H1N1, MF59/Novartis
pandemic influenza vaccine (surface antigen, inactivated, adjuvanted) A/California/7/2009 (H1N1) - Focetria (H1N1); Influenza A (H1N1) 2009 Monovalent Vaccine; monovalent pandemic (H1N1) 2009 influenza vaccine; swine flu vaccine
Status: European Union approval in Sept. 2009
Organizations involved:
Novartis Vaccines and Diagnostics Ltd. – Manuf; R&D; Tech.;World mark.
Novartis AG – Europe mark.; Intl. mark.; Parent
Cross ref.: See the Influenza H1N1 Vaccine Products and Influenza Vaccine Products entries. See the entry for Influenza vaccine, H1N1/Novartis, approved in the U.S and essentially this same vaccine but with MF59 adjuvant (which is not approved in the U.S.).
Description: Influenza A (H1N1) 2009 Monovalent Vaccine from Novartis is an aqueous sub-unit (purified surface antigen) formulation of influenza A/California/7/2009 (H1N1)v-like virus cultured in embryonated hens’ eggs, inactivated with formaldehyde with MF59 adjuvant (see related entry).
An analogous H1N1 vaccine is approved in the U.S, with the major differences being that this does not contain MF59 adjuvant and is inactivated with beta-propriolactone (BPL).
The MF59C.1 adjuvant contained in Focetria H1N1 (and Fluad and Focetria H5N1) is an oil-in-water emulsion, composed mainly of squalene, an intermediate metabolite in the synthesis of cholesterol.
The virus is conventionally cultured in the allantoic cavity of embryonated hens’ eggs inoculated with an A/California/7/2009 (H1N1)v-like virus suspension containing neomycin and polymyxin. The influenza virus strain is harvested and clarified by centrifugation and filtration prior to inactivation with beta-propiolactone. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of nonylphenol ethoxylat (a detergent), which removes most of the internal proteins. The nonylphenol ethoxylate is removed from the surface antigen preparation.
Focetria,(H1N1) with adjuvant is formulated to contain 7.5 µg hemagglutinin (HA) per 0.5-mL dose of A/California/7/2009 (H1N1)v-like virus, half of the usual 15 µg dose of monovalent unadjuvanted vaccines. And this is 6-times lower than the total amount of HA present in conventional unadjuvanted trivalent seasonal influenza vaccines that contan 15 µg HA per strain (or 45µg HA/dose).
The MF59C.1 adjuvant contains squalene 9.75 mg' polysorbate 80 (Tween 880) 1.175 mg; and sorbitan trioleate. Fluad (and now Focetria H1N1 an H5N1) is formulated using MF59 adjuvant containing citrate buffer to improve adjuvant stability, with this designated as MF59C.1.
Other ingredients (excipients and residuals) are sodium chloride; potassium chloride; potassium dihydrogen phosphate; disodium phosphate dihydrate; magnesium chloride hexahydrate; calcium chloride dihydrate; thiomersal (included only in multi-dose vials); sodium citrate; citric acid; and Water for injections.
The vaccine was originally approved by the EU for packaging in prefilled single dose syringes containing no adjvant and 10-dose vials containing adjuvant, with the syringes containing a singe 0.5-mL dose. However, shortly after approval, the single-dose non-adjuvanted syringe was withdrawn. Thus, only multi-dose vials are available. Thimerosal (mercury derivative; see related entry) is used during manufacture, but is removed by subsequent purification steps to a trace amount (≤ 1 µg mercury per 0.5-mL dose), so the vaccine is considered "thimerosal-free."
The 5-mL 10-dose vial formulation contains thimerosal added as an antimicrobial preservative. Each 0.5-mL dose from the multidose vial contains 25 µg mercury.
Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 µg ovalbumin), polymyxin (≤ 3.75 µg), neomycin (≤ 2.5 ≤g), beta-propiolactone (not more than 0.5 µg) and nonylphenol ethoxylate (not more than 0.015% w/v). The vaccine may contain trace levels of egg or chicken protein, ovalbumin (a protein in egg white), kanamycin or neomycin sulphate (antibiotics), formaldehyde, cetyltrimethylammonium bromide and polysorbate 80 (Tween 80).
Companies.: Novartis Vaccines and Diagnostics S.r.l (previously Chiron Vaccines), a subsidiary of Novartis AG, developed and manufactures this vaccine. Novartis facilities in Sienna, Italy, manufacture the bulk vaccine, which is shipped to facilities in Rosia, Italy, for final formulation, finishing and packaging.
