Smallpox Information Center


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Brief Synopsis of Smallpox Smallpox lesions on skin are shown in this photograph taken in 1973 in Bangladesh. Smallpox infection was eliminated from the world in 1977. Smallpox is caused by variola virus with an incubation period of about 12 days following exposure. Initial symptoms include high fever, fatigue, and head and back aches. A characteristic rash, most prominent on the face, arms, and legs, follows in 2-3 days. The rash starts with flat red lesions that evolve at the same rate. Lesions become pus-filled and begin to crust early in the second week. Scabs develop and then separate and fall off after about 3-4 weeks. The majority of patients with smallpox recover, but death occurs in up to 30% of cases. Routine vaccination against smallpox ended in 1972.

Microbiology and other forms Smallpox, a DNA virus, is a member of the genus orthopoxvirus. The orthopoxviruses are among the largest and most complex of all viruses. The virion is characteristically a brick-shaped structure with a diameter of about 200 nm. Three other members of this genus (monkeypox, vaccinia, and cowpox) can also infect humans, causing cutaneous lesions, but only smallpox is readily transmitted from person to person. Monkeypox, a zoonotic disease, presently is found only in tropical rain forest areas of central and western Africa and is not readily transmitted among humans. Vaccinia and cowpox seldom spread from person to person.

Index Vaccination: Should I? / Can I? Symptoms and Progression What can be done once a person is already infected? History and Potential as a Bioweapon Epidemiology (How it is spread) Frequently Asked Questions Enter your search terms Web smallpox.phages.org Submit search form

Go to the U.S. Center for Disease Control for government information.

Vaccination: Should I? / Can I? The quick answer is: At this time, a typical person can not get hold of the vaccine. Smallpox vaccine is currently approved by the US Food and Drug Administration (FDA) for use only in persons in special-risk categories, including laboratory workers directly involved with smallpox or closely related orthopoxviruses. Under epidemic circumstances, widespread vaccination would be indicated, as recommended by the working group. Vaccination has been successfully and safely administered to persons of all ages, from birth onward. However, there are certain groups for whom elective vaccination has not been recommended because of the risk of complications. Under epidemic circumstances, however, such contraindications will have to be weighed against the grave risks posed by smallpox. If available, VIG can be administered concomitantly with vaccination to minimize the risk of complications in these persons. Before 1972, smallpox vaccination was recommended for all US children at age 1 year. Most states required that each child be vaccinated before school entry. The only other requirement for vaccination was for military recruits and tourists visiting foreign countries. Most countries required that the individual be successfully vaccinated within a 3-year period prior to entering the country. Routine vaccination in the United States stopped in 1972 and since then, few persons younger than 27 years have been vaccinated. The US Census Bureau reported that in 1998, approximately 114 million persons, or 42% of the US population, were aged 29 years or younger. In addition, the immune status of those who were vaccinated more than 27 years ago is not clear. The duration of immunity, based on the experience of naturally exposed susceptible persons, has never been satisfactorily measured. Neutralizing antibodies are reported to reflect levels of protection, although this has not been validated in the field. These antibodies have been shown to decline substantially during a 5- to 10-year period. Thus, even those who received the recommended single-dose vaccination as children do not have lifelong immunity. However, among a group who had been vaccinated at birth and at ages 8 and 18 years as part of a study, neutralizing antibody levels remained stable during a 30-year period.31 Because comparatively few persons today have been successfully vaccinated on more than 1 occasion, it must be assumed that the population at large is highly susceptible to infection. In the United States, a limited reserve supply of vaccine that was produced by Wyeth Laboratories, Lancaster, Pa, in the 1970s is in storage. This supply is believed to be sufficient to vaccinate between 6 and 7 million persons. This vaccine, now under the control of the CDC, consists of vaccine virus (New York Board of Health strain) grown on scarified calves. After purification, it was freeze-dried in rubber-stoppered vials that contain sufficient vaccine for at least 50 doses when a bifurcated needle is used. It is stored at -20°C (James LeDuc, PhD, oral communication, 1998). Although quantities of vaccine have also been retained by a number of other countries, none have reserves large enough to meet more than their own potential emergency needs. WHO has 500,000 doses. There are no manufacturers now equipped to produce smallpox vaccine in large quantities. The development and licensure of a tissue cell culture vaccine and the establishment of a new vaccine production facility is estimated to require at least 36 months (Thomas Monath, MD, unpublished data, 1999). Because of the small amounts of vaccine available, a preventive vaccination program to protect individuals such as emergency and health care personnel is not an option at this time. When additional supplies of vaccine are procured, a decision to undertake preventive vaccination of some portion of the population will have to weigh the relative risk of vaccination complications against the threat of contracting smallpox. A further deterrent to extensive vaccination is the fact that presently available supplies of vaccinia immune globulin (VIG), also maintained by the CDC, are very limited in quantity. The working group recommends VIG for the treatment of severe cutaneous reactions occurring as a complication of vaccination.33, 34 Vaccinia immune globulin has also been given along with vaccination to protect those who needed vaccination but who were at risk of experiencing vaccine-related complications.33 It has been estimated that if 1 million persons were vaccinated, as many as 250 persons would experience adverse reactions of a type that would require administration of VIG (James LeDuc, PhD, oral communication, 1998). How much VIG would be needed to administer with vaccine to those at risk is unknown. -Vol. 281, No. 22 JAMA Consensus Statement

