The Return of Smallpox

On Tuesday evening, October 22, the phone rang. It
was a federal official I
have known for years. "The U.S. government can't sit on this much longer," he
told me. His normally calm voice was cracking. "Three people down in Florida have
a rash; 30 are in quarantine. The CDC is all over it." He would not say the word
we both were thinking: smallpox. "I can't stay on the phone; turn on the news,"
he said.

I thought it was the end of the world. By the end of next year, the U.S.
government probably will have grown enough cell-culture smallpox vaccine to
immunize everyone in the country. In four or five years, testing of new antiviral
drugs presumably will have progressed, giving us a good idea of whether
post-infection treatment of smallpox will actually work. But right now? What can
we do right now? Not a lot.

The Florida rashes were a false alarm. By the next morning, four doctors had
diagnosed shingles in the afflicted patients, who with their contacts were
released from quarantine. Smallpox had slipped back again from appalling
certainty to specter--a "low-risk, high-consequence threat," as experts like to
put it.

But that has new meaning nowadays. A few months ago, the CDC wouldn't have
dreamed of slapping three people with shingles into quarantine together with
their friends and relations. How serious is the smallpox threat? There is no
unambiguous answer. What we know is this:

Smallpox, unlike the ubiquitous anthrax, would be hard for terrorists to
obtain, but not impossible. Since 1980, when the disease was declared eradicated,
the only legal stocks of the smallpox virus have been held in two repositories,
the Centers for Disease Control in Atlanta, Georgia, and the Vector Research
Center in Koltsovo, Siberia. But American intelligence reports indicate that the
virus is also in the hands of the North Korean bioweapons program, as well as the
secret Russian military laboratory at Sergiyev Posad. And that's just for
starters. Most experts believe that the Iraqis also possess the virus--not least
because Iraqi soldiers captured during the Gulf War showed evidence of having
been recently vaccinated for smallpox, and this was 10 years after the disease
was supposed to have disappeared from the earth. Though with less certainty, the
experts also suspect Iran, China, India, Syria, and Israel of having illicit
stocks of the virus. In the circumstances, we cannot be confident that stocks of
smallpox could not fall into terrorist hands.

The common claim is that a smallpox attack, if it were to happen, would kill
about one infected person in three. But it is actually quite difficult to
calculate the damage a smallpox outbreak would cause--especially if the disease
were seeded in many locations at once, the most dangerous scenario.

In part this is because smallpox strains--even variola major, the form
responsible for most infections throughout human history--vary quite a lot in
their virulence. Experts say that variola-major strains from Africa typically
killed about 10 percent of those infected, while the much hotter strains from
India and Bangladesh, where crowded circumstances permitted the easy passage of
extremely lethal strains from one person to another, killed up to half of those
infected. Furthermore, some people, regardless of the strain involved, just get
much sicker than others do. Pregnant women, for instance, and persons with
compromised immunity are more likely than others are to develop hemorrhagic
smallpox, a severe and almost always fatal form of the disease. According to Ken
Alibek, former first deputy director of the Soviet bioweapons program, Russian
scientists weaponized India-67, an extremely lethal smallpox strain, years ago.
But the truth is that we have no idea what strain a bioterrorist might use.

Several factors suggest that the death rate from a smallpox attack in the
United States could be much lower than is usually projected. For instance, the
American public, and indeed the rest of the world, while certainly lacking total
immunity, is far from a virgin-soil population. When smallpox swept through
Native American communities after European settlers brought the disease with them
to the New World, 75-90 percent of those exposed to the disease apparently died
of it. This was because Native Americans lacked any genetic history of exposure
to the disease. But Asians, Europeans, and Africans have lived with smallpox for
more than 3,000 years. Over that much time, genetic resistance to so fatal a
disease must have evolved. Even Native Americans, given the intensity of their
exposure to the disease after its introduction, undoubtedly have some resistance
now: They didn't all die of it, and those who lived must have passed some measure
of inherent resistance on to their descendants.

