Variola virus belongs to the Poxviridae family, subfamily Chordopoxvirinae, as a member species of the Orthopoxvirus genus. Chordopoxviruses infect a wide variety of animals including birds, rodents, ruminants, and humans, and these viruses can exhibit wide to narrow “host” species specificities and host ranges. The Orthopoxvirus genus includes four virus species known to infect humans, variola, monkeypox, vaccinia, cowpox, as well as others not currently known to naturally infect humans. Orthopoxviruses are closely related and immunologically cross-reactive. Edward Jenner demonstrated cross-protection against variola in humans first using cowpox in 1798 and then using vaccinia virus. Poxviruses have large virions, approximately 140 to 260 nm × 220 to 450 nm. Oval-or brick-shaped virions encapsulate linear, double-stranded DNA genomes of approximately 200 kb in length. There are two epidemiologically characterized variants of variola infection: “variola major” and “variola minor”; each differs in case fatality rates and some viruses associated with the less severe disease manifestations can be distinguished in the laboratory or by genetic markers (2).

Much of the information about smallpox pathogenesis has been gleaned from using animal models with a variety of orthopoxvirus challenges. In human smallpox disease, epidemiologic information indicated that the common route for infection was via the respiratory tract; transmission via the skin or congenitally occurred less frequently. The virus asymptomatically replicates in the endothelium and enters the reticuloendothelial system. Additional replication occurs in the lymph nodes. Macrophages migrate to infected lymph nodes early in infection, and the production of cytotoxic T cells and B cells limits the spread of infection. Neutralizing antibodies can be found during the first week of infection. Secondary viremia followed by initial onset of symptoms occurs on average 12 days after transmission. Hemagglutination inhibition and complement fixation antibodies are present approximately 16 and 18 days postinfection, respectively. These antibodies may dissipate after 1 year; however, neutralizing antibodies are present for many years postinfection (2, 3 and 4). Currently, humoral immune responses to orthopoxvirus infections are more commonly measured
via immunoglobulin M and/or G enzyme-linked immunosorbent assays and neutralizing responses (5).

A rash develops over the entire body and goes through several stages (described below) as macrophages migrate to the epidermis. Aside from oropharynx and skin lesions, virus can be found in lymph nodes, bone marrow, spleen, liver, kidney, urine, and conjunctival secretions (2,3). In fact, virtually all organs are affected. Endothelial cells lining the sinusoids of the liver swell and can become necrotic, and parenchymal cells swell. The spleen enlarges with increased lymph involvement. Hemorrhaging of renal, gastric, and pharyngeal membranes and endocardium and myocardial tissue occurs. Thrombocytopenia, encephalitis, and necrosis of testis are also occasionally noted. Prominent pitted scarring is likely due to the destruction of sebaceous glands (6).

The exact cause of death due to smallpox is not completely understood. Secondary bacterial infections have been posited to play a role in death, but recent data do not support their role in fatalities. One retrospective study attributed many deaths to cytotoxicity or immune complex disease (7).

Edward Jenner demonstrated the principles of vaccination in 1796 when he used material from human cowpox lesions to protect individuals against smallpox. Today, live vaccinia virus is used to vaccinate against smallpox. Vaccinia virus is a closely related, yet distinct Orthopoxvirus species from variola. Routine vaccination was common in many countries until the early 1970s (4).

Variola virus has no nonhuman animal reservoir, and infection can be prevented with a single-dose, recent vaccination: these two characteristics made eradication a feasible accomplishment. WHO began an intensive surveillance, containment, and eradication campaign in 1967. Surveillance and containment consisted of the following five steps: (a) identification of cases, (b) isolation of patients, (c) identification of ring or close contacts, (d) vaccination of the ring contacts, and (e) vaccination of the associates of the ring contacts. This approach was used to eradicate smallpox and is recommended by WHO for use today if smallpox reappears (2,4). However, if a reintroduction occurs, widescale vaccination may occur in several countries.

In late 2007, the Food and Drug Administration licensed a new smallpox vaccine to replace Dryvax®. This new vaccine, ACAM2000®, is a cell culture grown, fully replicative vaccinia virus derived from a clonal isolate of Dryvax®. ACAM2000® was chosen based on its similar efficacy to Dryvax® (16). Focus of current research on smallpox vaccines is the further development of replication competent cell culture-derived vaccinia; replication deficient, highly attenuated vaccinia; and DNA-or protein-based vaccines. Preclinical and clinical trials are currently underway for some of these newer vaccines to determine their efficacy (17).

