Bird Flu, Part II: Do Antivirals Give Us a False Sense of Comfort Against Pandemic Flu?

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The world is due for the next global pandemic flu — whether it be bird flu or another strain — but neither the U.S. government nor the American public should rely on stockpiles of one or two vaccines or antiviral drugs to save them from any looming public health catastrophe, medical experts say.

Even though the H5N1 strain of avian (bird) flu has caused human deaths in Asia, by the time it arrives in the United States — if it ever does — the virus may have mutated in such a way that antivirals like Tamiflu won't be able to combat it effectively.

This mutation is known as "antigenic drift," and it is the reason why vaccines made too far in advance of an actual outbreak of the virus may not work when the time comes.

Editor's Note: This is the second in a five-part series on bird flu that will be featured throughout the week on

Click here to read Part I, "Bird Flu: All You Ever Wanted to Know About the Coming Pandemic."

"It takes a while for it to mutate, and even if it should have human-to human transmission and it takes several months to get to this country, I think we have a year now to prepare," said Dr. Steven Garner, chairman of radiology at New York Methodist Hospital, who previously served as chief medical officer at Saint Vincent’s Catholic Medical Centers of New York.

"I don't think the right place to put the money is buying vaccines in advance," Garner said. "The flu mutates, so what's good today will not be good for the flu that comes over here."

Even in the best of years, available flu vaccines are only about 75 percent of the right strain, Garner pointed out.

There currently is no vaccine approved for human use against the H5N1 bird flu strain, but the U.S. Department of Health and Human Services has contracted with several pharmaceutical companies in the hopes of producing one. The government wants to produce 20 million vaccines for bird flu and 20 million antiviral doses. There are about 300 million people in the United States.

The Swiss company Roche has an exclusive patent to make Tamiflu (oseltamivir) — one of the antivirals used to help fight avian flu that health officials hope will work against a mutated version of the virus — until 2016, and Roche has been trying to keep up with international pressure from 30 countries to mass produce it. The U.S. government has contracted with companies like North Carolina-based GlaxoSmithKline, which is getting $2.8 million to produce 84,300 treatment courses of the antiviral drug Relenza (zanamivir).

Chiron Corporation won a $62.5 million contract to supply the U.S. government with pre-pandemic influenza stockpiles against the H5N1 bird flu strain. That supply will be provided next year.

The government hopes to have 5.3 million doses of Tamiflu by January; the goal is to get 81 million treatment courses total, 6 million of which would be used to "put out the fire" of any immediate outbreak that may occur.

However, according to the World Health Organization, none of this will be of much benefit to developing countries, where the virus is first expected to mutate and jump species.

"On present trends, most developing countries will have no access to vaccines and antiviral drugs throughout the duration of a pandemic," WHO stated.

There is also a chance that people will become resistant to these antivirals the more they are used.

Some U.S. doctors say the United States waited too long to begin preparing for the possibility of a bird flu outbreak.

"There's already worldwide demand and shortage of the drug," said Dr. Brian Currie, vice president and senior medical director at Montefiore Medical Center in Bronx, N.Y.

Currie said other countries are ahead of the United States in this effort; Great Britain currently has enough antivirals to cover about 40 percent of its population.

"We were late in thinking about it and organizing ourselves in having a national program," Currie said. "As a result, the supply was scooped up by others and the production lags behind. We're one of the last people to be thinking about stockpiling and how to control it. By the time we talked about a national stockpile, I would wager most of our supply is in the hands of individuals."

The WHO estimates that it will take a decade to produce enough Tamiflu to treat 20 percent of the world's population.

How Antivirals Works

Tamiflu and Relenza are types of neuraminidase inhibitors that reduce the severity and duration of the flu. Another class of antivirals known as M2 inhibitors could be used, but resistance to these drugs can develop rapidly.

Click here to read more about how flu drugs work.

The surfaces of flu viruses are dotted with neuraminidase proteins, which are characteristic of each flu strain. Neuraminidase, an enzyme, breaks the bonds that hold new virus particles to the outside of an infected cell. Once the enzyme breaks these bonds, this sets free new viruses that can infect other cells and spread infection. Neuraminidase inhibitors basically prevent the enzyme from doing its job and trap the virus inside the cell, preventing new virus particles from being released and limiting the spread of infection.

These drugs are effective only if they're taken within 48 hours of the onset of illness, although many people don't realize they have anything more than a bad cold during the first days of the flu. Some human patients have also shown signs of resistance to Tamiflu.

"I believe that antiviral drugs really represent a tool, a limited tool," Michael Osterholm, associate director of the National Center for Food Protection and Defense at the Department of Homeland Security, told reporters in October. "What we don't know is if Tamiflu will work."

Once it enters the body, H5N1 rapidly duplicates itself and attacks more lung cells than other more common flu viruses do. This causes massive infection and a massive release of chemicals referred to as a "cytokine storm." Basically, too many immune cells are activated in one place and they therefore turn on the immune system to destroy it. A cytokine storm could cause lung damage and could harm other organs.

It's questionable whether Tamiflu needs to be given earlier or in higher-than-usual doses to stave off the storm.

