Yellow Fever Virus Vaccine, Live - Arilvax
Status: BLA filed, withdrawn, will be refiled; marketed in the U.K. and other countries
Organizations involved:
Acambis plc – R&D; Tech.; World mark.; USA mark
Chiron Corp. – Manuf.; Intl. mark.
Novartis AG – Parent
Baxter Healthcare Corp. – Former
Evans Vaccines Ltd. – R&D; Tech.; Former
PowderJect Pharmaceuticals plc – Former
Cross ref.: See the entry below for YF-VAX, the only yellow fever vaccine currently approved in the U.S.
Description: Arilvax is a stabilized lyophilized (freeze-dried) formulation of live attenuated 17D strain of yellow fever virus, the same strain as in YF-VAX, cultured in embryonated Specific Pathogen Free eggs. After reconstitution for subcutaneous injection, one dose (0.5 ml) contains live attenuated yellow fever virus (17 D strain; the same as in YF-VAX) at a titer >103.7 Plaque Forming Units (1 PFU equivalent to 1,000 mouse LD50 units). Excipients in the formulation are sorbitol; hydrolysed gelatin (bovine origin), sodium chloride, disodium hydrogen phosphate, potassium chloride, potassium dihydrogen phosphate, and Water for Injection.
Arilvax has superior stability compared to YF-VAX, i.e, it can be shipped at refrigeration temperature and has a two-year shelf-life, while YF-VAX requires shipping on dry ice and has a one-year shelf-life. The vaccine is stored at 2-8°C (refrigerated), and has a shelf life (in U.K.) of three years. Arilvax (and diluent) is supplied in packages of five vials (in U.K.).
Note, Japanese encephalitis vaccine, rDNA/Acambis (ChimeriVax-JE; see related entry) uses the yellow fever virus 17D strain as a recombinant vector.
Nomenclature: Yellow Fever Vaccine/Acambis [BIO]; Arilvax [TR]; Yellow Fever Vaccine [FDA]; Yellow Fever Vaccine (Live) [European Pharmacopiae]
Companies.: Arilvax was originally developed by Evans Medical Ltd., then a subsidiary of Medeva plc,, which was acquired and then divested by Celltech Group plc to PowderJect plc, which was acquired by Chiron Corp., which merged into Novartis AG in spring 2006. In fall 1997, OraVax, Inc., which was acquired by Peptide Therapeutics Group and became Acambis plc, concluded an agreement with Evans/Medeva (now Chiron) to become the exclusive U.S. marketer and distributor of Arilvax.
Arilvax later-stage development was conducted by Acambis plc, which holds exclusive U.S. marketing rights. Chiron Vaccines, Chiron Corp., holds exclusive international (ex-U.S.) marketing rights
Arilvax is manufactured by Chiron Vaccines (Speke, U.K.), CBER/FDA est. no. 1720, now Novartis Vaccines (previously owned by Medeva, Evans, Celltech and PowderJect).
In fall 2000, Baxter Healthcare had purchased 20% of Peptide Therapeutics Group plc, then parent of OraVax, Inc., now Acambis plc, investing about $40 million in the company over the next 2.5 years. Baxter also obtained the option to co-market Arilvax in the U.S. This agreement, including U.S. co-marketing rights, is no longer be in force, and Baxter has divested its holdings in Acambis.
Status: Acambis filed its BLA on Dec. 12, 2003. This was the first BLA submitted electronically to the vaccine division, CBER, FDA, and the first FDA filing by Acambis.
In Feb. 2004, Acambis “temporarily” withdrew its BLA, citing Chiron Vaccine’s ongoing upgrading of its manufacturing facilities (see the Fluvirin entry), making an FDA preapproval inspection of the Speke, U.K., facilities impossible within the 10 months required from BLA submission. Acambis expected to resubmit the BLA in the first half of 2005, with the manufacturing facility expected to be ready for pre-approval inspection in the first half of 2005.
On March 9, 2006, Acambis reported, “We are in ongoing discussions with Chiron to resolve a way forward for the ARILVAX programme. To date these have been constructive and we hope to conclude the discussions in the near future.”
In early 2005, a shortage of Arilvax developed worldwide, due to production problems at Chiron facilities in the U.K. (the same facility with problems manufacturing Fluvirin influenza vaccine). This shortage worsened with the manufacturing facility off-line.
In Sept. 2006, Novartis, which had acquired Chiron, paid Acambis $19 million to settle a “non-performance” dispute Acambis had originally initiated against Chiron arising from Acamabis having to withdraw/delay the BLA due to Chiron’s manufacturing/facility problems. Novartis also granted Acambis an exclusive option to negotiate a licence to the worldwide rights to the Arilvax.
Arilvax has received approvals and is marketed in a number of countries worldwide.
As of summer 2007, the BLA had not yet been reported as having been refiled, apparently as result of unresolved manufacturing issues at Novartis facilities in the U.K. Arilvax is approved for sale in more than 10 countries, including the United Kingdom.
Trials: In mid-2000, Peptide Therapeutics Group, now Acambis, reported results from a trial comparing Arilvax and YF-VAX in 1,440 healthy volunteers. A single dose of Arilvax was shown comparably safe and effective in terms of antibody production as YF-VAX. Arilvax met the trial’s primary endpoint of not being inferior to YF-VAX in terms of safety or immunogenicity (yellow fever virus neutralizing antibodies). Based on sampling of neutralizing antibodies from 310 subjects receiving each vaccine, both vaccines were highly immunogenic and provided 99% seroprotection. There were no vaccine-associated serious adverse events reported in any of the 1,440 subjects receiving either vaccine.
Medical: Adults and children aged 9 months and over receive a single dose of 0.5 ml of the reconstituted vaccine. Vaccination is given at least 10 days before entering an endemic area or other potential exposure. Protective immunity appears 7-10 days after injection. International Health Regulations require revaccination at intervals of 10 years in order to retain a valid vaccination certificate. However, some degree of immunity likely persists for more than 10 years.
Market: Acambis acquired Berna Products Corp., the U.S. marketing subsidiary of Berna Biotech, in 2003 with the expectation that it would use the company’s established sales force for marketing of Arilvax. However, the BLA has not been refiled and U.S. approval, dependent on Chiron/Novartis resolving its U.K. vaccine manufacturing problems, at worst, could be several years off.
Index Terms:
Companies involvement:
Full monograph
566 Yellow Fever Vaccine/Acambis
Nomenclature:
Yellow Fever Vaccine/Acambis [BIO]
Arilvax [TR]
Yellow Fever Vaccine [FDA]
Yellow Fever Vaccine (Live) [European Pharmacopiae]
FDA Class: Biologic BLA
biopharmaceutical products
bovine materials used<!-- bovinesource -->
bovine materials used<!-- bovinesource -->
chicken source materials
vaccines, live
vaccines, viral
chicken embryo (egg) culture
virus culture
yellow fever prophylaxis
disodium hydrogen phosphate
Gb-23-902-531
lyophilized (freeze-dried)
potassium chloride
potassium dihydrogen phosphate
sodium chloride
sorbitol
Sterile Water for Injection
apheresis (hemapheresis)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
FDA application withdrawn
North American coral snake
EU011 Approved Formerly in EU/withdrawn
UM999 Not Available/Not Marketed in US
US000 never filed/no plans
EM999 Not Available/Not Marketed in EU
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