Smallpox Disease³

The last case of naturally occurring smallpox occurred almost 25 years ago, and 24 years ago the last episode occurred in Birmingham, England, with the laboratory escape of variola virus. As a result of its eradication, virtually all clinicians, particularly in northern countries, are unfamiliar with this disease and research on human smallpox has practically stopped. Eradication was relatively easy to achieve because humans are the only reservoirs and vectors, the disease is clinically manifest, and there is no carrier or latent state. Moreover, one episode gives lifelong protection, transmission occurs when the disease is manifest, there is a stable vaccine, and it is relatively straightforward to trace chains of transmission.

The smallpox virus replicates in the cytoplasm. The virus enters the respiratory tract and multiplies in the oropharynx. There is a brief burst of viremia that goes into cells of the reticuloendothelial system, followed by a second viremia into the skin, after which the patients then manifest the disease, which then again spreads via respiration. The incubation period for smallpox is 10 to 12 days. The prodrome, which is a mean of two to three days, is very severe, with high fever, backache, headache, and prostration. The first few days involve a macular phase—a reddish rash that is not distinctive, followed in a couple of days by papules, then vesicles, then pustules, which can become confluent over the entire body. After about two weeks there is crusting, hypopigmentation and pitting, scarring, and eventually hyperpigmentation. The infectiousness period occurs when the lesions are heaviest.

There are five known classifications of smallpox. The ordinary form is the most common (~90 percent) with a 30 percent case fatality rate. The flat form accounts for about 5 percent of cases, and has a 97 percent case fatality rate. The hemorrhagic form accounts for less than 3 percent of cases but has a 100 percent fatality rate. The other classifications of smallpox are the modified form (occurring in less than 2 percent of cases and having less than a one percent fatality rate) and V. sine eruptione (occurring in less than 1 percent of cases with no known fatalities). There are no specific strains associated with hemorrhagic disease, thus it is believed to be a host response. Patients with hemorrhagic disease die despite post-exposure vaccination. The hemorrhagic cases do not look like smallpox and many of them will not resemble an infectious disease. It is likely that initially these cases will come into emergency rooms, perhaps diagnosed as acute leukemia or a variety of other things, in which case emergency room personnel are not likely to have taken the necessary precautions one would take if smallpox were suspected.

Conditions that resemble the maculopapular eruptions of smallpox include drug eruptions, measles, secondary syphilis, and vaccine reactions. Chickenpox, monkeypox, and generalized vaccinia can resemble the papulovesicular eruptions of smallpox. With newer molecular approaches to diagnosis, however, more rapid and precise screening, if not confirmation, of variola and chicken pox can help in diagnosis. However, cell culture is the only reliable diagnostic tool for the orthopoxes when the clinical symptoms are indistinguishable.

Smallpox is transmitted person-to-person by large airborne droplets, that is, face-to-face contact of 2 to 2.5 meters. Thus homes and hospitals are major transmission sites. However, carriers are symptomatic so investigations done with due diligence can prevent further spread. In general, it has been believed that smallpox can not be carried by the wind and travel great distances, although outbreaks in hospitals might have been due to movement of the virus through air ducts.

There are certain features of smallpox making it, in temperate areas, a winter or early spring disease, and in the tropics, a hot, dry season disease, mainly because the virus persists longer on droplets in aerosols, and the nasopharynx might be more eroded and therefore more susceptible to invasion by the virus.

The most important epidemiological index for smallpox spread or that of any infectious disease is the number of persons in an environment who, when in contact with a patient, will come down with the disease. Studies in Asia and Africa found that the attack rate in unvaccinated persons ranged from roughly 40 to 90 percent with variola major. Despite being a somewhat milder disease, the secondary attack rate for variola minor is still about 50 percent. The case fatality rate increases as years from vaccination increase, from nearly 0 percent if vaccination occurred less than 10 years prior to contact to over 10 percent when vaccination occurred more than 20 years prior to contact. Deaths from smallpox are generally due to secondary infection of lesions, pneumonia, toxemia, and hypotension. Death rates in unvaccinated patients, particularly those with the more severe form of the disease, can be as high as 50 percent.