"Frankly we just don't know," Osterholm said.

But if a virus goes unchecked and bacterial pneumonia sets in, antivirals like Tamiflu won't be that effective. That's why, experts agree, more emphasis needs to be put on encouraging the production of more vaccines at a faster rate. They point out that only vaccines have been able to rid the world of smallpox and nearly wipe out polio.

"If you want to control the spread of the disease or control an epidemic, treating a disease [with antivirals] isn't really going to get you that," said Steven Salzberg, director of the Center for Bioinformatics and Computational Biology at the University of Maryland at College Park. "If you vaccinate people, then the flu never takes hold in their system, the disease never takes hold, you never spread it … we should get better and better at vaccinating."

The Vaccine Problem

By February of each year, the CDC and the WHO identify three flu strains they believe have the potential to be the next pandemic. Those strains are then given to vaccine manufacturers, then the race starts to be able to produce it and distribute it before the flu season starts. Seasonal flu vaccines are made of the three inactivated strains of the virus health authorities think will hit the hardest that season.

The problem is, the flu season doesn't hit for another eight months; by that time, whatever flu strain was killing people in China, for example, could have mutated by the time it gets to the United States, thereby rendering those vaccines stockpiled not as effective.

"The evolution of the flu is driven by its response to our immune system basically," explained Salzberg. "It's just natural selection and action … basically the flu that will win the competition each year is the one that makes the most copies of itself and spreads itself around to the most victims."

Salzberg said the scientific community must find a faster way to produce vaccines than the current process of growing them inside eggs.

"The way we make vaccines is ridiculously old-fashioned, ridiculously old-fashioned. We shouldn't be growing them in eggs … if we grew then faster, we wouldn't have to decide in February, we could decide in August with much better accuracy," he said. "If you're going to do an effective vaccine design, what you want to do is put the strain into the vaccine that represents what's circulating. Because it's changing from year to year quite rapidly, you have to keep up with it."

Salzberg is co-leading a sequencing study that is helping to better predict which viral flu strains will attack during the next flu season. That study is being funded by the National Institute for Allergy and Infectious Diseases and overseen by the Institute for Genomic Research.

A flu virus is made of a genetic material called ribonucleic acid (RNA), which is similar to DNA found in plant and animal cells. Changes to a virus' RNA, however, are critical to the flu's ability to survive. The genes of a flu virus are like a program that allows the flu virus to proliferate.

"You can think of it as a little machine that's programmed to get into our system, kind of hijack our own genetic machinery to make copies of itself," explained Salzberg. "Once those copies are made, it can package itself back up into a nice little ball and escape out of the cell and go onto infect other cells and infect other people."

But a vaccine given before the flu hits specifically targets the harmful flu strain before it infects one's cells. It allows the immune system to recognize the virus when it tries to attack the cells and sends out biological fighters to destroy the invaders. But if the proteins characteristic of the flu strain mutate, the body won't recognize it as something it has weapons to battle with.

This all means that vaccines made to protect against certain harmful strains of the flu may not work once the flu mutates and gets passed on — in the case of bird flu, from poultry to humans.

There are currently myriad studies and trials underway aimed at turning around flu vaccines that are more effective and quicker. Some use processes known as reverse genetics and RNA interference, the latter of which is being studied by experts at the Massachusetts Institute of Technology to hinder the flu's ability to multiply inside of the cells it attacks.

Many vaccines are currently in clinical trials.

Chiron, for example, is working a less pathogenic strain of the H5N1 virus and is using the MF59 adjuvant, which is an agent added to a drug to aid its effectiveness, to boost the body's immune response to the vaccine's active ingredient, known as the antigen. The company found that without the adjuvant, multiple doses of vaccine did not induce protection. But with the adjuvant, the vaccine induced protective antibody levels against the original H5N1 strain, including when used at low doses. People injected with the adjuvant also not only showed increased protection against the H5N1 strain but against mutated strains as well.

Philadelphia-based Hemispherx Biopharma has developed an adjuvant called Ampligen, which, when used in combination with Tamiflu, has shown to better prevent cell destruction caused by avian influenza. Hemispherx is also looking into the effectiveness of putting Ampligen into influenza vaccines.

But another problem is a lack of a seamless distribution system to get drugs to everyone who needs them, experts said.

"We have a tremendous investment in developing the vaccines, but we don't have a mechanism for distributing it. Will it be the states who are doing it, will it be the private sector?" Jeff Levi, senior policy advisor at Trust for America's Health, said during a recent Council on Foreign Relations event on bird flu. "I guess the good news is, it will be awhile before we have a vaccine so don't need to solve this problem now."

Respond to the Writer is taking an in-depth look at the initiatives, strategies and policies being employed to prepare the United States and the world against the next pandemic flu.

Stories this week will look at new cell culture technology that would accelerate the production of flu vaccines; why the United States should not be content to rely upon the stockpiling of one or two antiviral medications or vaccines; how the government and medical community hope to entice pharmaceutical companies back into the vaccine production business through incentives such as financial subsidies and liability protections.

Click back to tomorrow to read, "Bird Flu, Part III: Congress Ponders Liability Protection for Vaccine Makers," in the Politics section.