In addition, the better people's general level of immunity, the better they're
able to fight off even a serious infectious disease. (According to virologist
Alexis Shelokov, who was part of a 1992 investigational team that studied the
notorious 1979 outbreak of inhalational anthrax in the Russian city of
Sverdlovsk, the range of victims was extremely skewed: Of the 68 people who died,
the overwhelming majority were heavy smokers over 40, probably with damaged
lungs, and in generally poor health.) It is thus quite possible that smallpox
would not cause the damage in America that it once did--and might again--in, say,
Calcutta or Bangladesh.

Finally, anyone who was vaccinated against smallpox before routine
vaccinations were stopped in 1972 probably has a certain amount of residual
immunity, and the literature suggests that this protection may be considerable.
In one study of 680 infections in Canada between 1950 and 1971, 52 percent of
unvaccinated people died, compared with 1.4 percent of those vaccinated 10 years
or less before exposure and 11 percent of those vaccinated 20 years or more
before exposure.

That's the good news. The bad news is that the world is much more crowded than
it was back when our models of smallpox infection were constructed. This means
that the disease could now spread more easily (which would also make it possible
for more virulent strains to persist). We have, moreover, much better means of
transportation now, which could result in infection rapidly spreading to all
parts of the globe. And in the United States, there are many more severely
"immunocompromised" people (despite the overall general health of the American
population) than there ever have been before, because of AIDS and because of
anticancer therapy. The experts believe that immunocompromised individuals,
besides being more vulnerable themselves, may shed more virus than infected
people with normal immune systems do.

If smallpox were to return now, it would come back to a world crucially
different from what it was a generation ago. In one respect, though, the world is
the same: Grave or slight, the threat of smallpox again exists in it.

The surest way to deal with that threat is to take it completely off the
table by reimmunizing the world's population against smallpox. There then would
be no point in unleashing the virus anywhere as a biological weapon. Widespread
immunization is not, however, the Bush administration's policy.

This may be in part because the government doesn't have the vaccine. Over the
years that we've known of the existence of illicit stocks of the smallpox virus,
it's never been official U.S. policy to produce more vaccine. Consequently, we
now have only some 15.4 million doses, which is not even enough to control one
major outbreak if it were to happen, say, along the eastern seaboard of the
United States.

Experiments are now under way to test diluted vaccine. In theory, our existing
stocks of vaccine could be stretched in this way to cover 75 million people. But
the only way to tell if diluted vaccine will work in practice is to try it out:
If the vaccine produces a significant pock on the skin after inoculation, it most
likely will provide effective immunity against smallpox. Meanwhile, a new
cell-culture vaccine (as opposed to the old vaccine, which was produced by
scraping the bellies of infected calves) is now being developed. But even in the
most optimistic scenarios, it will be a year before there's enough smallpox
vaccine for everyone in the country--and this assumes that the new vaccine will
actually work as well as the old one did.

Smallpox vaccine is not without its dangers. Immunocompromised individuals
can develop progressive vaccinia, an often fatal condition in which the vaccinia
sores spread over the body. AIDS isn't the only disease that produces such severe
reactions. After vaccination, even the uncomplicated skin disease eczema can
produce a severe, sometimes fatal condition called eczema vaccinatum. During the
mass vaccination of between five million and six million New Yorkers in 1947, 28
people developed this condition just from exposure to someone who was vaccinated.
Furthermore, people who touch their vaccinia pocks and then rub their eyes can
develop serious and even blinding eye infections.

Given these risks, many experts believe that mass vaccination of the public is
just too dangerous. Lance Gordon, a vaccinologist who developed a vaccine now
routinely given to prevent bacterial meningitis in children, thinks that the
government's best strategy is to stockpile enough vaccine to provide for everyone
in the nation--but not to use it unless the disease actually strikes. "It's a
question of risk/benefit," he says. "The risk of adverse reactions with vaccinia
is too great if we don't have smallpox. By keeping it stockpiled ... we have the
benefit without the risk." This is the administration's position as well. We
would first try to contain an epidemic by isolating the patients and vaccinating
only those who've been in contact with them, the strategy called "ring
vaccination." Eventually, the entire nation might need to be immunized, but only
if an outbreak were spiraling out of control. Ring vaccination, developed by
William Foege, now of Emory University's Rollins School of Public Health, worked
brilliantly in the past. But this painstaking and labor-intensive method was
designed for a natural outbreak and might not work at all in a bioterrorist
attack, especially if terrorists launched many simultaneous releases across the
country.

