Smallpox: could a deadly disease--declared eradicated on Earth--come back to haunt humans as a bioweapon? (Life Science Infectious Viruses).

It's one of history's oldest and most fearsome killers. Smallpox causes scorching fever, oozing blisters, terrible scarring--and death, especially in children. Thought to have taken its first human life 10,000 years ago in Africa or Asia, the earliest evidence of its deadly mischief is found on the scarred faces of mummies in the Cairo Museum.

It's also written all over the history books: Mass outbreaks of the disease gutted the world's greatest empires, from the Romans to the Aztecs, and spared neither peasants nor princes: King Louis XV of France died of it; Abraham Lincoln survived, but probably carried lasting battle scars.

Smallpox is also the only disease to be deliberately--and successfully--wiped out by man. The drive to defeat it accelerated in the 18th century, when a British doctor named Edward Jenner developed the first smallpox vaccine, a substance to shield humans against the disease.

Millions lined up for Jenner's lifesaving discovery in the centuries that followed--and slowly the number of cases began to drop. Smallpox hasn't been seen on U.S. soil since 1949, but in Africa and Asia the disease continued to ravage poor and remote regions. So in 1967, the World Health Organization (WHO) launched a global vaccination campaign to eradicate smallpox. The strategy worked--the world's last natural case occurred on October 27, 1977, in a hospital cook in Somalia.

Today, the virus (microscopic panicle) that causes smallpox officially exists in just two places: a high-security U.S. government laboratory in Atlanta and a similar lab in Russia. But in the aftermath of 9/11, some experts fear that terrorists or nations such as Iraq may have secretly acquired the virus for use as a biological weapon. To prepare for any potential threat, the U.S. government in January announced a far-reaching program to vaccinate 11 million health-care workers and military personnel. But the plan has sparked raging controversy. More than 80 U.S. hospitals are refusing to administer the vaccine, which can trigger rare but severe side effects--including death. "The cost in deaths from vaccine complications will outweigh any benefits," argues Dr. Thomas Mack, a University of Southern California smallpox expert.

Others disagree: "The threat of bioterrorism is real," stresses Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. To show Americans they have nothing to fear, President George W. Bush rolled up his sleeve to receive his own shot last December. What exactly is this disease, and just how real is the threat? Read on.

Q: What is smallpox, and what are its symptoms?

A: Smallpox is a contagious and often-fatal disease caused by the variola virus, a particle so tiny that roughly 1,000 linked together span the width of a human hair. Despite its size, variola is a potential killing machine: Nearly one out of every three infected people die.

The disease assumes different forms. But a person infected by the virus usually feels nothing for the first seven to 17 days. Then, signs of malignant smallpox set in: high fever, chills, body aches, and vomiting--most people are too sick to get out of bed. After two to four days, a scarlet rash appears in the mouth and throat, then on the face and forearms; soon it spreads to the entire body. As the rash spreads, the fever usually breaks. The person may even start to feel better--but actually the worst is yet to come.

The rash gives way to tiny bumps, which fill up with a thick milky fluid. The fever returns and the bumps become painful pustules--dense pus-filled blisters that look like BB pellets embedded in the skin, mostly on the face, arms, and legs. By the second week, the pustules start hardening into crusty brown scabs, which fall off after three to four weeks, leaving permanent pitted scars.

"The exact cause of death in fatal smallpox is unknown to science," notes Richard Preston in his book The Demon in the Freezer. But he says physicians who have watched it know its horrors: "As the end approaches, the smallpox victim can remain conscious, in a kind of frozen awareness."

Q: How is the disease spread?

A: Smallpox passes from person to person primarily through air on virus-laden water droplets that explode from a patient's mouth when he or she coughs or sneezes. Occasionally someone can become infected by contaminated bedding, clothes, or other objects. As far as scientists know, neither insects nor animals transmit the disease. But a human infected with the disease is contagious until the last smallpox scab falls off.

Q: What is the smallpox vaccine?

A: The most common vaccine used today is made from the vaccinia virus, a close relative of the smallpox virus. Like all vaccines, it works by stimulating the body's disease-fighting immune system (see diagram, p. 10).

"Vaccinia and smallpox are so much alike that our immune systems have trouble telling them apart," Preston notes. As a result, he says, "within days, a vaccinated person's resistance to smallpox begins to rise."

The logic behind the smallpox vaccine has changed little in the last two centuries, ever since Edward Jenner developed medicine's first successful vaccine. Jenner's breakthrough occurred in 1796, when he observed that dairy-maids exposed to cowpox, a disease of cows that causes only mild blistering in humans, rarely contracted smallpox. On a hunch, Jenner inserted pus from the blistered hands of a dairymaid into the arm of a healthy 8-year-old boy. When the boy was later exposed to smallpox, Jenner found it had no effect. He called his treatment "vaccination," from the Latin word vacca for cow. Vaccinia, the virus used to make the vaccine today, is also made with the help of cows, and scientists say it's all but indistinguishable from the virus Jenner used in his landmark experiment.