The preferred site for vaccination is the upper arm over the deltoid muscle. Vaccine is delivered by scarification using a sterile bifurcated needle that has been dipped into the rehydrated suspension. Fifteen perpendicular strokes to the skin are given through the droplet within a diameter of about 5 mm. The appearance of a drop of blood indicates that the strokes were vigorous enough to puncture the skin. Following successful primary vaccination, a major cutaneous reaction should appear at the site of inoculation by day 6 to 8 (Fig. 104-5). Within 2 to 5 days postvaccination, a papule will appear that will become vesicular, then pustular, and reach maximum size at day 8 to 10. The pustule will dry forming a scab which typically separates within 14 to 21 days, often leaving a pitted scar, and hypo- or hyperpigmentation is not unexpected. Persons who are revaccinated after successful primary vaccination may have a modified cutaneous response but this does not necessarily indicate an unsuccessful vaccination (18).

Because the current smallpox vaccine is a live, fully replicative vaccinia virus and can cause secondary transmission,
the inoculation site must remain covered until the scab has completely detached and a new epidermal layer has formed. A gauze bandage held in place by adhesive tape should loosely cover the site. If the vaccinee has an occupation that puts him or her in direct contact with patients, the gauze should be covered with an additional barrier using a semipermeable dressing and a layer of clothing. The use of only a semipermeable dressing is not recommended as it might lead to maceration of the vaccination site. Maceration can cause prolonged irritation and itching, potentially leading to increased touching or scratching and therefore contamination of hands. If maceration does occur, the lesion should be left uncovered to allow the site to dry. This is only suitable when a healthcare worker has no direct contact with patients or other persons. The vaccination site must remain covered until the scab separates (19). Contaminated bandages should be sealed in a plastic bag and thrown in the trash. After direct contact with the vaccination site, hands should be washed with soap and warm water or with alcoholbased hand rubs. Potentially contaminated clothes, towels, or sheets should be washed separately in warm water (18).

The Advisory Committee on Immunization Practices lists a number of contraindications to smallpox vaccination in a routine nonemergency setting for both vaccinees and their household contacts. For both, these include a past or present history of eczema or atopic dermatitis; acute, chronic, or exfoliative skin conditions such as burns, chickenpox, or Darier’s disease; immunodeficiency or those currently on immunosuppressive therapy; inflammatory eye diseases leading to use of steroid eye drops; and pregnancy or plans to become pregnant in the next 4 weeks. Additional contraindications for vaccinees only include: allergy to smallpox vaccine components, including polymyxin B, neomycin, streptomycin, and phenol; symptomatic or asymptomatic heart disease or three or more cardiac risk factors (hypertension, diabetes, hypercholesterolemia, heart disease at 50 years of age in a first degree relative, or current smoker); breastfeeding; persons under 18 years of age, especially infants <12 months, and those older than 65 years; severe allergy to latex; or “moderate” to “severe” illness at vaccination time. There are no absolute contraindications to vaccination for a person with a high-risk exposure to smallpox (18,20,21).

In the United States, routine smallpox vaccination of civilians was discontinued in 1971 following reduction of smallpox importations in the 1960s. In 1976, routine vaccination of healthcare workers was also discontinued (22). In 2002, a preparedness plan was initiated to protect the United States against a possible smallpox bioterrorist attack. This plan calls for vaccination of both military and civilian personnel. Under the U.S. Civilian Smallpox Preparedness and Response Program, groups of public health and medical response teams who would care for smallpox patients during the first 7 to 10 days of an outbreak were voluntarily vaccinated (Table 104-1). Approximately 40,000 civilian personnel received licensed vaccine from January to December 2003 (23). Since 2003, CDC continues to provide smallpox vaccine to state public health authorities for vaccination of smallpox response team members. CDC recommends revaccination of volunteer responders on an “out-the-door” basis, meaning only after a smallpox outbreak has been confirmed or is highly suspected, or there is credible evidence of a release or imminent release (24). The US military continues to vaccinate personnel who serve in high-risk parts of the world. Additionally, laboratory researchers who work with or may be exposed to nonhighly attenuated vaccinia virus are often vaccinated (21,25,26).