Manufacture: The Drug Substance is Monovalent Pooled Harvest (MPH) of Pandemic Influenza vaccine, surface antigen, inactivated. This is a buffered suspension containing predominantly the purified outer membrane proteins, hemagglutinin (HA) and neuraminidase (NA), of a pandemic H1N1 influenza virus strain recommended by the WHO-EU for the Pandemic.
The manufacture of the MPH involves the cultivation of the influenza virus strain in embryonated chicken eggs, harvesting of allantoic fluid, concentration by ultrafiltration and formaldehyde inactivation, followed by whole virus purification using sucrose gradient centrifugation and diafiltration. The virus is grown in pre-incubated, candled, fertile hens eggs. The virus inoculum is prepared from the WS (see below) at a dilution calculated to ensure total egg infection and maximum virus yield, and it is injected into the allantoic cavity of each production egg. After inoculation, the eggs are incubated at an optimum temperature and time for maximum virus yield. After incubation, the eggs are cooled to 2-8°C and fed directly into the Harvesting room. The allantoic fluid (AF) is collected into the harvesting vessel. The resultant fluid is then clarified by centrifugation, collected in a refrigerated tank, which is then connected to an ultrafiltration system to concentrate the allantoic fluid. An aqueous solution of formaldehyde is added to the clarified concentrated allantoic fluid to incactive (kill) the viruses. The content of the tank is transferred to a sanitized and temperature controlled inactivation vessel and stirred throughout the inactivation period. The inactivation cycle depends upon the characteristics of specific virus strain. The inactivation temperature is selected in order not to compromise antigenicity.
The virus is removed from the inactivated allantoic fluid using continuous flow ultracentrifuges. The virus is collected using a sucrose density gradient, which concentrates and purifies the virus through isopycnic centrifugation. The purified virus Pool is diluted with phosphate-buffered saline (PBS) and diafiltered. A clarifying filtration takes place with pre-filters and filters of different pore sizes. The filtered product represents the Whole Virus Concentrate, and it is sampled for testing. A Polysorbate 80 solution is added to the Whole Virus Concentrate and the product is stored waiting for the Split test results.
The HA and NA antigens from the surface of the purified whole virus are solubilized by treatment with a detergent, cetyltrimethylammonium bromide (CTAB). The solubilized antigens are then separated from the non-solubilized components of the virus by continuous flow centrifugation and the supernatant collected. A polystyrene resin is added to this Subunit Supernatant Pool to absorb the CTAB. The product then undergoes a clarifying filtration to remove the resin, a stabilizer solution is added and the product is then filtered into a stainless steel tank. After filtration, the monovalent pool is transferred to Rosia, Italy, facilities where it is sampled for bioburden, and sterile filtered into a sterile container. The Monovalent Pooled Harvest (MPH) is sterile filtered. The filtered Monovalent Pooled Harvest (i.e. the active substance) is sampled for release testing and stored at 2-8°C in a stainless steel tank. The MPH complies with the Ph.Eur. monograph 01/2006:0869 on Influenza Vaccine (Surface Antigen, Inactivated). The MPH is tested for release for Haemagglutinin Identity and Content (SRID), Neuraminidase Identity (ELISA), Viral inactivation, Purity (SDS-PAGE), Sterility, CTAB, Polysorbate 80, Barium, Citrates, Endotoxin, Formaldehyde, Ovalbumin Content and Appearance. Due to the presence of the adjuvant in the finished product, the test for formaldehyde is performed on the Monovalent Pooled Harvest. Polysorbate 80 is used as an excipient of in both the vaccine and MF59C.1 adjuvant. The finished product is a combination of MPH, MF59C.1 adjuvant bulk and buffer solutions. The process for the Final Bulk preparation consists is a simple mixing operation. In case of formulation with preservative, which is possibilty with future Focetria H1N1 vaccines, a thiomersal solution is added. The formulated suspension is filled into vials. The packed product is stored at 2-8˚C until released. The potency of the vaccine is expressed as the concentration of the HA protein.
The Final Lot is tested for release for Hemagglutinin Identity and Content (SRID), Sterility, Endotoxin, Appearance, Abnormal toxicity, Squalene identity and content (HPLC), Particle size distribution, pH, Thiomersal (if added) and Extractable volume. The release tests are the same approved for the inter-pandemic Fluad vaccine. The specifications might differ from the Ph.Eur. monograph for the influenza vaccine (surface antigen inactivated) due to the presence of the MF59C.1 that could interfere with some analytical methods. The test for free formaldehyde is performed earlier in the process, on the Monovalent Pooled Harvest, rather than on the Final Bulk vaccine or the Final Lot, as required by Ph.Eur. The MF59C.1 adjuvant in the finished product interferes with the performance of this test.