Smallpox Control Strategies and Vaccine Availability⁴

Although the smallpox vaccine works well in a pre-exposure and post-exposure setting, quarantine and isolation are also valuable means by which to control spread of the disease. Estimates of vaccination efficacy originally were not based on controlled clinical trials, but rather on comparisons of secondary attack rates among vaccinated and unvaccinated family contacts of cases. Vaccination status was determined by the presence of a scar and did not account for vaccine potency, scarring secondary to skin infection rather than vaccine take, or “on-time” vaccination. Estimates of pre-exposure vaccination efficacy were conservative, yet the general medical opinion is that successful vaccination or re-vaccination within three years provided 90 to 97 percent efficacy against disease. However, even with vaccination, both flat and hemorrhagic smallpox continue to have high case fatality rates—in the 90 percent range—which might reflect a host response rather than protective immunity.

Effectiveness of post-exposure vaccination ranges from 20 to 90 percent. For those receiving primary post-exposure vaccination, the efficacy is around 70 percent—yielding either protection from disease or manifestation of modified smallpox, which has a much lower case fatality rate. In re-vaccinated individuals, efficacy protections are over 80 percent. Effectiveness is clearly present in those vaccinated less than seven days after exposure.

Experience in developing countries, in which hospitals had very high rates in terms of smallpox transmission, demonstrated that poor infection control practices were the cause of rapid spread of the virus. Airborne precautions, including discharge of air to the outside or through a HEPA filter, closed doors, and using a N-95 or better respirator would be expected to prevent this disease. A fitted respirator can provide 90 percent protection against any type of air leakage. Contact precautions can also help control the spread of the virus, for example, use of hand washing, masks, and eye protective gear.

Several characteristics of smallpox led to its control and eventual eradication: 1) cases could be identified because smallpox is a clinically evident disease and there is no subclinical illness; 2) the disease moves relatively slowly— transmission does not occur during prodrome and maximum transmission is at the time of substantial illness; and 3) the vaccine is highly effective.

Mass vaccination was the earliest strategy used. It was not until 1968 that surveillance and containment became the strategy that finally eliminated smallpox. In this approach, cases are searched for and when clinically evident disease is found a ring of immunity is created and if possible, contacts are isolated or quarantined. Determining the size of the ring is the challenge.

Accumulating evidence suggests that surveillance and containment were more effective than mass vaccination in the eradication of smallpox. In West and Central Africa in 1968–1969, cases continued to occur in spite of mass vaccination, until surveillance and containment were initiated. Prolonged and intense exposure was the norm for person-to-person transmission of smallpox, suggesting that control of the movement of these contacts was central to containment.

Operationally, surveillance and containment begins with case detection, followed by vaccination and quarantine of contacts of cases, and delineation of functional and geographic boundaries around cases or outbreaks (e.g., wide-area vaccination), followed by communication among areas about cases.

Protocols are in place for vaccine handling, dilution, and administration in the United States. There are 162 million doses of calf-lymph-derived vaccine and there will be 362 million doses of cell-cultured-derived vaccine by January 2003. The vaccines are currently part of the national pharmaceutical stockpile, located in four regions throughout the United States. Initial shipments can be sent with a confirmed case of smallpox via Vaxicools—self-contained storage and transport units holding 300,000 doses. Any site in the United States can be reached within 12 hours. The entire stockpile could be deployed to multiple locations within a 5-day period.

In summary, vaccination provides high levels of protection, both pre- and post-exposure. Current infection control practices should prevent occupational and nosocomial acquisition of smallpox. Surveillance and ring containment is the most effective means to control this disease in populations with relatively high levels of immunity from immunization, as well as in parts of the world where there are low levels of immunity, both from immunization as well as from naturally occurring disease.

Smallpox Vaccination: Efficacy, Availability, Duration of Immunity, and Timing⁵

Successful primary vaccination confers full immunity to smallpox in greater than 95 percent of persons for a period of approximately 5 to 10 years. Successful re-vaccination provides protection for 10 to 20 years.

The 15.4 million doses of Dryvax that had been produced in 1982 or earlier were tested in a dilutional study (dilutions were 1:5 and 1:10), the results of which were published in the April 25, 2002, issue of The New England Journal of Medicine. ⁶ Vaccination initially was successful in a high percentage of individuals with the 1:5 dilution—a 99.1 percent take rate—compared to the 97.2 percent take rate of undiluted doses. The 1:10 dilution had a 97.1 percent take rate, not statistically different from the 1:5 dilution or the undiluted sample. Thus, the diluted vaccine can be added to the current stockpile (the 15.4 million doses can be diluted to create 77 million doses).

The duration of smallpox immunity has not been satisfactorily measured. Studies of case-fatality rates in Liverpool, England, in the early 1900s showed that when decades separated vaccination from the time of a smallpox outbreak, non-vaccinated individuals had a much higher case fatality rate than vaccinated individuals.

