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Ever-Changing Virus Challenges Drugmakers

By Shankar Vedantam and Michael Rosenwald
Washington Post Staff Writers
Saturday, May 2, 2009

The swine flu virus is a wily foe whose central weapon against humans is its ability to rapidly change its form. But the virus also benefits from the slow pace at which people technologically adapt to it.

Scientists must decide the components that go into each year's flu vaccine about six months before the virus shows up -- more than enough time for the virus to change in ways that the vaccine cannot defend against. Technical and cost challenges, moreover, limit public health officials' ability to drastically change the previous year's vaccine, even if they know the coming flu season will bring different strains.

Dodging a global flu pandemic, in other words, is a little like being told you can make one change in a ship's course to avoid hitting an iceberg, only the iceberg is six months away.

The swine flu outbreak has brought all of the challenges into focus -- and left public health officials unsure if they should change the composition of next year's vaccine to guard specifically against swine flu. The formula was decided on about a month ago, six months ahead of the start of the fall flu season in September, and officials now have limited ability to redesign the vaccine. If it turns out that swine flu is a passing storm, it would be unwise to change the vaccine. If swine flu turns out to be a major pandemic, leaving the vaccine as is could have grave consequences.

The trouble is, it may take several weeks to discern whether swine flu is a real problem. Officials have yet to conduct detailed epidemiological research to find out how many people have become sick and how deadly the strain is.

As a precaution, the government is preparing a vaccine aimed exclusively at swine flu -- meaning that people this fall might need to supplement their regular flu shot with a swine flu shot. But Anne Schuchat, acting deputy director for science and public health at the Centers for Disease Control and Prevention, said the swine flu vaccine would not be ready until September at the earliest.

Successful Mutants

While the flu is unpleasant and potentially deadly, the virus that causes it is an elegant demonstration of a central tenet of Darwinian evolution: The fitness of an organism is tied to its niche. What is superior in one niche can be inferior in another, and vice versa. Natural selection is interested only in what works.

The tendency of the flu virus to mutate rapidly stems from its inability to accurately copy itself. But what ought to be a flaw turns out to be a virtue (for the virus): While most mutations lead to dead ends and death, a few variants are successful because human immune systems do not know how to guard against them. In short order, those strains become dominant in the next outbreak.

"Last year's virus can evade today's immune response," said Peter Palese, an influenza virus expert at Mount Sinai Medical Center in New York. "We have all been infected with influenza and have a certain immunity, but the virus has changed enough so many of us can get sick again."

The current outbreak has three strains of viruses -- an avian strain, a human strain and a swine strain -- meaning that all must have come together in the same animal somewhere in the world.

Andrew Pekosz, a flu expert and immunologist at the Johns Hopkins Bloomberg School of Public Health, said scientists and companies are trying to figure out whether there are common elements to all flu strains. If a common factor were found, a single vaccine might provide permanent protection.

Aiming to Be Faster

There are also efforts to reduce vaccine manufacturing time. Currently, the vaccine is grown in chicken eggs -- approximately one egg for each dose. Companies are experimenting with ways to accelerate the process, which would allow health officials, in effect, to get closer to the iceberg before deciding which way to turn the ship.

Several companies, including large drugmakers Baxter International and Novartis, are trying to grow the vaccine in cell cultures. Currently, no cell culture vaccines are approved in the United States, but Novartis is building America's first such manufacturing facility in North Carolina. Novartis has an approved cell culture vaccine in Europe.

Andrin Oswald, chief executive of Novartis Vaccines, said producing the flu vaccine in cells instead of eggs shaves about a month from the process. In a best-case scenario, he said, the company could produce a swine flu vaccine in about three months.

Companies such as Rockville-based Novavax are trying to cut production times even further. Novavax also grows flu vaccines in cells, but instead of using the actual virus, the company uses genetic information from the virus to create a decoy.

Rahul Singhvi, Novavax's chief executive, said his company can make flu vaccines in up to three months and is working on a swine flu vaccine. The technology has not made it to final-stage testing and, like other experimental vaccines, the product would need emergency authorization from the Food and Drug Administration.

While promising, the new technologies are not likely to help right away, said Scott Gottlieb, a former FDA deputy commissioner for medical and scientific affairs.

Doctors got a new tool against the flu in the late 1990s, when antiviral drugs such as Tamiflu and Relenza came to market. They block a protein called neuraminidase that is found on the surface of the virus and helps it spread in the body.

As with flu vaccines, production of neuraminidase inhibitors is complicated. With Tamiflu, which is made by Roche, the process can take up to eight months.

So far, world health officials say Tamiflu and Relenza work against the swine flu virus, and the companies that make them are scrambling to boost production. But the flu virus can become resistant to the drugs, making their effectiveness unpredictable.

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