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Symptoms and Progression Smallpox is characterised in its classical form by the sudden onset of fever, headache, backache, vomiting, marked prostration and even delirium. At this early stage the patient may be very ill and compelled to take to his bed. Early in the illness there may appear in about 10% of patients a fleeting rash in the form of a reddening of the skin, not unlike the rash of German Measles. This is the so-called prodromal rash and, in the absence of a history of exposure to a source of infection, there is nothing about this rash to arouse suspicion of smallpox. The incubation period from exposure to the onset of this feverish illness is nearly always 12 days with very little variation either way. About two to three days after the onset of illness the true smallpox rash appears. At this time any prodromal rash will be fading. This true or so-called focal rash is normally diagnostic of smallpox and is characteristic both in its evolution and distribution on the body. It begins as tiny discrete pink spots, macules, which enlarge and become slightly raised papules. Each of these progresses by the third day to become a tense blister, vesicle, 6mm in diameter, deep in the skin. After two more days the fluid inside becomes turbid and the lesions are not described as pustules or by the older term of pocks. In the following days these shrink and dry up to become hard lentil-like crusts ni the skin. Eventually they separate leaving a sunken scar. The hard material which comes away contains smallpox virus in its substance. The distribution of this focal rash is characteristic, affecting the head and extremeties much more than the trunk. These features make classical smallpox easy to diagnose clinically when once the thought of the disease has entered the mind. There is some correlation between severity of illness and extent of focal rash. Toxaemia may be so sever as to cause death even before the rash is fully developed, but more commonly death, if it ocurs, will be between the 11th and 15th day of the rash. In severe cases the rash may cover the entire body and the individual lesions run into one anotehr to become confluent.

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What can be done once a person is already infected? At this time, the best that can be offered to the patient infected with smallpox is supportive therapy plus antibiotics as indicated for treatment of occasional secondary bacterial infections. No antiviral substances have yet proved effective for the treatment of smallpox, and the working group is not aware of any reports that suggest any antiviral product is therapeutic. Encouraging initial reports in the 1960s describing the therapeutic benefits of the thiosemicarbazones, cytosine arabinoside, and adenine arabinoside proved questionable on further study. Recent studies on tissue culture, mice, and a small number of monkeys have suggested the possibility that cidofovir, a nucleoside analog DNA polymerase inhibitor, might prove useful in preventing smallpox infection if administered within 1 or 2 days after exposure (John Huggins, PhD, oral communication, 1998). At this time, there is no evidence that cidofovir is more effective than vaccination in this early period. Moreover, the potential utility of this drug is limited, given the fact that it must be administered intravenously and its use is often accompanied by serious renal toxicity. -Vol. 281, No. 22 JAMA Consensus Statement