A review by Thomas Mack of the introduction of smallpox in Europe from 1950 to 1971 looked at case fatality rate vis-a-vis vaccination status.⁷ The case fatality rate among 680 cases of variola major was 52 percent for those never vaccinated and as high as 11 percent for those vaccinated more than 20 years before exposure. The data for those vaccinated between 1 and 20 years before exposure suggest a duration of immunity.

Immunity is defined by surrogates of immunity—which can be neutralizing antibody, cellular immunity, and skin reactions. A 1990 study looked at the persistence of neutralizing antibody after re-vaccination against smallpox.⁸ The titer is significantly decreased after the first 3 years after re-vaccination but remains stable at a low level for at least 30 years thereafter. Whether that low level is protective is not clear but clinical observations from other studies suggest that it is.

Cellular immunity is more problematic in its measurement and relevance. A study was conducted of 26 healthy male military recruits who were vaccinated 15 to 18 years earlier.⁹ Blood samples collected before re-vaccination to study antigen-specific proliferative response—an indicator of cellular immunity—indicated that there was virtually no existing specificity of responses of lymphocyte proliferation prior to vaccination. However, a more recent study found that T-cell vaccinia-specific immunity can actually persist up to several decades following immunization.¹⁰

Skin reaction to vaccinia in people who previously had smallpox vaccine provides an additional source of projections about the state of immunity. In a study published in 1968, immunity to smallpox of 425 people in Afghanistan who previously not only were vaccinated but also actually had smallpox showed that 9 to 11 years after their disease more than 50 percent actually had takes, suggesting that they had lost immunity to pox viruses.¹¹

An NIAID protocol is studying 80 individuals from 32 to 60 years old who have been previously vaccinated at least once, but not more recently than 1971. Neutralizing antibody, cell-mediated immunity will be analyzed, as well as interferon-gamma using ELISPOT assays. Baseline measurements will aim to establish the long-term persistence of immunity 30 years or longer.

As for vaccination timing, if administered within four to five days following exposure it may prevent or significantly ameliorate subsequent illness. In an outbreak in Bangladesh of over 1,300 cases, including 372 deaths, few if any individuals who were vaccinated as late as 5 days into their incubation period developed clinical disease, and vaccination performed after 5 days actually reduced the clinical attack rate by 50 percent.¹²

In summary, primary smallpox vaccination probably provides full immunity for at least three to five years. However, beyond that, the immunity duration is still somewhat uncertain. Post-exposure vaccination within several days may prevent or ameliorate disease. However, vaccine with vaccinia, although highly effective, is one of the least safe of all licensed human vaccines. These data must be considered in deciding whether to proceed with voluntary pre-emptive mass vaccinations without credible threat of smallpox attack, voluntary pre-emptive vaccination of “first responders” only, or the use of ring versus mass vaccination in the event of a smallpox attack.

Smallpox Vaccination Safety¹³

Data on the safety of vaccinia are 35 to 40 years old. There is very little in the way of controlled data and immunological knowledge at the time was primitive. Moreover, differences in administration of vaccinia produced different reactions, depending on the number of insertions and therefore the amount of virus delivered.

The first and probably most common reaction to vaccine is erythema multiforma, which occurs 7 to 14 days after vaccination. After re-vaccination, it may occur much sooner. It is sporadic and most likely an allergic or toxic reaction to components of the virus. The rash differs from a macular rash, becoming maculopapular, occasionally vesicular or even pustular, and urticarial. In rare cases, Stevens-Johnson syndrome occurs after vaccination. Diagnosis is by clinical appearance and by temporal association with the vaccine. The treatment is symptomatic, primarily benadryl. Stevens-Johnson syndrome requires more extensive measures, including systemic and topical steroids.

In the past, diseases (including tetanus, syphilis, streptococcal and staphylococcal infection) may have been transmitted from patient to patient due to methods that involved dipping the needle into the bottle prior to vaccinating. Further, the use of totally occlusive dressings in the past to prevent the spread of virus created an anaerobic environment with the potential for subsequent infectious complications. In recent studies, semi-permeable occlusive dressings have been used.

Accidental vaccination (by ingestion or injection) sometimes occurred with no serious adverse consequences, as compared to accidental inoculation, which could have quite serious consequences (such as keratitis, burns, eczema vaccinatum). About 20 percent of complications were, in fact, due to transmission of vaccinia from a vaccinee to some other person.

