Status: supplemental BLA approved in April 2012

Organizations involved:

MedImmune Inc. – Manuf.; R&D; Tech.;

World mark.

AstraZeneca plc – Parent

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

National Institutes of Health (NIH) – Parent

University of Michigan - R&D; Tech.

Cross ref.: See the entry for Influenza Vaccine, live rDNA, liquid (FluMist), the prior 3-antigen seasonal influenza of this vaccine. See the Influenza Vaccine Products entry.

Description: FluMist Quadrivalent (Influenza Vaccine Live, Intranasal) is a formulation of four purified live influenza virus strains obtained from virus strains cultured in chicken eggs for administration by intranasal spray. FluMist Quadrivalent contains four vaccine virus strains: an A/H1N1 strain, an A/H3N2 strain and two B strains. For 2012, FluMist Quadrivalent contains B strains from both the B/Yamagata/16/88 and the B/Victoria/2/87 lineages. FluMist Quadrivalent is manufactured according to the same process as FluMist (see entry 191.1).

The influenza virus strains in FluMist Quadrivalent 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 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 (c) attenuated (att) (i.e., they do not produce classic influenza-like illness in the ferret model of human influenza infection). No evidence of reversion has been observed in the recovered vaccine strains that have been tested (135 of possible 250 recovered isolates) using FluMist [see Clinical Pharmacology (12.2)].

For each of the four reassortant strains in FluMist Quadrivalent, the six internal gene segments responsible for ca, ts, and att phenotypes are derived from a master donor virus (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. Thus, the four viruses contained in FluMist Quadrivalent maintain the replication characteristics and phenotypic properties of the MDV and express the HA and NA of wild-type viruses. For the Type A MDV, at least five genetic loci in three different internal gene segments contribute to the ts and att phenotypes. For the Type B MDV, at least three genetic loci in two different internal gene segments contribute to both the ts and att properties; five genetic loci in three gene segments control the ca property.

Each of the reassortant strains in FluMist Quadrivalent express the HA and NA of wild- type viruses that are related to strains expected to circulate during the 20XX-20XX influenza season. IN 2012, three of the viruses (A/H1N1, A/H3N2 and one B strain) have been recommended by the U.S. Public Health Service (USPHS) for inclusion in the annual trivalent and quadrivalent influenza vaccine formulations. An additional B strain had been recommended by the USPHS for inclusion in the quadrivalent influenza vaccine formulation.

Each pre-filled FluMist Quadrivalent sprayer contains a single 0.2 mL dose. Each 0.2 mL dose contains 106.5-7.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants of each of the four strains (X's indicate variation in strains each year): A/XXX/XX/XXXX (H1N1), A/XXX/XX/XXXX (H3N2), B/XXX/XX/XXXX (B/Yamagata/16/88 lineage), and B/XXX/XX/XXXX (B/Victoria/2/87 lineage). Each 0.2 mL dose also contains 0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, and 0.96 mg/dose monobasic potassium phosphate. Each dose contains residual amounts of ovalbumin (< 0.24 mcg/dose), and may also contain residual amounts of gentamicin sulfate (< 0.015 mcg/mL), and ethylenediaminetetraacetic acid (EDTA) (< 0.37 mcg/dose). FluMist Quadrivalent contains no preservatives and is stored refrigerated.

Nomenclature: Influenza Vaccine, live rDNA, 4-valent [BIO]; FluMist Quadrivalent [TR US]; Fluenz Tetra [TR EU]; Influenza Vaccine Live, Intranasal [FDA]; Influenza Virus Vaccine, Trivalent A & B Live, Cold Adapted [FDA former]; Cold Adapted Influenza Vaccine (Liquid Formulation) [SY]

Companies.: FluMist was originally developed by Aviron, Inc. which was acquired by MedImmune, Inc. in Jan. 2002, and became MedImmune Vaccines, Inc. MedImmune was acquired by AstraZeneca plc in April 2007. MedImmune/AstraZeneca has worldwide marketing rights.

The vaccine is manufactured at MedImmune’s facilities in Speke, U.K., near Liverpool, which were originally acquired from Evans Vaccines Ltd. The Speke facilities include a bulk manufacturing facility that has been 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. Final filling and packaging of the product, at least for the U.S. market, is apparently performed by MedImmune within the facilities of Packaging Coordinators, Inc. (Philadelphia, PA).

Manufacture: Specific pathogen-free (SPF) eggs are inoculated with each of the reassortant strains and incubated to allow vaccine virus replication. The allantoic fluid of these eggs is harvested, pooled, and then clarified by filtration. The virus is concentrated by ultracentrifugation and diluted with stabilizing buffer to obtain the final sucrose and potassium phosphate concentrations. The viral harvests are then sterile filtered to produce the monovalent bulks. Each lot is tested for ca, ts, and att phenotypes and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. Monovalent bulks from the four strains are subsequently blended and diluted as required to attain the desired potency with stabilizing buffers to produce the quadrivalent bulk vaccine. The bulk vaccine is then filled directly into individual sprayers for nasal administration.

FDA class: Biologic sBLA

Approvals: Date = 20120229, supplemental BLA (sBLA)

Status: The sBLA was filed early in the second quarter of 2011. The sBLA was grantd on Feb. 29, 2012.

On Sept. 24, 2013, the EMA/EU recommended approval of Fluenz Tetra. The vaccine will replace the 3-valent version in the 2014-15 flu season. Formal approval was granted on Dec. 6, 2013.

Indications: [full text of the "Indications and USAGE" section of the product insert/labeling]:

FluMist Quadrivalent is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FluMist Quadrivalent is approved for use in persons 2 through 49 years of age.

Tech. transfer: See the Influenza Vaccine, live rDNA, liquid entry (FluMist, frozen), no. 191.

Trials: The nasal spray vaccine was tested in approximately 2,300 children between 2 and 19 years of age. The children were randomly receive 1 of 3 vaccines: a vaccine containing 4 strains of influenza – 2 of influenza A and 2 of influenza B, or 1 of 2 vaccines that contained both influenza A strains and 1 of each of the influenza B strains. Researchers looked at the safety and antibody response to both influenza A and B viruses in the children of different age groups who were vaccinated. The children who received vaccine containing 4 strains of flu had as robust of an immune response as those who received the vaccine that contained 3 strains, i.e, the products were shown to be comparable, supporting sBLA approval.