Q: Why is the vaccine so controversial?

A: Simple, says Thomas Mack: "This is the single most dangerous live-virus vaccine we have." Vaccines for flu and other viral diseases are typically made from weakened or killed disease-causing particles. Since the smallpox vaccine employs vaccinia at full-strength, the virus can be unpredictable--and hits some people hard. Routine side effects include a fever and sore, swollen muscles; about one in every 1,000 people requires medical treatment for severe rashes and other side effects.

But 15 of every 1 million people will suffer permanent blindness or other potentially life-threatening reactions, says the U.S. Centers for Disease Control and Prevention: "Based on past experience, it is estimated that between 1 and 2 people out of every 1 million people vaccinated may die."

Since side effects are more common in people who are pregnant, have skin infections like eczema, or weakened immune systems, opponents to the vaccination plan argue it's even more dangerous today that it was in previous generations. More than 60 million Americans are estimated to have compromised immune systems from cancer, an organ transplant, or HIV, for example,

Despite the risks, some doctors are determined to get vaccinated. "I sort of feel a sense of duty to get it done," Dr. Joel Geiderman, co-chairman of the Department of Emergency Services at Cedars-Sinai Medical Center in Los Angeles, said recently. "Duty to my patients, to the public, even to my country. I want to be able to help my patients if they need me."

Q: Does smallpox really pose a threat as a lethal weapon?

A: Most experts believe the chances are slim. "The possibility scares me," virologist Don Francis, who worked the front lines in the global effort to eradicate smallpox, admitted in USA Today. "It's a dangerous disease, and we have little immunity."

One way terrorists could turn smallpox into a weapon is by putting the virus in a sprayer and misting the air. "It's not that difficult," notes D.A. Henderson of Johns Hopkins Center for Civilian Biodefense Studies in Baltimore. The toughest part, he says, is getting hold of the smallpox itself. "It's harder to get than anthrax." Another possibility: a "living bomb" scenario, in which a terrorist infects himself with smallpox, then fans out through U.S. airports or other crowded areas to spread the disease.

Still, many scientists believe an outbreak can be contained if caught fast enough. "The idea is to build a fire-break of immune people," says Jonathan Tucker, author of Scourge: The Once and Future Threat of Smallpox.

An infected person would be quarantined as authorities vaccinated anyone who had come in contact with him, says Tucker. The strategy, known as ring vaccination, is the same one WHO officials used to quash the disease in the 1970s. By denying the virus a new host, it soon burns itself out.

One problem is that despite centuries of experience, scientists don't know how easily smallpox can spread. Some think it's as infectious as viruses such as chickenpox or measles, which can race through human populations like wildfire. Other experts think terrorists trying to use smallpox as a weapon would ultimately be undermined by the disease itself--since its classic scarlet rash and disfiguring pustules make smallpox very difficult to hide.

"It's not anthrax in an envelope," says virologist Francis. "It's a person with a rash who's very sick." And that just might give authorities the warning they need to avert a smallpox disaster.

HOW THE SMALLPOX VACCINE WORKS

Vaccines are altered forms of disease-causing bacteria or viruses, which imitate a natural disease to stimulate the immune system. Smallpox is caused by the variola virus, and the vaccine is made from its relative vaccinia.

1 Diluted live vaccinia virus is injected into the bloodstream, replicating itself and stimulating the immune system without causing the disease.

2 The immune system sends out white blood cells called macrophages, which identify the virus as an invader and begin to gobble up viral particles.

3 Some macrophages collect information about the virus and transmit it to the bone marrow, where all white blood cells are produced.

4 Bone marrow produces two kinds of white blood cells called lymphocytes: B cells and T cells. B cells mature into plasma cells, which produce antibodies tuned specifically to destroy the vaccinia virus. T cells travel to the lymph nodes, where they mature.

5 When the body manufactures T and B cells specifically designed to combat vaccinia, the cells become concentrated in the lymph nodes. If the actual smallpox virus enters the body, these lymphocytes will destroy virus particles before they can reproduce.

It's Your Choice

After reading the article, choose the correct answer to these questions:

1 Which of the following statements about smallpox is not true?

A Nearly one third of all people infected by the variola virus die.

B Smallpox pustules give way to scabs, which fall off to leave permanent scars.

C An infected person is contagious for two weeks.

D The disease is especially dangerous for children.

2 The smallpox vaccine

A derives from the dead vaccinia virus.

B is given using a conventional needle.

C causes no side effects in people with compromised immune systems.

D is virtually the same vaccine today given by Edward Jenner 200 years ago.

3 Aerosolizing smallpox means

A transmitting the virus by coughing.

