Saturday, October 15, 2005

I have a long and intimate relationship with influenza virus. More than 30 years ago, I co-discovered one of the viral enzymes essential for the virus to duplicate and proliferate. Later, my medical training taught me respect for this pathogen. Real influenza — as opposed to a garden-variety cold — is a serious illness. Its victims don’t soon forget the fever, headache, muscle aches and profound weakness. In an average year — despite usually at least moderately effective vaccines — it kills tens of thousands in this country.

It seems the flu virus is now poised to repeat a several-times-a-century metamorphosis into something far worse.

First, some background. The exterior of the flu virus consists of a lipid envelope from which project two surface proteins, hemagglutinin (H) and neuraminidase (N). The virus constantly mutates, which may cause significant alterations in either or both of these, enabling the virus to elude detection and neutralization by humans’ immune system.

A minor change is called genetic drift; a major one, genetic shift. The former is the reason flu vaccines need to be updated from year to year; an example was the change in subtype from H1N1 to H2N2 that gave rise to the 1957 pandemic. This new variant was distinct enough that people had little immunity: The rate of infection of symptomatic flu that year exceeded 50 percent in urban populations, and 70,000 died from it in the United States alone.

In the 1957 outbreak, the mortality rate (the fraction of infected persons who die) was low. But we appear to be on the verge of another, much worse pandemic.

During the last several years, an especially virulent strain of avian flu, designated H5N1, has ravaged domesticated poultry in Asia and spread to migratory birds and (rarely) to humans. Now found from Russia and Japan to Indonesia, it is moving inexorably toward Europe. Since 2003, more than 60 human deaths have been attributed to H5N1.

Public health experts and virologists are concerned about the potential of this strain because it already has two of the three characteristics needed to cause a pandemic: It can jump from birds to human, and can produce a severe and often fatal illness. If additional genetic evolution makes H5N1 very transmissible among humans (the third characteristic of a pandemic strain) a devastating worldwide outbreak could occur.

Moreover, this is an extraordinarily deadly variant: The mortality rate for persons infected with the existing H5N1 appears about 50 percent. The usual annual flu kills fewer than 1 percent.

We are ill-prepared for a flu pandemic. Reserves are grossly inadequate of vaccines, drugs and hospital beds. Technological, economic and logistical obstacles abound to the best and most cost-effective intervention — a preventive vaccine.

Anti-flu drugs exist but are not a panacea. Unlike vaccines, which confer long-term immunity after one or two doses, drugs must be taken for long periods. The only drug shown to prevent the flu is Tamiflu. A prophylactic dose is one tablet daily, the effect lasting only as long the drug is taken. (The other major anti-flu medicine, Relenza, has been shown effective only for treating, but not preventing, flu.)

Historically, flu pandemics have come in two or three waves, lasting 13-23 months. In other words, the need to take Tamiflu — by first responders, health-care workers and ordinary citizens — could go on for months and months, or even years.

U.S. public health officials have said they plan to buy 20 million doses of Tamiflu, but that would be enough to treat only 200,000 people (fewer than total attendance of a seven-game World Series) for 100 days. And the retail price per pill is around $8, so it would cost $160 million to treating that small number of people for that length of time.

According to various models, without enough effective vaccine — which is not yet within reach — to blunt a pandemic, we would need to treat perhaps a third to a half of the population with Tamiflu. Do the math: 100 million people for 100 days equals 10 billion doses, at a retail cost of $80 billion, to blunt the pandemic’s first wave.

Though President Bush and Health and Human Services Secretary Mike Leavitt are saying some of the right things about the need to prepare for the pandemic, if they or their staffs have calculated all this, they give no sign of it.

We need push-pull incentives to forming public-private partnerships. Public policy must reward both inputs on research and development (via grants, tax credits and waiver of regulatory registration fees) and treatment outputs (with guaranteed purchases, payments for the regulatory approval of new drugs or vaccines, and liability indemnification).

Part of this effort should be R&D on various new technologies and approaches to making flu vaccine, to boosting the immune response to vaccines, and to creating greater reserve capacity for producing drugs like Tamiflu and Relenza.

Preparing for pandemic flu involves many thorny issues of science, technology and medicine, but also much more. It requires contingency plans for “social” aspects of a deadly pandemic — when to shut our borders to travelers from infected regions, close schools, restrict public gatherings and enforce quarantines, and a designated chain of command to carry out those decisions.

Like the WWII Manhattan Project to develop the atomic bomb, preparation for a flu pandemic involves scientific uncertainties, strategic decisions that span many specialties and government departments, and prodigious resources. To oversee all this, we’ll need a flu-pandemic czar — someone analogous to U.S. Army Gen. Leslie Groves, who headed the Manhattan Project: a plenipotentiary with broad powers and discretion.

There is no time to waste.

Henry I. Miller, a physician and fellow at the Hoover Institution, was founding director of the Office of Biotechnology at the Food and Drug Administration, 1989-1993. Barron’s selected his latest book, “The Frankenfood Myth … ” as one of the 25 Best Books of 2004.

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