The flu vaccine shortage in the US for the 2004–2005 season meant some—like these people in New York—had to wait in long lines for a flu shot. Today there are more developers in the field, and new products on the horizon. Credit: newscom

The imminent approval in the European Union of the first seasonal influenza vaccine based on mammalian cell culture marks the beginning of a technology shift in the industry. However, transitioning away from the 50-year-old, egg-based manufacturing process is likely to be gradual rather than abrupt. The traditional vaccine franchises continue to expand, to the point that a significant oversupply in the USA during the 2007–2008 influenza season is a strong possibility.

Notwithstanding the debacle three years ago, when contamination problems at its Liverpool, UK, plant meant that Chiron, of Emeryville, California, was unable to supply vaccine to the US market, egg-based manufacturing has been an efficient and cheap method of producing large quantities of influenza vaccine every year. However, it's also a cumbersome, inflexible process that is not without shortcomings.

The US seasonal influenza vaccine supply is now far more diversified and more secure than it was just three years ago.

Manufacturers have to order specially bred hens' eggs up to 12 months in advance of production, and surge capacity is not an option unless millions of these eggs are kept in reserve—an expensive consideration (one to two eggs are needed for each dose of vaccine). The viruses have to be adapted to grow in eggs, which can both delay delivery of finished vaccine and, if there is a significant mismatch between the adapted and circulating flu strains, impair the efficacy of the final product. The threat of an influenza pandemic has further sharpened awareness of the need to move beyond dependence on the old system, as the avian influenza strains that are considered likely to give rise to a human pandemic strain are toxic to the eggs used for cultivating epidemic strains.

The Committee for Medicinal Products for Human Use of the London-based European Medicines Agency on April 26 issued a positive opinion for OptaFlu, a seasonal vaccine produced in Madin-Darby canine kidney cell culture. Basel-based Novartis acquired the product when it took over Chiron (the acquisition closed April 20, 2006). Marketing authorization from the Brussels-based European Commission is now a formality, and a launch for the 2007–2008 season is expected, although that would be limited in scope and well below the total capacity of 100 million doses the company will eventually be able to produce. Novartis spokesman Eric Althoff says the first-year production will be “a more limited volume,” given that it is taking place before actual approval.

“The trouble is, there is limited capacity [for production] at this point. That makes it almost by definition a medium-to-long-term thing,” says Karl Heinz Koch, analyst at Zurich-based Vontobel. Novartis will ramp up production in Marburg, Germany, for the European market, and a new facility at Holly Springs, North Carolina, will produce supply for the US market. The company aims to submit a biologics license application (BLA) in the US for OptaFlu next year, and it now appears to have gained first-mover advantage in the next era of influenza vaccines.

Its two main rivals, Sanofi Pasteur, the vaccines arm of Paris-based Sanofi-Aventis, and London-based GlaxoSmithKline (GSK) are at earlier stages of development. The former moved its vaccine, based on the PER.C6 cell culture platform from Leiden, Netherlands–based Crucell, into the clinic last September. GSK also has a cell culture seasonal influenza vaccine program, but has yet to report on its progress. Also in the race are Brussels-based Solvay; Gaithersburg, Maryland-based MedImmune (now owned by London-based AstraZeneca); and DynPort Vaccine, of Frederick, Maryland. The US Department of Health and Human Services awarded all six firms (including Novartis) an aggregate $1.1 billion to subsidize their cell culture development programs, as part of its efforts to encourage development of pandemic vaccines, as well.

Another contender, biotech firm Protein Sciences, of Meriden, Connecticut, is delaying filing of its BLA for FluBlØk, which it originally planned to complete earlier this year. FluBlØk, a recombinant subunit vaccine based on the hemagglutinin antigen of the three dominant circulating strains of influenza virus, is produced using a baculovirus expression vector cultivated in the insect species Spodoptera frugiperda. The US Food and Drug Administration (FDA; Rockville, MD) has requested a larger safety database in healthy adults using the high-dose formulation that Protein Sciences will eventually release to the market. The firm now aims to commence a rolling BLA this fall, which it hopes to complete by February 1, 2008, in time for next year's flu season, says COO Manon Cox.

If approved, FluBlØk would be competing in a crowded market—GSK, MedImmune, Novartis and Sanofi Pasteur—which will produce up to 132 million doses for the US market for the forthcoming season. On April 2, Parkville, Australia–based CSL disclosed that it had submitted a BLA for its vaccine, and it will eventually have capacity to produce up to 20 million doses for the US. Even if AstraZeneca decides to offload MedImmune's underperforming FluMist franchise, which is expected to deliver 7 million doses this year, CSL faces a significant challenge. “There is no urgent need for new companies entering the market,” says Hedwig Kresse, infectious disease analyst at London-based market researcher Datamonitor.

Cox, at Protein Sciences, realizes the market is tough, although it will target its high-dose vaccine at the elderly and at those unable to take existing vaccines because of egg allergy. “There is a huge oversupply in the US market,” Cox says, with GSK putting “an enormous amount of product” into the US. That firm has capitalized most on the 2004 crisis and is the only supplier with two products licensed for the US. In August 2005, it gained FDA approval for Fluarix, which had been licensed in many other markets. The following December it closed its acquisition of ID Biomedical, of Vancouver, Canada, the maker of FluLaval, a product that gained FDA approval in October 2006. It plans to continue its dual-product strategy, says GSK spokesman Jeffrey McLaughlin, maintaining production of both FluLaval and Fluarix.

The US seasonal influenza vaccine supply is now far more diversified and more secure than it was just three years ago, and the advent of cell culture–based products should only further strengthen the supply.