B spraying the virus in the air.

C containing the virus through vaccination.

D combating the virus with antibodies.

ANSWERS

1. c 2. d 3. b

BEYOND SMALLPOX: OTHER BIOWEAPONS

Unfortunately, smallpox is only one of several potential biological
agents that can be exploited as a bioweapon. Here are four others:

PLAGUE                   HOW IT'S SPREAD       HOW IT ATTACKS

Caused by the highly     Fleas that have fed   Plague attacks
contagious bacteria      on infected rodents   lymph nodes, which
Yersinia pestis,         spread plague to      fight infections. One
commonly found in rats.  humans. Also          to six days after
                         spreads via air       exposure, fever and
                         through coughing.     chills set in, then
                         Can be aerosolized,   coughing up blood.
                         or sprayed in air.

BOTULISM

Caused by a toxin        The bacteria can      Botulism poisons
from Clostridium         grow in canned        the nervous system,
botulinum bacteria,      foods. As a germ      causing symptoms
which thrive without     weapon, the toxin     such as blurred
oxygen in soil           could be used to      vision and extreme
or canned food.          poison food, but is   weakness.
                         not contagious.

EBOLA

Four virus families      Spread by rodents,    Fever and aches
cause hemorrhagic        ticks, mosquitoes,    begin four to 16
(profuse bleeding)       person-to-person      days after infection.
diseases: Marburg,       contact. Highly       Virus interferes with
Ebola, and others.       contagious. Can       blood clotting.
                         be aerosolized.       Severity: mild to
                                               deadly.

TULAREMIA

Caused by Francisella    Highly infectious,    Within three to
tularensis, a bacteria   the disease easily    14 days of exposure,
in rodents and ticks.    passes through        swollen glands,
                         body tissues into     fever, and
                         bloodstream. Can      pneumonia set in.
                         be aerosolized.

PLAGUE                   HOW IT'S TREATED

Caused by the highly     Caught early,
contagious bacteria      plague is treatable
Yersinia pestis,         with antibiotics like
commonly found in rats.  streptomycin.
                         Untreated, plague
                         can kill in days.

BOTULISM

Caused by a toxin        If found early,
from Clostridium         botulism can be
botulinum bacteria,      treated with
which thrive without     antitoxin drugs
oxygen in soil           that neutralize
or canned food.          poisoning.

EBOLA

Four virus families      No vaccines exist.
cause hemorrhagic        The infected person
(profuse bleeding)       must be isolated to
diseases: Marburg,       prevent virus from
Ebola, and others.       spreading.

TULAREMIA

Caused by Francisella    Antibiotics work,
tularensis, a bacteria   but even without
in rodents and ticks.    them, up to 95
                         percent of infected
                         people recover.

DEBATE IT: A voluntary public vaccination program may begin next year. Should every American be vaccinated? Should there be exceptions? Would you want to be vaccinated?

Did You Know?

* The word variola was coined around 580 A.D. to describe smallpox from the Latin "mark on the skin," the pus-filled blisters that are the hallmark of the disease.

* In 980, the Arab scientist Rhazes wrote that while smallpox was transmitted from person to person, survivors never developed it again--the first scientific theory of acquired immunity.

* In January, the U.S. Environmental Protection Agency (EPA) upgraded 3,000 air-quality monitoring devices around the country--which normally measure air pollution--to additionally detect smallpox, anthrax, and other pathogens within 24 hours of their release.

Cross-Curricular Connection

History: Research a well-known historical figure who contracted smallpox and write a brief report about his or her experience with the disease.

Critical Thinking:

Smallpox was officially declared eradicated in 1980. Why do you think two laboratories--one in the U.S. and one in Russia--kept samples of the virus that causes the disease?

Resources

Scourge: The Once and Future Threat of Smallpox, Jonathan B. Tucker, Grove Press, 2002

"Smallpox: Your Questions Answered," Time Online Edition, December 13, 2002

www.time.com/time/nation/article/0,8599,399780,00.html

"Smallpox: The Triumph over the Most Terrible of the Ministers of Death," Annals of Internal Medicine, October 15, 1997

www.acponline.org/journals/annals/15oct97/smallpox.htm

CHECK FOR UNDERSTANDING

Directions: Circle the correct answer(s) to complete the sentence.

1. Smallpox was declared (a global threat, eradicated, under control) after 1977, when a natural case appeared in (the U.S., Russia, Somalia).

2. Vaccines work by stimulating the body's (immune, digestive, respiratory) system.

3. Smallpox is (contagious, fatal). Inspiration for Dr. Edward Jenner's breakthrough vaccination came from (chicken pox, cowpox).

4. Most experts believe the threat of smallpox as a bioweapon is (slim, high, very high.)

ANSWERS

1. eradicated, Somalia 2. immune 3. slim 4. contagious, fatal; cowpox