Devilish Dilemmas Surround Pandemic Flu Vaccine

Martin Enserink and Jocelyn Kaiser
Published in SCIENCE:  VOLUME 324:703-705,2009

If and when a pandemic of H1N1 swine flu hits, vaccines might be the world’s best hope for softening the blow. But major uncertainties cloud the prospects for vaccines against the new  strain. No pandemic vaccine yet exists, and it is unclear how much vaccine would have to be available, and by what time, to have any impact. Should manufacturers halt the production of seasonal influenza vaccine to focus on a pandemic version, and if so, when? And is there any way to ensure that people around the world have an equal chance to get the new vaccine?

These topics have been the subject of frantic, almost daily discussions among scientists, vaccine manufacturers, regulatory agencies, and the World Health Organization (WHO) over the past few weeks. But so far, there are few concrete answers, in part because no one knows just how severe a threat the new virus poses, or how difficult it will be to mass-produce a vaccine. One thing is certain, however: There won’t be nearly enough vaccine to protect all the world’s citizens, and the question of who has first dibs could get ugly, says David Fedson, a former pharma executive and influenza vaccine expert living in France.

Almost all seasonal flu vaccine is made using a clunky, 50-year-old process, in which companies adapt the virus to multiply in hens’ eggs, grow the virus in eggs, then purify the  key antigens needed to make vaccine—the hemagglutinin and neuraminidase molecules that stick out from the virus’s surface. In all, the process takes more than 5 months. This is also how at least the vast majority of a pandemic vaccine will be made, because promising alternative production strategies won’t be ready in time.

Immediately after isolating the new H1N1 strain, the U.S. Centers for Disease Control and Prevention and other labs began producing a “seed stock” of virus, which will be given to manufacturers in a few weeks for vaccine production. But how much pandemic vaccine will they be able to produce once they get going? A study funded by the Bill and Melinda Gates Foundation, whose main outcomes were announced in February, gives an indication. The study, carried out by Adam Sabow of the consulting company Oliver Wyman, in collaboration with WHO and the International Federation of Pharmaceutical Manufacturers & Associations, showed that all manufacturers combined can currently produce some 680 million doses of seasonal flu vaccine per year—a number that is expected to grow to at least 1.4 billion by 2014.

It’s not easy to translate that figure into doses of pandemic vaccine. The number depends, among other things, on how successfully scientists can make the new virus grow in eggs, how much antigen is needed for an adequate vaccine response, and whether a so-called adjuvant can reduce the amount of antigen needed per shot. But Sabow’s study concluded that in the most likely scenario, the world’s vaccinemakers combined could produce almost 2.5 billion doses of pandemic vaccine in the first year.

Assuming, as many scientists do, that two shots would be needed for adequate protection— as opposed to one for seasonal vacine—that means there would be enough for 1.2 billion people, less than 20% of the world’s population, that first year. The study was based on the assumption of a pandemic of H5N1 avian influenza, but the figures are not expected to be vastly different for swine flu.

Achieving that output assumes, however, that vaccine manufacturers immediately stop their production of seasonal vaccine, which they are now making for 2009–10, and go full-bore on a pandemic vaccine—a very unlikely scenario. In reality, WHO has to weigh the risk of a shortage of seasonal vaccine, and the increased risk of disease and death that would ensue, against the threat posed by the new strain. For the moment, the new virus doesn’t appear to be highly virulent, but that could change over time. After a relatively mild first wave in the spring of 1918, the Spanish flu returned with a vengeance in the fall.

“It’s a devilish dilemma,” says Jaap Venema, global project director influenza at vaccine producer Solvay in the Netherlands. At a press briefing last week, WHO vaccine expert Marie-Paule Kieny said the agency is in close contact with manufacturers; some are further along with their seasonal production than others, and those might switch first to pandemic vaccines while others do so later.

How to ensure equitable distribution of the vaccine is trickier still. Since the threat of an avian influenza pandemic became urgent 6 years ago, a few developing nations have been fighting hard to ensure they will have access to vaccines if a pandemic strikes. Indonesia even went so far as to refuse participation in WHO’s system for virus sharing in an attempt to wrest hard guarantees from the agency. WHO responded with a plan to increase production capacity in the developing world, which is now home to some 13% of the global vaccine production capacity—but the plan is still in its infancy. To ensure equal access, WHO Director-General Margaret Chan has called for “international solidarity,” and Kieny says WHO is already talking to donors and major global health funders about ways to buy vaccine for the world’s poorest.

But there are some major obstacles. Several countries already have first dibs on any pandemic vaccine. In 2006, for instance, the Dutch government signed a contract with Solvay  guaranteeing that it gets the first 16 million doses of a pandemic vaccine to protect its own population. Other governments have signed similar deals, Kieny says, so “the books  of the manufacturers are already quite full.”

In addition, the governments of the countries with a flu vaccine plant in their territories will be under tremendous political pressure to protect their own populations first, Fedson predicts. “You don’t need a contract,” he says; “all you need is an army” to prevent the vaccine from going across the border. Thus, even rich countries like Sweden and Spain that lack a vaccine plant could find themselves empty-handed, he says.

Unfortunately, there are few alternatives for the moment. Most flu vaccine manufacturers are working to replace the antiquated chicken-egg technology with a cell-based method, in which the vaccine virus is grown in mammalian cells. This has several advantages: Manufacturers are less dependent on the supply of chicken eggs—which is difficult to increase quickly and can become vulnerable during bird flu outbreaks—and it could shave 10 weeks from the 22 weeks now needed to make influenza vaccine using eggs.

But although more practical and cleaner, cell-based vaccines don’t promise a major boost in production capacity. Moreover, success with the technique has been slow to come, despite more than $1.5 billion in U.S. Department of Health and Human Services contracts to several companies to fund clinical trials of cell-based vaccines and scale up manufacturing. “The cell-based vaccines are coming, but we’re not going to see them for this pandemic,” says influenza expert Arnold Monto of the University of Michigan School of Public Health in Ann Arbor. Other recombinant vaccines that could truly lead to an explosion in production capacity are even further down the road, says John Treanor of the University of Rochester’s School of Medicine and Dentistry in New York state.

That means that, at least for now, the world is still dependent on chicken eggs.

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