Preparing for the Worst
The Economist, May 9, 2009
MEXICO CITY sprang back to life this week after two weeks of fear and inactivity. Officials shut down most of the economy to halt the spread of a previously unknown strain of the mongrel H1N1 virus, which is comprised of avian, swine and human influenza viruses. The hope is that the outbreak has now peaked.
If so, that will come as a relief to many, as the virus has spread rapidly around the world. On May 6th the World Health Organisation (WHO) reported 822 confirmed cases in Mexico, including 29 deaths. Altogether, 403 cases have been detected in the United States, including at least one death. Dozens of non-lethal cases have been found in 22 other countries. If a cluster of self-sustaining cases in a region outside the Americas is confirmed, the WHO will raise its concern from level five to the top of its six-level scale for global pandemics.
Richard Besser, the acting director of America's Centres for Disease Control (CDC), said the virus "so far is not looking more severe than a strain that we would see in seasonal flu." That is not as reassuring as it sounds. An influenza outbreak in 1918 began in a mild way, but returned in a lethal form months later and killed millions. Margaret Chan, the WHO's boss, cautioned: "it may come back…the world should prepare for it."
One of the best ways to do so is vaccination. Surveillance systems and antiviral treatments will help contain a disease, but they cannot halt it the way a vaccine could. Such a treatment would have to come from the makers of vaccines for the more ordinary, seasonal strains of flu. Yet despite all the advances in biological science, this industry still relies on capital-intensive, inflexible and old-fashioned technologies, such as producing vaccines from millions of chicken eggs.
The drift and shift
The production of flu vaccine has developed to cope with seasonal flu. The disease may seem no more than a nuisance to many, but the flu still kills perhaps 500,000 people a year around the world. It is hard to develop a perfect vaccine against seasonal influenza because it is so fleet-footed. There are usually several different strains of influenza active at any time, and these variations evolve. Alan Barrett of the University of Texas says travel by carriers of influenza, be they people in aeroplanes or birds on the wing, means regional mutations quickly spread around the world. Hence, even when flu subsides at the end of the northern hemisphere's winter, the disease merely shifts to the southern hemisphere (which is now entering its winter). Six months later, it moves back. When the mutations are gradual, as with seasonal flu, it is known as drift; when they are abrupt, as with the new strain of H1N1, you have a shift on your hands.
To help the vaccine manufacturers plan, the WHO issues guidelines every six months listing the three strains of seasonal flu that appear to pose the biggest threat during the relevant hemisphere's approaching winter. The firms then prepare their genetic cocktails and develop them inside live chicken eggs in sterile conditions. The resulting "trivalent" vaccine provokes the patient's immune system into producing antibodies, and that primes it for an attack by the worrying strains of flu.
The final product comes in two forms. Most of the world's flu vaccine is a killed virus, given as an injection; Europe's Sanofi Pasteur and Novartis are leading producers that use this approach. America's MedImmune has come up with a nasal spray that uses a live flu virus in a weakened form. Both methods use lots of eggs.
If a global pandemic is declared and manufacturers are asked to produce a vaccine for H1N1, they are unlikely to be able to respond quickly enough. Firms can produce perhaps a billion doses of seasonal vaccine every year. The details of dosing for a pandemic vaccine are not yet known, but it is clear that even if all the capacity was switched to pandemic flu there would still be a huge global shortfall. Keiji Fukuda of the WHO summed it up this way: "There's much greater vaccine capacity than there was a few years ago, but there is not enough vaccine capacity to instantly make vaccines for the entire world's population for influenza."
Switching production also poses risks. A lack of vaccines for seasonal flu guarantees that many unprotected people will die of the otherwise mundane version of influenza. Nor is there any guarantee that, having switched production, a second wave of an H1N1 strain will indeed be deadly. So producing pandemic vaccines as a precaution may turn out to be a waste of resources with deadly results. Or it may save millions of lives. No one knows.
The main problem is that egg-based manufacturing cannot mount a rapid response. It could take only a few more weeks for the WHO and CDC to develop a "seed" strain of the pandemic virus, but experts say producers would then need four to six months before they could create large volumes of vaccine.
Could more innovative manufacturing techniques help? One promising approach involves growing vaccines not in eggs but in cell cultures, which is speedy and easily scaled up. Another is to add adjuvants, which are catalysts that improve the efficacy of a vaccine and reduce the amount of active ingredient required.
A number of companies have been hoping to get such technologies to the market by 2011 or 2012, and some might be able to help with any shortfall should there be a pandemic later this year. Anthony Fauci, head of America's National Institute of Allergy and Infectious Diseases, says the American government has been funding many such firms in preparation for bioterrorism and pandemics. But he points out that none of the firms has so far got a pandemic flu vaccine past safety trials. "They are not ready for prime-time," he says.
Yet desperate times may lead to desperate measures. Cell-based manufacturing is already used to make vaccines against many other diseases, so it might win rapid approval for flu. European regulators have been more enthusiastic than American ones about allowing adjuvants in flu vaccines. Mexican officials are reportedly in discussions with biotech firms to build flexible vaccine-facilities quickly. The WHO this week called such novel approaches a risky "leap of faith". But if a crisis does engulf the world, that may be a leap some are willing to make.