Important bump!
The future of flu vaccine production
18/Jul/09
If a more deadly form of mutated swine flu virus strikes the northern hemisphere this coming winter, governments want to be as prepared as possible. Orders for an as-yet non-existent vaccine have been pouring in to major producers in the last few months. The methods still used to produce most of the world’s flu vaccine stocks however have remained largely unaltered for decades. The A(H1N1) seed viruses the WHO provided to manufacturers at the end of May were planted in huge numbers of 11-day-old fertilised eggs, and it will take an additional 5-6 weeks to adapt a fast-growing strain for production in ‘high-growth’ cycles. It takes between one and two eggs to produce a single dose of vaccine, yet most producers are betting on the slow but reliable method in the current pandemic. But swine flu could also prove to be the spark that lights the fire of next-step technology – scalable cell-based vaccines.
A week after the World Health Organisation declared a pandemic in mid-June, 32 flu vaccine producers began preparing to accelerate production of the A(H1N1) seed virus that had been distributed at the end of May. The first wave of the disease has proven fairly moderate, with mild symptoms and few deaths (the official mortality rate at the beginning of July was just 0.49%). “But that’s also what happened in the last two flu pandemics in 1956/57 and 1968/69,” warned Dr. Susanne Stöcker from Germany’s Paul Ehrlich Institute, the country’s regulatory authority for vaccines. A mutated, more deadly version of the virus sparked a second wave of infections in both cases, killing more than a million people. Although some have questioned whether it makes economic sense to mass-produce a vaccine for what is after all still a mild disease, the latest statistics could now change a few minds. According to Germany’s Robert Koch Institute, a deadly mutated virus would possess a unique combination of characteristics that could make it particularly tricky to diagnose: 70% of those infected in the country so far have been under the age of thirty, and 20% showed no signs of fever. In the southern hemisphere, H1N1 is beginning to displace other seasonal influenzas as the most common form of the disease.
Major vaccine producers have reacted promptly. In mid-June, scarcely a day went by without press release assurances from the big manufacturers about possible production start dates. That’s unsurprising, given that the business provided by a looming pandemic will come in addition to an already booming market for the seasonal trivalent vaccines, which target antigens in virus types H1N1, H3N2 and the varying influenza B-virus.
Vaccines = Big Business
According to analysts, the last few years have seen strong growth in the areas of seasonal vaccines. The seven most important pharma markets for example saw around US$1.8bn in turnover in 2005, according figures provided by Datamonitor. Three years later that number had climbed by around a third to US$2.5bn. The market leaders are Sanofi-Pasteur, GlaxoSmithKline and Solvay, which together have around 70% of total sales. The increase can be traced back to the more comprehensive policies and programmes headed by the WHO and national agencies, which are no longer directed at just the old and infirm. In the US, there are plans in place to vaccinate around 85% of the population against seasonal flu, which experts say would have meant continued strong growth in the sector even in the absence of a swine flu threat.
Estimating market volume for pandemic vaccines is a tricky business, because important parameters for setting prices remain vague. It is still unclear for example how much antigen per egg will be produced per dose. The market for a pandemic vaccine can also be expected to follow different rules than those that dictate conditions for seasonal vaccines. However, most deal options were closed between governments and manufactuers back during the bird flu epidemic, and were ready for activation at the end of June. The big six – Sanofi-Pasteur, Novartis, GlaxoSmithKline, Baxter, AstraZeneca’s MedImmune and Australian vaccine producer CSL – all landed contracts or preliminary agreements.
First on the market – scalable cell-based vaccines
If vaccine producer Baxter is able to back up its claims, then the most advanced pandemic vaccine against the A(H1N1) virus will come from the field of biotech. The company’s spokeswoman Jutta Brenn-Vogt claimed that Baxter is “expecting the vaccine to be available sometime in July.” Pre-series testing and evaluation are already complete, she said, and mass production in Vero cells is underway at Baxter’s facility in the Czech Republic. If all goes according to plan, the commercial release will be a record-breaker in terms of time to market.
Baxters’ only competitor Novartis, which produces in MDCK cells at its Marburg site, has just begun a Phase III clinical trial, and hopes to receive approval from the regulatory authorites for its pandemic flu vaccine by October. Because of the authorisation procedure, the first vaccine doses could only be delivered at the earliest by the end of the year.
All other major producers still rely on the classic method of breeding a weakened and reassorted version of the virus in millions of fertilised chicken eggs – a slower process, but a tried and trusted one. GSK, Sanofi-Aventis and MedImmune will only be able to deliver vaccine doses by October at the earliest. Only CSL, which like Baxter began working from a CDC-isolate before the release of the seed viruses at the end of May, has said that it will be able to deliver doses by mid-August in an emergency situation.
That is an ambitious plan, as the egg-based production of vaccines generally takes around 6 months from virus isolation to market. But although the cell-based vaccine made by Baxter might be produced more quickly, experts also expect it to be more expensive. In spite of that drawback, most analysts consider the method very promising for another reason – it could provide the means for a much shorter lag in the time it takes to respond to an outbreak with a vaccine. According to Brenn-Vogt, scalable cell-based vaccine production systems are able to cut roll-out times in half because the company is able to work immediately with an unaltered version of the isolated virus. In the classic procedure, seed virus strains have to be tweaked to cope with replication conditions inside the egg. Additionally, egg-based production cannot be performed in the BSL3 safety environment required for production of highly pathogenic viruses – and the cell-based method can.
Acceptance will depend on price
Because they offer the ability to react more quickly to the fast-moving demographics of modern pandemics, scalable cell-based vaccines seem destined to replace egg-based production in the long run. To reach the end-user in time, the logistics of seasonal vaccines have to be planned around two years in advance. Optimistic WHO predictions that between one and two billion doses of swine flu vaccine could be available by this fall do not take into account the impact that production will have on the manufacture of seasonal flu vaccines. A major drawback at the moment is price. It isn’t clear exactly how much more expensive vaccines grown with the new method will cost, but if the price difference is dramatic, it could prolong the life of the outdated egg-production alternative for years. Analysts say that vaccine production based on insect-cell or bacteria is the next step.
However, many vaccine experts doubt that most cell-based processes could fully replace the traditional production method. “The current yield in cell-based methods is significantly lower – by a factor of 4-5 – than with egg-based production,” Dr. Rodney Carbis, Head of Vaccine Development at the International Vaccine Institute (Seoul, South Korea) told EuroBiotechNews at the 5th European Downstream Technology Forum (Göttingen) in mid-June. That view was confirmed by European vaccine experts at the European Centers for Disease Control and Prevention (ECDC) in Stockholm: “Growing influenza virus in egg-based culture usually results in significantly higher virus yield than in cell-culture, meaning more vaccine doses are produced in the end.” Carbis believes that there are good reasons to change production from egg-based to cell-based systems, among them allergenicity against egg proteins, time to market, scalability and safety in case of a bird flu pandemic. “But we have yet to develop the right cell lines to do it.” According to Carbis, it could take a decade before cell-based production displaces the traditional method.