Traumatic and surgical wounds predisposed individuals to accidental inoculation, as did dermal infection of any type that disrupts the skin (such as eczema, which could predispose those individuals to eczema vaccinatum). Mucosal inoculation occurred via dental extraction, tonsillar extraction, and other mucosal lesions. Young infants and children tended to have more of these complications than others, for obvious reasons. The vaccination site itches, and by scratching they would transfer the virus on to their hands. Because transfer was often by hand, inflammatory eye disease predisposed some individuals to peri-orbital and corneal lesions as a result of their rubbing their eyes. Bathing can result in autoinoculation, particularly in young infants who have lesions elsewhere on their body.

Antiviral agents and vaccinia immunoglobulin (VIG)¹⁴ are useful treatments for these complications, except for use in the eye, although doses are not clearly established. The recommended dosage of the currently available VIG for treatment of complications is 0.6 ml/kg of body weight. VIG must be administered intramuscularly and should be administered as early as possible after the onset of symptoms. Future reformulations of VIG might require intravenous administration.

There remains a need for pharmaceutical therapy, either for the management of smallpox or for the management of smallpox side effects. The eventual development of such drugs would materially change the severity and, therefore, frequency and relevance of the side effects. The development of a drug could become an alternative to vaccination, particularly in some of the containment-oriented scenarios.

Generalized vaccinia is likely to be a problem should vaccination begin. Despite its appearance, it is a benign disease with multiple lesions that heal, except in rare cases of persistent recurrent lesions. However, extensive immunological studies are needed to understand why this disease occurs. Progressive vaccinia is a greater concern. It occurs in immunologically-deficient individuals, primarily in those with cell-mediated immune deficiencies. The disease involves progressive enlargement of the primary site, with viremic spread to other parts of the body, and each lesion expands as does the primary site until the lesions overcome the individual and become fatal. Children with severe combined immunodeficiency do not survive vaccinia and children with hypogammaglobulanemia can be overwhelmed by virus and die. Other populations that are vulnerable if inoculated include those with graft-versus-host disease following solid organ transplantation, cancer survivors, and HIV-infected individuals. Thus, appropriate screening for contraindications to vaccination should be implemented and should include vaccinated persons as well as their contacts. Because there are a growing number of asymptomatic and unknown HIV-positive individuals in society, vaccination strategies must consider the implications of HIV testing.

Footnotes

3

This section summarizes the presentation by Joel Breman, Fogarty International Center, National Institutes of Health.

4

This section summarizes the presentation by Harold S.Margolis, Centers for Disease Control and Prevention.

5

This section summarizes the presentation by Anthony Fauci, National Institute of Allergy and Infectious Disease, National Institutes of Health.

6

Frey SE, Couch RB, Tacket CO, Treanor JJ, Wolff M, Newman FK, Atmar RL, Edelman R, Nolan DM, Belshe RB. 2002. Clinical responses to undiluted and diluted smallpox vaccine. New England Journal of Medicine 136(17):1265–1274.

7

Mack TM. 1972. Smallpox in Europe 1950–1971. Journal of Infectious Diseases 125(2):161–169.

8

el-Ad B, Roth Y, Winder A, Lublin-Tennenbaum T, Katz E, Schwartz T. 1990. The persistence of neutralizing antibodies after revaccination against smallpox. Journal of Infectious Diseases 161(3):446–448.

9

Moller-Larsen A, Haahr S, Heron I. 1978. Lymphocyte-mediated cytotoxicity in humans during revaccination with vaccinia virus. Infection & Immunity 21(3):687–695.

10

Demkowicz WE Jr, Littaua RA, Wang J, Ennis FA. 1996. Human cytotoxic T-cell memory: Long-lived responses to vaccinia virus. Journal of Virology 70(4):2627–2631.

11

Vichniakov VE. 1968. A study of immunity to smallpox in persons who have experienced a previous attack. Bulletin of the World Health Organization 39(3):433–437.

12

Sommer A. 1974. 1972 smallpox outbreak in Khulna municipality, Bangladesh II. Effectiveness of surveillance and containment in urban epidemic control. American Journal of Epidemiology 99:303–313.

13

This section summarizes the presentation by Vincent A.Fulginiti, University of Arizona, University of Colorado.

14

During the discussion, D.A.Henderson noted that there is currently enough VIG available to treat an estimated 700 persons—based on past experience, it is estimated that 100 persons per million vaccinated would require treatment. In other words, there is enough VIG at the present time to be able to vaccinate roughly 7 million people. More will be available later in 2002.