Smallpox. A Review of Clinical Disease and Vaccination

Smallpox is caused by variola, a DNA virus and a member or the genus Orthopoxvirus. Humans are its only known host.[1] It spreads from person to person through infective droplets or aerosols released from the oropharynx of infected individuals and by close direct contact, and can also be spread through contaminated clothing or bedding.[2] In the smallpox era, occurrence of the disease was highest in winter and early spring.[1]

Smallpox exists in two clinical forms; variola major and variola minor. Variola major is the severe form, which is highly fatal. Variola minor is a mild form and is associated with fewer symptoms and a sparser rash. These viral strains are immunologically identical and can only be differentiated clinically. Currently, no clinically proven treatment exists for smallpox.[3]

Smallpox infection occurs after the virus implants in the oropharyngeal or respiratory mucosa.[1] Symptoms begin 12-14 days after exposure (range 7-17 days), allowing the virus to replicate in regional lymph nodes and spread systemically, causing a widespread viremia.[2] After this incubation period, patients experience a pre-emptive stage that lasts for 2-3 days and is characterized by high fever (>40 °C), malaise, and prostration with severe headache and backache. This is followed by the eruptive stage, characterized by the appearance of a maculopapular rash that progresses to papules 1-2 days later, vesicles appear on the 4th or 5th day; pustules appear by the 7th day; and scab lesions appear on the 14th day. The rash appears first on the oral mucosa, face, and forearms, and then spreads to the trunk and legs. Lesions may also be present on the palms or soles. These lesions are deeply embedded in the dermis and feel like firm round objects embedded in the skin. As the lesions heal, the scabs separate and pitted scarping gradually develops.[2,3]

Smallpox virus can be transmitted once mucosal lesions appear. The viral-laden mucosal lesions precede the characteristic skin rash by about one day. Patients with smallpox are most infectious once the rash appears because live virus is shed from the lesions, and during the first week of the rash when the oral mucosal lesions ulcerate and release substantial amounts of virus into the saliva. They are no longer infectious once all scabs have separated.[2] Except for the skin and mucous membranes, other organ systems are rarely involved. Secondary bacterial infections are uncommon. Death from smallpox usually occurs during the second week of the illness and most likely results from hypotension and toxemia. The mortality rate for smallpox is approximately 30%. A case-fatality rate of 30% was observed during smallpox epidemics in Asia. Fatality rates are higher among unvaccinated individuals. [2]

Before the introduction of smallpox vaccination, nearly everyone in the world contracted the disease. [1] The last case of endemic smallpox was reported in Somalia in 1977, and global eradication of the disease was declared in 1980. In the United States, routine smallpox vaccination ended in 1972.[4] Smallpox, however, remains a potential agent for bioterrorism, and is classified as a "category A" biological weapon because it is easily transmittable, has a high mortality rate, would likely cause panic and social disruption, and requires special action for public health preparedness. [5] If used as a biological weapon, Smallpox has the potential to cause widespread disease and death and could devastate a city or region. The number of cases could be quite high and significant resources will be necessary to halt an outbreak.[5] Unvaccinated individuals are the most vulnerable targets. Also, it is uncertain whether previously vaccinated individuals maintain their immunity. Historically, vaccinated persons had a case-fatality rate of 7% a decade after vaccination and 11% two decades after vaccination, indicating a waning of protection and increasing the number of potentially susceptible individuals.[3]

All known remaining isolates of smallpox virus are stored at the Centers for Disease Control and Prevention (CDC) in Atlanta, USA, and at a repository near Koltsovo in Russia. However, the existence of other samples cannot be ruled out. From the 1970s until the early 1990s, the former Soviet Union produced large amounts of smallpox, anthrax, and other agents of mass destruction. It is postulated that some of these samples may have been sold to various governments and potential bioterrorists.

The most effective method against smallpox and for preventing epidemic progression is vaccination. The smallpox vaccine is a live vaccinia virus preparation that is administered by scarification with a bifurcated needle on the deltoid muscle or the posterior aspect of the arm over the triceps muscle.[2,3] Formation of a hard, pock-like vesicle within 7-9 days at the vaccination site is the indicator of successful vaccination? Formation of the vesicle may be accompanied by several transient adverse effects, most of which begin 7-12 days after vaccination and include redness and pain at the vaccination site, fever, headache, fatigue, muscle aches, chills, nausea, and rash distal to the vaccination site (usually the chest or back), [2,3] in addition to general swelling and tender-ness of regional lymph nodes. However, the efficacy of the vaccine has not been measured in clinical trials, and data regarding duration of immunity are limited.2 Interestingly, the origin of vaccinia virus is uncertain It has been suggested that it is a result of mixing cowpox virus and another orthopoxvirus during early immunization efforts.[1] The vaccine does not contain variola virus, but the immune response to the vaccinia virus induces a protective response to both variola virus and other orthopoxviruses.