Stockpiling vaccines is considered the conservative strategy. But it may not
be the fairest or the wisest one. "If we have a vaccine which is given to the
majority of the population, an epidemic would not get out of control," says
Konstantin Chumakov, a former Russian scientist who is now a vaccinologist with
the U.S. Food and Drug Administration's Center for Biologics Evaluation and
Research. Some of the most thoughtful people in the field agree.

If we choose to stockpile and not immunize, says Paul Ewald, a specialist in
the evolution of infectious disease and author of the recent Plague Time,
we
are accepting the deaths of the first people who become infected in a
bioterrorist attack. "People are canaries in the mines here. Are you going to
plan to sacrifice these people, without giving them a chance to protect
themselves?" Meanwhile, terrorists will not be deterred. They could simply adjust
their strategy to cause maximum damage--panic, terror, death--in the period
before the disease was recognized and a vaccination campaign begun.

Furthermore, in the event of a smallpox attack, you'd probably have no choice
about being vaccinated unless you were seriously ill with an immune disorder. The
decision would be made for you, out of necessity, given the rush of events. It
would be far better, Ewald thinks, to allow people to make that choice for
themselves to the extent possible, particularly since massive voluntary
immunizations in advance of any crisis could well be sufficient to prevent one.

If you could choose whether to be immunized, you'd have a number of factors to
weigh, such as your general health, your HIV status, your age, your anxiety over
the smallpox threat. You might decide that the risks are too great and you'd
rather not be vaccinated. Or you could decide that although you are HIV-negative
now, your personal behavior might someday expose you to AIDS and it would be far
better to be immunized now than later on, when a smallpox vaccination could kill
you. Women who plan to become pregnant might make a similar choice to be
vaccinated now rather than put themselves and their babies at risk later. And
many Americans might choose vaccination just because they understood that getting
a smallpox shot could reduce the chances of a smallpox attack on the nation.

Whether the U.S. strategy is to immunize or to
stockpile, however, producing
the necessary vaccine will take time--and time is what we may not have. For this
reason alone, the administration ought to be looking into the most obvious
alternative: getting help from the Russians. Recently, Russian Minister of Health
Yuri Shevchenko offered the United States that assistance: "The Ministry is
ready, in case of an emergency, to provide medical assistance and vaccines to
America... . Besides vaccines, Russia has technology, a collection of strains,
and much experience to offer." Shevchenko seems to have been speaking
specifically of anthrax, but American officials I've spoken with--all of whom
insist on anonymity--suggest that the offer extends beyond anthrax to the whole
range of potential biological weapons. Russian scientists at Vector claim to have
developed an oral vaccine against smallpox, according to one American official;
another says that the Russians are in the process of developing a multipurpose
vaccine for smallpox and hepatitis B. At the very least, the Russian Ministry of
Health certainly has large supplies of vaccinia virus, the traditional smallpox
vaccine--a useful resource, should we need it.

Some U.S. biodefense experts argue that collaboration with the Russians could
have other benefits as well, including helping to transform wary former enemies
into allies. Although both sides have their "dinosaurs," as one official
acerbically puts it, we can learn a lot about biodefense from Russian scientists
and there's much we might prevent by working together. "If Russians [were to]
throw their support to the Taliban," says the FDA's Chumakov, "it would be the
end of the world."

At this writing, the Bush administration is not saying what it might be
discussing with the Russians--if, indeed, it's discussing any of this. The
official U.S. policy is to press forward with the stockpiling of our own vaccine
and hope that there's no attack in the meantime. It's a policy that we ought to
be debating.

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