Smallpox: a clinical perspective Speaker: Donald A. Henderson, MD, MPH University of Pittsburgh Medical Center audio presentation

Highlights

	Smallpox is a real and present threat as a bioterrorist agent.
	The risk was heightened by the development in the USSR of an extensive biological weapons program.
	Shortly after the World Health Organization announced that smallpox had been eradicated (May 1980), the Soviet military command issued an order to maintain a stockpile of 20 tons of the virus.
	Today, at least 75% of the US population is susceptible to smallpox—i.e., never vaccinated or vaccinated more than 30 years ago.
	Vaccination decisions for public health involve balancing risks: likelihood that smallpox will be used as a weapon; adverse reactions and public response; likelihood that vaccination will effectively control outbreaks.

Here we are again

"When, in May 1980, the World Health Organization (WHO) declared that smallpox had been eradicated and that we could stop vaccinations throughout the world, I folded up my notes on smallpox, thinking we would never be talking about it again," said Donald A. Henderson of the University of Pittsburgh Medical Center. "But here we are again, many years later, back on the subject—and with very good reason: smallpox now poses a threat for bioterrorism."

In his teleconference presentation, Henderson reviewed the history and clinical presentation of smallpox, a viral disease that has been infecting humans for at least 3000 years. Smallpox lesions were found on unwrapped mummies of Ramses V and other Egyptians, he noted. "But, even in the 20th century, there were an estimated 300 million or more deaths due to smallpox before eradication was achieved."

Immunity or death

The clinical course of smallpox has been well documented, Henderson observed. The incubation period is 7 to 17 days, after which the infected person develops a high fever, feels "miserable," and then develops a rash.

Once the rash develops, the disease is contagious. Macules and papules appear; then the fever drops suddenly and remains relatively low as the macules develop into vesicles and pustules. Once the lesions scab over, very little transmission occurs.

The virus spreads from person to person only when the rash is present, said Henderson. "Because there are no subclinical infections, only individuals who have the rash will be able to spread it, mainly by face-to-face contact. This is a great advantage in being able to stop an outbreak, because by the time most individuals get the rash, they have already taken to bed because they are so sick, and thus few people get exposed to the infected person. Most of those people will either be in the home or in the hospital, and this tends to limit the spread of the disease."

The infected person can spread the virus only after s/he becomes sick.

Once an individual recovers from smallpox, he or she has permanent immunity. However, smallpox has a 30% mortality rate, making it among "the most lethal" of pestilential diseases, Henderson noted. No antiviral drugs are available to treat it, and none in development today look promising, he added.

Eradication: victory, for a time

Henderson gave a short history of the smallpox eradication program, which began in 1967. At that point, he said, there were 10 to 15 million cases in some 43 countries, with an estimated 2 million deaths that year. The eradication program had two components: vaccination, with the goal of at least 80% coverage; and case detection, followed by isolation of patients and vaccination of close contacts of patients. "We called this 'surveillance-containment' or 'ring vaccination,' " he said.

The virus spreads from person to person only when the rash is present.

Both efforts were successful. By 1970, all of West Africa, with the exception of Nigeria, was smallpox-free. By 1973, South America was free of smallpox, and in Africa, only Ethiopia and Botswana were still experiencing cases.

However, the program was proving to be less effective in India, Pakistan, and Bangladesh. So, in the summer of 1973, a new approach was introduced. During a 10-day period, health workers visited all villages throughout India, searching for individuals with smallpox, to locate people with the disease and to set in motion investigation and containment measures whenever cases were discovered. Some 120,000 people participated in the search effort.

By the third search, "at least 90% of houses in India were being visited; within 18 months, smallpox was gone from India and, soon after, from Bangladesh." The last cases remaining were in the horn of Africa, but in October 1977 the last case was detected, in Somalia, a hospital cook named Ali Maalin. "Smallpox clearly was the disease that every country was most concerned about, and to see the demise of it was regarded as a great victory," Henderson said.

Hint of a weapon

During the eradication period, one outbreak of concern occurred in Meschede, Germany, in 1970. A young German engineer contracted the disease in Asia, came home, and became symptomatic. He was hospitalized. At first, because he had high fever and severe abdominal pain, he was diagnosed as having typhoid. Once he developed a rash, however, he was quickly moved to a special smallpox hospital.

Everyone in the hospital and in the town of Meschede—about 100,000 people in all—was vaccinated, but additional cases occurred. All but one was either a patient in the hospital or a member of the staff. A visitor who entered the hospital went upstairs and opened a door to a corridor near the engineer's room to find out where he could find the person he had come to visit. He was told that he was in the wrong building, and so he closed the door and left—and later developed smallpox.

"This patient had an unusual symptom, a cough, which we don't usually see with smallpox," Henderson said. "With a cough, one can generate very fine aerosol particles containing the virus, which can remain suspended for as much as 24 to 48 hours. So, we postulate that this individual was coughing and putting up a fine particulate aerosol, which disseminated throughout the building. We were later able to do smoke studies in the building to demonstrate that this is the pattern you would get from an aerosol dispersion in the room of a patient."

An aerosol could infect a very wide area and be a potent weapon.