The MF59C.1 is produced in Germany and transported to Italy, where it is filtered and used to formulate the Final Bulk. Bioburden is controlled before the sterilizing filtration, while sterility and other in-process parameters are monitored after filtration and before the addition into the Final Bulk mixing tank..
The only animal derived starting materials are eggs and squalene (used in the MF59C1 adjuvant). The squalene in MF59 is a commercially available natural product distilled from shark liver oil. It is then redistilled and supplied by qualified manufacturers.
In addition to formaldehyde inactivation, sucrose gradient centrifugation should also contribute to virus removal as well as the centrifugation steps, which follow the Polysorbate 80/CTAB treatment.
FDA class: Biologic BLA
Approvals: Date = 20090915; sBLA; approval letter reports BLA supplement BL 103837/5514 (but the product insert is labeled with "BLA 1750")
Status: Focetria was first developed as a ‘mock-up’ vaccine that contained an H5N1 strain of the flu virus called A/Vietnam/1194/2004. Following the start of the H1N1 pandemic, Novartis replaced the virus strain in Focetria H5N1 with the H1N1 strain causing the pandemic, and presented data relating to this change to the Committee for Medicinal Products for Human Use (CHMP).
In the European Union, Focetria, as an H5N1, vaccine (see related entry), was approved in May 2007 as a mock-up file to be used once the WHO declared a pandemic. This previous approval was based on clinical studies involving the MF59 adjuvant and different influenza strains with pandemic potential, including H5N1 and H9N2.
On Sept. 22, 2009 Novartis applied for a variation in order to update its mock-up H5N1 approvel for the composition of the strain of Focetria to A/California/07/2009 (H1N1)v officially recommended by WHO and CHMP/EU for the H1N1 pandemic, i.e., the company applied for approval of Fecetria H1N1.
On Sept, 29, 2009, one week after filing, the European Union granted mock-up based approval to Focetria H1Nl for active immunization of persons of six months of age and older against influenza disease caused by the novel pandemic A(H1N1) influenza virus. The same manufacturing process, with the exception of strain-dependent parameters, and safety precautions were previously approved for the production of H5N1 and A(H1N1)v, which includes the release and shelf-life specifications. Similarly, because the H5N1 approval was based on similarity to the Fluad seasonal vaccine, Focetria H1N1 and H5N1 are manufactured with the same process and have the same adjuvant used for Fluad.
As of Oct. 2009 and before EU approval, Novartis had already started first deliveries of pandemic vaccines under quarantine (until approved) to governments in Europe.
Indications: [Full text of the "Indications and USAGE" section of the product insert/labeling];
Influenza A (H1N1) 2009 Monovalent Vaccine is an inactivated influenza virus vaccine indicated for active immunization of persons 4 years of age and older against influenza disease caused by pandemic (H1N1) 2009 virus.
Trials: The H5N1 mock-up vaccine was shown to bring about protective levels of antibodies in at least 70% of people in which it was studied. In line with the criteria laid down by the CHMP/EU, this was acceptable as an appropriate level of protection. Focetria H1N1 is presumed to be comparably effective.
The CHMP was also satisfied that the change of strain did not affect the characteristics of the vaccine.
Clinical trials suggest that just one dose of this adjuvanted vaccine can protect healthy adults, which means that the vaccine can be provided to more people than if two doses were needed.
Medical: Children 4 through 9 years of age receive two 0.5-mL intramuscular injections approximately 1 month apart. Children 10 through 17 years of age receive a single 0.5-mL intramuscular injection. Adults 18 years of age and older receive a single 0.5-mL intramuscular injection.
Market: In Oct. 2009, it appeared that Baxter would only be selling its vaccine to goverments.
Index Terms:
Companies involvement:
Full monograph
483.11 Influenza vaccine,
Nomenclature:
Influenza vaccine, H1N1, MF59/Novartis [BIO]
Focetria (H1N1) [TR]
Influenza vaccine, monovalent pandemic (H1N1) 2009 [SY]
FDA Class: Biologic BLA
chicken source materials
nonoxynol 101 (Triton N101)
vaccines, inactivated
vaccines, subunit
vaccines, viral
chicken embryo (egg) culture
infertility treatment
virus culture
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM001 Marketed Product in EU
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