Flu season

World War I will be remembered as a gruesome and deadly war. The number of dead in certain battles are staggering: 306,000 at la Somme (almost 20 thousand british dead on the first day of battle), over 260,000 at Verdun. The war killed, mamed, wounded, taumatized, widowed and orphaned. To think that after such a muderous war, the world was hit with a pandemic flu which turned out to be more deadly.
The 1918-19 "Spanish flu" pandemic killed at least 20 million people, and perhaps as many as 100 million. In India alone an estimated 17 million died, a morbidity of about 5% of the population. In the US, 28% were infected and half a million died. In a time before the fluid, rapid interconnectedness of jumbo airplanes, the disease spread across the world and took its toll in a mere 6 months. The only sizable city with no documented outbreak is a town on the island of Marajo at the mouth of the Amazon River. In most cities, 20% of its inhabitants were infected. Global morbidity was estimated at 2.5% of the population. In 1957 and 1968, there were two milder pandemics of global impact.

The recent issue of Science had a New in Focus section on the Flu and risks of new pandemics. Of course, now an infection can spreak around the world with greater speed. A model by Rebecca Grais at Johns Hopkins University predicted an outbreak would peak in most of the 52 cities within 6 months. Some of the more catastrophic predictions estimate that when a new pandemic "finally peters out 18 months later, more than 2 billion people have become ill, and more than 40 million are dead--twice the number claimed by AIDS in 25 years". But even more conservative models, like that of Meltzer from the CDC predict a "pandemic could cause between 314,000 and 734,000 hospitalizations and claim between 89,000 and 207,000 lives, they found. Even the lower figures would overwhelm the U.S. health system, says Meltzer: Hospitals were under severe stress when the 1999-2000 flu season was worse than usual."

The memory of old pandemics together with such grime posibilities causes great concern when small outbreaks occur, they could mean a big one. This was the case in 1997, when an outbreak of H5N1 avian flu in Hong Kong killed six people, and when SARS, not a particularly contagious virus, infected fewer than 9000.Where do the new viruses come from?

"For decades, the dominant theory was that new pandemic viruses arise when avian and human flu viruses reassort, or hybridize, inside pigs, which can be infected with both. (Chinese farms, where ducks, humans, and pigs mingle, were seen as plausible locales.) But since 1997, three avian flu viruses--including H5N1, the virus that has infected poultry in 10 Asian countries--have been found to infect humans directly. Now, the predominant worry is that humans infected with both avian and human viruses may be mixing vessels.
Fortunately, chances of this happening still seem low, says Neil Ferguson, an epidemiologist at Imperial College in London. Even if you assume that reassortment occurs in each and every patient infected with the two viruses--which is unlikely--more than 600 people would have to be infected with H5N1 to create a 50% chance of reassortment, Ferguson and his colleagues wrote earlier this year in Science (14 May, p. 968). So far, fewer than 50 people in Vietnam and Thailand are confirmed to have
been infected with H5N1. What's more, most reassortants are likely to pose no threat."

An issue of major concern is how prepared we are in case of a major pandemic? Antiviral drugs albeit effective are expensive and in short supply. Oseltamivir, a potent antiviral sold as Tamiflu, which would act as the initial defense against H5N1, the potent Asian bird flu, if it assumed a form transmitted between humans, is made by only one company, Roche, at a single plant in Switzerland.
The other weapon are vaccines. The prospect of avian viruses being able to directly infect humans actually posed a challenge.

"Flu vaccines are traditionally made by infecting eggs with a target virus and a nonpathogenic strain that grows well. In the eggs the viruses mix their eight genes. Manufacturers then select a strain with genes for neuraminidase and hemagglutinin (two glycoproteins on the virus's surface) from the target virus, and the rest from the normal flu strain; inactivated virus is then used to make vaccine. But H5N1 kills eggs [because the same form that infects humans, infects birds].
A solution exists: reverse genetics(Science, 27 February, p. 1280). Using this technique, the two genes for neuraminidase and hemagglutinin, as well as the six genes from a safe virus, are cloned in bacterial DNA and then reassembled. With highly virulent strains like H5N1, the hemagglutinin gene is first modified to reduce its pathogenicity so the seed virus can be grown in large quantities in eggs. Using reverse genetics, teams at St. Jude and the U.K.'s National Institute for Biological Standards and
Control (NIBSC) each produced an attenuated Vietnam H5N1 strain within 3 to 4 weeks earlier this year--"clearly a phenomenal advance," notes Iain Stephenson of the U.K.'s Leicester Royal Infirmary."

Vaccine supply is a motive of concern. Only 15 countries have preparedness plans, and global supply is short: "the world's capacity for making a monovalent pandemic flu vaccine is now 900 million doses, enough for only 15% of the world's population." Few companies are willing to place their R&D into making them. Only 9 countries in Europe produce 85% of the world's flu vaccine. There is one major supplier in the US: Aventis Pasteur.

"Of the world's 12 major flu vaccine manufacturers, so far only two are willing to tackle the financial, regulatory, and patent issues involved in making a new pandemic vaccine, mainly for the U.S. market. (...) Companies have little incentive to test pandemic vaccines for a market that may never materialize. Intellectual-property and liability issues are also major deterrents. The reverse-genetics flu vaccine is licensed by MedImmune, which uses technology from St. Jude. But Mount Sinai School of Medicine and the University of Wisconsin have patents on similar technology. MedImmune has licensed it for research purposes to Aventis Pasteur and Chiron, but if these companies or others wanted to market a vaccine, they would need an agreement with the other patent holders, says Hugh Penfold of the Centre for the Management of IP in Health R&D, a nonprofit in Oxford, U.K. (...) Even if companies worldwide had the ability and commitment, it could still take 4 to 6 months to manufacture a reverse-genetics vaccine matching a new pandemic flu strain. "

Bundle up this season. Don't get sick.