This suggested several things: that the visitor could not have had a very high dose of virus; that many of the others who were infected could not have had a high dose of virus; that an aerosol of smallpox has the capacity to infect over a very wide area; and that it can be a potent bioterrorist weapon."

The defection in 1992 of Ken Alibek, deputy director of the Soviet biological weapons program, also raised a red flag. Alibek revealed that the Soviet military command had issued an order to maintain an annual stockpile of 20 tons of smallpox virus. And a manufacturing facility was developed near Moscow that was capable of producing 80 to 100 tons of the virus annually.

"That manufacturing plant was a secret facility," said Henderson. "It remains a secret facility today. We have no idea what's there. However, we do know that there was a huge biological weapons program in the Soviet Union—larger than their nuclear program. With the break up of the Soviet Union, support to the different laboratories was markedly reduced, and of the 60,000 people who worked in the 50 different laboratories, probably only a third to a half of the individuals are still working there.

"The others have dispersed all over the world, including the United States. So there's a real possibility that biological weapons programs may have been established in other countries—in Korea, Syria, Iran, and other areas. This is a matter of real concern, not only with regard to smallpox, but for other biological weapons."

A vulnerable nation

The greatest concern is that the United States has a highly susceptible population, Henderson emphasized. At least 75% have never been vaccinated or have lost their immunity because of being vaccinated more than 30 years ago.

When experts met on September 18, 2001, to assess how well the nation might deal with a biological event such as a smallpox release, the results were "alarming." There were no smallpox vaccine manufacturers anywhere in the world; the United States had only about 15 million doses of smallpox vaccine in storage; and a WHO worldwide inventory revealed that there might be no more than 80 million doses altogether, all of it produced at least 25 years earlier and not all of it properly preserved.

Worse, if a release had occurred in September 2001, only about 90,000 doses would have been available for emergency distribution. Some of the diluent for the vaccine had gone bad, and there were limited quantities of needles and vaccinia immunoglobulin.

Getting more vaccine became a top priority, and by 2004 the picture had changed. Today, there are about 95 million doses of calf-lymph vaccine, made years ago but still potent, and 150 million doses of a more contemporary vaccine. Moreover, testing has shown that diluting the available vaccine fivefold would be acceptable, significantly extending the number of vaccinations that could be administered.

Who gets access?

But who should get the vaccine? The question has not been completely resolved. In 2001, the experts asked three questions. What is the probability that smallpox would be used as a bioweapon? How frequent are adverse reactions, and how would the public respond to them? How effective would outbreak control be?

They decided that it was unlikely that smallpox would be used as a weapon, but the risk was not zero. If the virus were released, it would spread in the now-susceptible population and the results could be catastrophic. With respect to adverse reactions, data from the 1960s suggested we could expect 15 to 20 serious events of various sorts per million persons vaccinated and one death.

The vaccine confers protection even if given three or four days after infection.

More recent experience, derived from vaccinating some 700,000 military personnel, revealed significantly lower rates. There was just one case of postvaccinal encephalitis, no cases of progressive vaccinia, no cases of eczema vaccinatum, and direct transfer in 49 cases—almost all spouses, children, or other very close contacts to the individuals who were vaccinated.

The lower rates were thought to reflect more careful screening for contraindications than was conducted in the 1960s, along with the vaccination of an otherwise healthy group of young adults. That favorable experience would not necessarily hold, however, for a civilian program aimed at vaccination of all ages.

Unexpectedly, a minimally symptomatic myopericarditis occurred in about 1 of 8,000 to 10,000 vaccinees. All patients recovered uneventfully. A number of other cardiovascular events were reported, such as angina and myocardial infarction, but it was determined that the incidence was no greater than what one might see in an unvaccinated military population during a three-week period.

With respect to outbreak control, it was agreed that smallpox does not spread readily, and that the vaccine will confer protection even if it's given three or four days after infection. This means that vaccinating in hospitals and homes of patients could significantly curtail the spread of the disease.

"At this point, the program to vaccinate medical and public health staff at special risk, and later first responders, came to a halt. Several factors account for this. There is a perception that smallpox is no longer a risk because none was found in Iraq. Hospital directors and public health officials, already stressed by limited funds and a lot of obligations, felt that they didn't want to go through the effort of getting people vaccinated," Henderson said. Moreover, concerns about potential litigation arising from complications made a lot of people "back off." However, he added, "we do have a good supply of vaccine now, ready to move at a moment's notice."

Although we are better prepared than on 9/11, we are not really fully prepared.

"Frankly, I do not feel concerned at this time that we do not have a larger number of people vaccinated," he continued. "I believe that we could control an outbreak resulting from a release of smallpox much better now than we could in September 2001. But although we are better prepared we are not really fully prepared, because we could do better in having hospitals prepared to house a large number of people who are potentially contagious, and we should have better mechanisms for distributing vaccine than we now have. This has not as yet been worked out well at most local levels."

More work clearly is needed in these areas, he continued. "Some people have asked, 'how long must we sustain the efforts?' And I'm afraid the answer has got to be 'probably forever.'

"There's no way in the world that we can put the genie back in the bottle. Smallpox is out there, individuals could retain stocks of it, we would not know anything about it, and the release of the smallpox virus could be easily done," Henderson concluded.