influenza vaccine shortage, MedImmune manufactured 3 million doses of FluMist. However, MedImmune sold only approximately 2 million doses of frozen FluMist and destroyed or donated the rest. This was another year of dismal sales, despite a much-publicized shortage of influenza vaccine due to withdrawal of conventional vaccine manufactured by Chiron Corp. For the 2004/5 season, MedImmune had reduced the price per dose from $46 to $23.50/dose. The markup to patients is generally $10-$15/dose, so the vaccine still cost the consumer much more than the $15-$25/dose for injectable vaccine. Besides the vaccine still costing on the order of twice that of the injected vaccine and many consumers still not aware of its availability, low sales were attributed to a relatively mild flu season and waning demand for flu vaccination, particularly among healthy adults, the core market for FluMist.

In Sept. 2005, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention’s (CDC), included FluMist in its priority influenza immunization schedule. FluMist was found suitable for administration at any time for vaccination of nonpregnant healthy persons aged 5-49 years, including most healthcare personnel, other persons in close contact with groups at high risk for influenza-related complications, and others desiring protection against influenza.

The 2005 Average Wholesale Price (AWP) (for the 2005/6 flu season) was $180.00 for 10 dosage devices or $18.00/dose (Red Book, 2005). The 2005/6 flu season prices were roughly in line with those of the prior year.

In early 2006, it became obvious that problems continued to plague FluMist sales during the 2005/6 flu season. MedImmune manufactured between 2.5 million and 3 million doses of FluMist for the 2005-2006 flu season. Most sales took place between Sept. and Nov. However, only 1.3 million doses were sold, and MedImmune ended up giving away 300,000 to schools, hurricane Katrina relief programs, and destroying the rest that was either unsold or returned.

Cost will continue to be a major issue for FluMist (and CAIV-T) in the next few years. With much lower manufacturing levels projected, the cost of manufacture per dose is higher and profit margin is lower. Prior to Wyeth dropping out, many had expected MedImmune and Wyeth would reduce the price of FluMist for the 2004-5 and upcoming flu seasons, perhaps to the $20/dose offered late in the 2003-4 season to public vaccination programs. However, now that MedImmune alone is involved, with added manufacturing expenses, royalty payments to Wyeth, CAIV-T development costs, etc., MedImmune must retain a premium price for FluMist (relative to injected vaccine), at least until the market expands significantly, e.g., with FluMist approvals for younger and older groups and launch of CAIV-T. MedImmune still expects FluMist/CAIV-T to (or hopes it will) eventually become the preferred influenza vaccine, particularly for infants and children.

Factors contributing to the vaccine’s disastrous launch and subsequent marketing include: its high cost (relative to injected vaccine); restricted target population (leaving out the elderly and children, the groups that need influenza vaccine the most); difficulties in obtaining access, even for those seeking the vaccine (not every physician clinic carried it in stock, and large-scale vaccination programs stayed with the cheaper injected vaccine); the slow process of informing health care professionals and others about the new vaccine; misconceptions that the vaccine could cause influenza; the requirement that the vaccine be continuously stored frozen; and overly cautious interpretation of warnings to health care professionals to limit contacts with immune suppressed patients (causing many health care workers and organizations to pass on the vaccine) Other factors affecting the product launch included Wal-Mart and other major pharmacy chains not bothering to purchase vaccines for administration in their pharmacies (in states where pharmacists can administer vaccines). Wal-Mart had originally decided to offer FluMist at about 1,000 pharmacies, but later reversed this decision in mid-October (early in the flu season). In early Feb. 2004, the CEO of Wyeth (conveniently) blamed fears of contracting influenza from FluMist as affecting its sales.

Ongoing: See the entry for CAIV-T below. Prior to dropping out of its relationship with MedImmune, Wyeth had been conducting clinical trials with a second generation, refrigerator stable, liquid, trivalent, cold adapted influenza vaccine (CAIV-T; see the next entry). These were assumed by MedImmune. The original FluMist (this entry) must be shipped frozen. Unlike the U.S. and certain other developed countries, most international markets are not equipped with appropriate cold-storage equipment to handle broad distribution of temperature-sensitive, frozen vaccines. Standard refrigeration would make the vaccine more feasible for use in lesser developed countries, and generally simplify distribution. In 2001, Wyeth completed a Phase II in more than 1,300 children in the southern hemisphere showing safety and immunogenicity with this formulation. Wyeth was conducting several Phase III clinical trials with liquid CAIV-T: a pan-Asian efficacy trial in more than 3,000 participants from 12 to 36 months of age; a pan-European pediatric day care efficacy trial in >1,500 children in day care from 6 to 36 months of age; and an efficacy trial in healthy elderly over 60 years of age in South Africa. The primary endpoint in these trials was protection against culture confirmed influenza.

Competition: An intranasal influenza vaccine in advanced development experienced problems in clinical trials, likely giving FluMist additional several years without competition from another intranasal vaccine. Nasalflu, an intranasal inactivated virosome (liposomal) influenza virus vaccine containing a heat-labile Escherichia coli (E. coli) toxin as adjuvant, from Berna Biotech AG (and its collaborator for further development, Aventis Pasteur S.A., now Sanofi Aventis S.A.) had received approval in Switzerland. However, the vaccine was withdrawn in summer 2001 after reports of Bell’s palsy, a type of temporary facial paralysis. Berna then began a trial which enrolled 11,000, but this was halted in mid-2002 after cases of Bell’s palsy were observed in both vaccine and placebo recipients. The adverse reactions have primarily been attributed to the bacterial toxin adjuvant. Unable to rule out the vaccine as the cause (and with the vaccine’s reputation tainted), Berna and Aventis Pasteur restarted trials but without the toxin adjuvant.

R&D: A live intranasal influenza virus vaccine long used in Russia and the former Soviet Union has been licensed by Merck & Co., Inc. An intranasal proteosome (Neisseria meningitidis bacteria outer membrane proteins used as vaccine carrier and adjuvant) influenza virus vaccine from ID Biomedical Corp. is in Phase II trials. A number of cell cultured and other influenza virus vaccines, including vaccines administered by skin patch, are also in development worldwide.

In Fall 2005, MedImmune concluded a Collaborative Research and Development Agreement (CRADA) in with the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), for development and testing of attenuated, live intranasal influenza vaccines against pandemic H5N1 avian influenza strains. This effort will use MedImmune’s reverse genetics technology.