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History and Potential as a Bioweapon Smallpox probably was first used as a biological weapon during the French and Indian Wars (1754-1767) by British forces in North America. Soldiers distributed blankets that had been used by smallpox patients with the intent of initiating outbreaks among American Indians. Epidemics occurred, killing more than 50% of many affected tribes. With Edward Jenner's demonstration in 1796 that an infection caused by cowpox protected against smallpox and the rapid diffusion worldwide of the practice of cowpox inoculation (ie, vaccination), the potential threat of smallpox as a bioweapon was greatly diminished. A global campaign, begun in 1967 under the aegis of the World Health Organization (WHO), succeeded in eradicating smallpox in 1977. In 1980, the World Health Assembly recommended that all countries cease vaccination. A WHO expert committee recommended that all laboratories destroy their stocks of variola virus or transfer them to 1 of 2 WHO reference laboratoriesthe Institute of Virus Preparations in Moscow, Russia, or the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga. All countries reported compliance. The WHO committee later recommended that all virus stocks be destroyed in June 1999, and the 1996 World Health Assembly concurred In 1998, possible research uses for variola virus were reviewed by a committee of the Institute of Medicine (IOM). The IOM committee concluded, as did the preceding WHO committee, that there were research questions that might be addressed if the virus were to be retained. However, the IOM committee did not explore the costs or relative priority to be assigned to such an effort, and that committee was not asked to weigh the possible benefits resulting from such research activities contrasted with the possible benefits resulting from an international decision to destroy all virus stocks. These considerations will be weighed and decided by the 1999 World Health Assembly. Recent allegations from Ken Alibek, a former deputy director of the Soviet Union's civilian bioweapons program, have heightened concern that smallpox might be used as a bioweapon. Alibek reported that beginning in 1980, the Soviet government embarked on a successful program to produce the smallpox virus in large quantities and adapt it for use in bombs and intercontinental ballistic missiles; the program had an industrial capacity capable of producing many tons of smallpox virus annually. Furthermore, Alibek reports that Russia even now has a research program that seeks to produce more virulent and contagious recombinant strains. Because financial support for laboratories in Russia has sharply declined in recent years, there are increasing concerns that existing expertise and equipment might fall into non-Russian hands. The deliberate reintroduction of smallpox as an epidemic disease would be an international crime of unprecedented proportions, but it is now regarded as a possibility. An aerosol release of variola virus would disseminate widely, given the considerable stability of the orthopoxviruses in aerosol form and the likelihood that the infectious dose is very small.10 Moreover, during the 1960s and 1970s in Europe, when smallpox was imported during the December to April period of high transmission, as many as 10 to 20 second-generation cases were often infected from a single case. Widespread concern and, sometimes, panic occurred, even with outbreaks of fewer than 100 cases, resulting in extensive emergency control measures. -Vol. 281, No. 22 JAMA Consensus Statement

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Epidemiology (How it is spread) Smallpox was once worldwide in scope, and before vaccination was practiced, almost everyone eventually contracted the disease. There were 2 principal forms of the disease, variola major and a much milder form, variola minor (or alastrim). Before eradication took place, these forms could be differentiated clinically only when occurring in outbreaks; virological differentiation is now possible. Through the end of the 19th century, variola major predominated throughout the world. However, at the turn of the century, variola minor was first detected in South Africa and later in Florida, from whence it spread across the United States and into Latin America and Europe. Typical variola major epidemics such as those that occurred in Asia resulted in case-fatality rates of 30% or higher among the unvaccinated, whereas variola minor case-fatality rates were customarily 1% or less. Smallpox spreads from person to person, primarily by droplet nuclei or aerosols expelled from the oropharynx of infected persons and by direct contact. Contaminated clothing or bed linens can also spread the virus. There are no known animal or insect reservoirs or vectors. Historically, the rapidity of smallpox transmission throughout the population was generally slower than for such diseases as measles or chickenpox. Patients spread smallpox primarily to household members and friends; large outbreaks in schools, for example, were uncommon. This finding was accounted for in part by the fact that transmission of smallpox virus did not occur until onset of rash. By then, many patients had been confined to bed because of the high fever and malaise of the prodromal illness. Secondary cases were thus usually restricted to those who came into contact with patients, usually in the household or hospital. The seasonal occurrence of smallpox was similar to that of chickenpox and measlesits incidence was highest during winter and early spring.16 This pattern was consonant with the observation that the duration of survival of orthopoxviruses in the aerosolized form was inversely proportional to both temperature and humidity. Likewise, when imported cases occurred in Europe, large outbreaks sometimes developed during the winter months, rarely during the summer. The patient was most infectious from onset of rash through the first 7 to 10 days of rash. As scabs formed, infectivity waned rapidly. Although the scabs contained large amounts of viable virus, epidemiological and laboratory studies indicate that they were not especially infectious, presumably because the virions were bound tightly in the fibrin matrix. The age distribution of cases depended primarily on the degree of smallpox susceptibility in the population. In most areas, cases predominated among children because adults were protected by immunity induced by vaccination or previous smallpox infection. In rural areas that had seen little vaccination or smallpox, the age distribution of cases was similar to the age distribution of the population. The age distribution pattern of cases in the United States presumably would be such if smallpox were to occur now because vaccination immunity in the population has waned so substantially. -Vol. 281, No. 22 JAMA Consensus Statement

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