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Why aren't we asking the hard question about smallpox?

Last month I wrote a column about the threat that smallpox might be used as a bioweapon. The possibility terrified me then, and in the passing weeks this feeling has not diminished but grown. With the sinking certainty of a really bad nightmare, I see the exact shape and form of the danger, a demon genie that, once released, can never again be put back in the bottle. If you don't want to be scared, stop reading now, for I want to tell you my nightmare.

Every nightmare has a horror that drives its terror, and in this nightmare the horror is a virus named variola (from the Latin word for "spotted"). Like Ebola virus, the hemorrhagic form of variola attacks human connective tissue. An infected person feels normal for about ten days as the virus multiplies in the body's connective tissues -- blood vessel walls, skin, and the like. Then fever sets in, and red spots appear all over the body. Smallpox. Over the following days, the virus proceeds to destroy the body's protective layer of connective tissue. The surface skin tears away from its underlayers, while the linings of the digestive passage, the membranes that coat the throat, stomach, and intestines, disintegrate. Like the worst of Ebola virus outbreaks, hemorrhagic smallpox simply dissolves the membranes that hold you together. It is almost always fatal.

Hemorrhagic smallpox and Ebola are both terrifying because they kill in the same gruesome way, but in two ways smallpox seems to me far more terrifying. First, Ebola infection requires physical contact, so it does not spread quickly. Smallpox, by contrast, is spread through the air in the tiny water droplets you expel with every breath, making it very infective indeed. Chicken pox is infective in the same way, and in a classroom with an infected child, few children escape infection. Second, outbreaks of the Ebola virus seem to loose severity after three or four passes through infected people, as if the Ebola virus is not well-adapted to reproducing in humans. Variola, by contrast, is a human virus, beautifully adapted to our bodies. Smallpox outbreaks go on and on, stopping only when everyone is infected or when all infected individuals are isolated so as not to infect others. Only quarantine or death stop smallpox.

If you are one of the few to survive smallpox, you are now immune to future infection. It is by studying the nature of this immunity to smallpox that Edward Jenner first developed vaccines just over 200 years ago. Vaccines are the only weapons we have to fight smallpox. In the nightmare, they don't work.

A vaccine works by teaching your body's immune system how to recognize a threat, without killing you in the process. In some vaccines a virus is heat-inactivated so it can no longer reproduce itself, then injected into people. The body of an immunized person develops antibodies directed against the "dead" virus, which protect that person should the real thing come along. Without going into a lot of detail, the

way this works is that in your body a whole bunch of different pre-antibody proteins "feel up" each invading virus particle, caressing its surface. When the shape of one of the pre-antibodies fits the virus surface exactly, like a hand in a tight glove, the pre-antibody goes berserk, destroys the virus, and fires up the manufacture of millions of antibody proteins like itself, all with that virus-recognizing surface. These millions of defenders then lie in wait, should any other virus particles attempt to infect the immunized person.

Ready for the nightmare? Here it is. The twenty year old vaccines that are our nation's only defense against smallpox, and the new vaccines we are only beginning to think about producing, are all based on natural isolates of smallpox collected over twenty years ago. The smallpox that threatens our future would have been smuggled out of Russian bioweapons research labs over the last few years. So who says the Russians, in their massive research effort to "weaponize" smallpox, never took the easy step of altering the genes that encode the virus's surface proteins? This sort of targeted mutagenesis is done all the time in genetics laboratories all over the world, and is not technically difficult to do in viruses. Making the smallpox weapon resistant to its target's defenses seems an obvious precaution.

Now lets turn up the volume of the nightmare. I was reading last week a powerful New Yorker July 12 article by Richard Preston (he wrote THE HOT ZONE about Ebola virus). Buried deep in the middle of this excellent account of how smallpox became a bioterrorist threat is a truly scary paragraph. In 1991, a team of U.S. inspectors was allowed to briefly inspect some of the Russian biowarfare laboratories. In one of these the Russians seemed to be actively working on smallpox. When the American inspectors asked to put on spacesuits and go inside the principle test chamber, the Russians refused to let them. "They said our vaccines might not protect us," the Americans recount. "It suggested that they had developed viruses that were resistant to American vaccines."

That's the hard question I don't hear being asked in the public discussions about preparing for a potential smallpox threat. Was the weaponized Russian smallpox modified to avoid American vaccines, its surface proteins altered so that our vaccines no longer recognize them? If so, obtaining the form of the virus that the Russians developed, so we can prepare vaccines against that, the true threat, ought to be a national priority. Surely we can ask this hard but necessary question -- or is the nightmare just too scary?

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