Smallpox vaccination is, however, associated with moderate to severe complications. While complications are rare, they occur 10 times more often among primary vaccines and are more frequent among infants than children and adults. Those at the highest risk for complications from immunization are also at the highest risk for morbidity and mortality from smallpox.[2,6] High-risk groups for whom routine vaccination is not recommended include people with eczema or exfoliative skin conditions; those with leukemia or lymphoma; those receiving chemotherapy with alkylating agents, antimetabolites, or high-dose corticosteroids; people infected with HIV or with hereditary immune disorders; solid organ transplant patients; and pregnant women.[2]

The most frequent complication of smallpox vaccination is inadvertent inoculation, usually autoinoculation, which accounts for about 50% of all complications, whereby an individual may touch the vaccination site and then touch the face, eyelid, nose, mouth, genitalia, or rectum and spread the virus to these sites, causing lesions to form. The lesions are usually self-limiting. [2] Generalized vaccinia, is an eruption of lesions usually occurring 6-9 days after vaccination and results frot9 blood-borne dissemination of the virus.[6] The rash is usually self-limiting, but individuals with severe dissemination or are immunocompromised require therapy to help minimize the severity of symptoms, which coup result in death. Eczema vaccinatum is another complication which generally affects vaccines and unvaccinated contacts with either active or healed eczema or other exfoliative skin disorders, whereby the virus spreads to most or all eczematous areas. Progressive vaccinia is characterized by necrosis of the vaccination area and distal sites, including bones and viscera. This often fatal complication primarily occurs in immunocompromised individuals.[2,6] Another serious complication is postvaccinial encephalitis, which occurs at a rate of one case per 300,000 vaccinations and has only been observed among primary vaccines.[2] Because of complications resulting from the smallpox vaccine, the decision to stop universal vaccination was made in 1972, even before global eradication of the disease.[4] Vaccinia Immune Globulin (VIG) is the only treatment option for complications of vaccinia vaccination, but it is not used for the treatment of smallpox.[2]

Until recently, only 15.4 million doses of smallpox vaccine (Dryvax, produced 20 years ago by Wyeth Laboratories) were available in the United States. Researchers have explored the option of diluting the current stockpile of Dryvax should the immediate need for mass vaccination arise. Efforts for vaccine production are now focused on a live cell-culture derived vaccinia virus vaccine. Vaccinia vaccine is only available under investigational new drug protocols. Therefore, informed consent and documentation are required for its use in humans.[2]

The Advisory Committee on Immunization Practices (ACIP) recommends vaccinating only limited populations, including laboratory workers who work with cultures of the virus or with animals contaminated or infected with non-highly attenuated vaccinia strains Health care workers who may come in contact with contaminated materials should also be vaccinated. These populations should receive booster doses every 10 years to ensure continued immunity. Widespread vaccination would be indicated under epidemic circumstances, occurring only from a laboratory accident or an act of bioterrorism.[2,5] Recently, the ACIP recommended that all acute care hospitals establish smallpox health care teams to facilitate investigating and responding to initial cases should the need arise. Although vaccination of the public is not currently recommended, those seeking vaccination may be accommodated by offering them an unlicensed vaccine this year or a licensed vaccine in 2004.[7]

Because the development of new vaccines is directed toward cell-derived formulations, currently known complications and fatality rates may not apply to new smallpox vaccines. This will not be known until the new vaccine is administered and studied either in clinical or epidemiologic trials. The population for whom immunization is contraindicated will be much larger than when the vaccine was first routinely administered. The frequency of cancer, immunosuppression for solid organ transplantation and other diseases, HIV/AIDS, and skin conditions is higher today than it was in the middle or the 20th century, and these patients are most likely to experience complications. Thus, although a new vaccine may be associated with fewer complications, far more people could potentially experience vaccine-related complications. It is estimated that 1 death will result from vaccination in every 1 million primary vaccines.[2] In the U.S. it is estimated that if 50% of the population is exposed to smallpox as a result of a bioterrorist attack, approximately 5% of unvaccinated individuals and 3% of those with partial immunity (vaccinated before 1972) will die from smallpox or its complications. This conservative estimate translates into 100,000-1 million deaths whereas preemptive vaccination would likely result in about 200 deaths.[7]