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The Variola virus, which is the most virulent member of Genus Orthopoxvirus, is the causative agent of smallpox. It specifically infects humans. The primary reason for infection in humans is due to its ability to evade the host immune responses, and avoid complement activation. Over the centuries, this naturally occurring virus has spread throughout the earth, through various environments, to cause severe outbreaks. The most devastation outbreak had a case-fatality rate of 40 percent in individuals who have not been vaccinated.

The Variola virus is a double-stranded DNA virus. It has two envelopes: the outer envelope is present only in the extracellular state. The outer surface or the core membrane, which surrounds the core of the virus, contains lipids and proteins and has a complex symmetry. The core, which has a dumbbell-shape, contains a large amount of the double-stranded DNA (186kbp), about 10 enzymes to mediate gene expression and lots of nucleoproteins- both specific and common. These proteins are involved in DNA transcription, as well as inducing cross-reactive immunity (IOM, 1999). The space outside the core contains lateral bodies – which do not have any known functions.

There are two forms of the variola virus: variola major and variola minor. Variola major is the lethal strain, while variola minor is not lethal, but a mild strain, which is very similar to major but is only genetically different. The most common strain is the variola major, which produces the more severe symptoms, and with a fatality rate of 20% to 40%, within the 7th day of infection. The variola minor is the milder form of the disease that has a death rate of less than 1%. Surviving infection from either strain provides cross-immunity, thereby having immunity to both variola major and minor (Koplow, 2003). An infection of the variola virus starts out with flu-like symptoms, then rashes and scabs form throughout – similar to chickenpox, eventually in fatal cases, leading to malignant diseases such as intravascular coagulation, hypotention, cardiovascular collapse or bleeding of skin and intestinal tract (IOM, 1999).



The history of the smallpox is still a mystery. It is speculated to have appeared among human population during the first agricultural settlements in northeastern Africa, around 10,000 BC (Baraquet and Domingo, 1997). Perhaps the scars, which appear on Pharaoh Ramses V’s delicately preserved mummy dating back to 1157 BC, may be the earliest signs of smallpox exposure (Ellner, 1998). It is speculated that throughout history, exposures to smallpox have been known in all parts of the world, along with the observance of gaining immunity to smallpox upon surviving an exposure. The observance of such a phenomenon throughout history, has led to healthy individuals, to be exposed on purpose in attempts to gain immunity.

Inoculation of healthy individuals by placing pus or powdered scab material from an infected individual, to the nose of the intended was recorded by the Chinese as early as tenth century (Ellner, 1998). The procedure of inoculation a healthy individual with smallpox was widely used in England by 1740. Around 1765, English physicians noticed that milkmaids were immune to smallpox, as a result of being exposed to the less severe cowpox. As a result, in May of 1796 Edward Jenner, a brave scientist, inoculated an eight-year old boy, with the cowpox virus, and was exposed to smallpox. The boy became immune to smallpox, and Jenner was credited for creating the first smallpox vaccine (Barquet and Domingo, 1997). This became the starting point of the attempt to eradicate smallpox on a global scale, which was eventually confirmed and declared by the World Health Organization in 1980. The last confirmed case of smallpox in the United States Occurred in 1949, and the last naturally occurring case in the world was recorded in Somalia in 1977.



Attachment of the virus to the host cell is the initial step in infecting an individual (Life-cycle). Variola usually enters through the respiratory tract. It attaches to the mouth, trachea or lung mucosa. The cells comprising of the mucous membrane are not tightly packed therefore allowing it to penetrate and move into the saliva. Once the virus reaches the cell membrane, it is brought in through endocytosis. Once in the host cell, the core protein in released.

Variola replicates in the cytoplasm of the host cell. DNA replication and transcription can start immediately because the virus itself contains enzymes for replication and transcription – not relying on host cell enzymes to initiate replication. First the DNA and RNA ploymerase are made, along with other transcription factors. Then, the proteins, which form the virion structure, various immunosuppressive proteins, and proteins that bind to certain molecules of the immune system such as TNF, C4b, and IL1 are made. The proteins that bind to immune molecules are either secreted or bound to the infected cell’s membrane. Also, the enzymes, which are to be carried in the newly synthesized virion, are created. The virion then exists the host cell through fusion of the host cell membrane (Koplow, 2003). It is thought that host cell death occurs as a result of having excessive amounts of viral mRNA, which reduces the ability of the host cell in conducting its own transcription and production of normal proteins.

The variola virus is able to survive mainly by evading the immune response through several virulence factors. Smallpox has been studied to have a complement-regulatory protein (CRP). The CRP acts a co-factor for the serine protease factor I by cleaving C3b and C4b, which inactivates the complement system, thereby protecting the host cell in which it resides from being hit by the complement-mediated attack (Nature Review, 2002). Also, the ability of the virus to fuse out from the host cell using fusion proteins as a virulence factor is harmful to the host cells – rendering them to be exposed to the extracelluar material, and promote degradation of the cell.


Since the virus only infects humans, it is spread through human-to-human interactions. The virons are usually found in the mouth and nose secretions of the infected individual. It is most often transmitted in air droplets when an infected person coughs, sneezes or talks. Also, ventilation systems in a building or exposing a cut or wound with contaminated clothing or bedding may be sources of encountering the virion (Mayo, 2002).

The exposure to smallpox first leads to an incubation period. In most cases the incubation period ranges from 7 to 17 days. In cases where an inoculation has occurred, in which variola enters through the skin, either on purpose (to produce immunity) or by accident, the incubation time can be dramatically cut down to 2 to 3 days. During the incubation time, the infected individual is not contagious. High fever, and appearance of skin lesions begins the sometime contagious, initial phase. For 2 to 4 days, the infected individual experiences a fever ranging from 101 to 104 degrees Fahrenheit, along with body aches or vomiting. The rash phase is the most contagious. It appears as small red spots on the tongue and mouth, and then progress into sores, which burst open to release virions into the mouth and throat. Within 24 hours, the rash appears throughout the body’s surface, starting with the face and then down to the lower extremities. Within 3 days, the rash will progress into bumps, which eventually fill with a think, opaque fluid. The bump begins to form a crust called a pustule and then into a scab. Scabs may begin to fall off after three weeks from the day the rashes appeared, but the person remains contagious until all the scabs have fallen off (CDC overview2).
The way the variola virus travels through the body is not clearly known. It travels through the body and infects by a series of activities. It first spreads through the body locally by infecting adjacent cells. It will then enter the lymphatic system and travel around the body to various locations. Traveling through the lymphatic system gives it the ability to reach various organs, which are essential for the survival of the host individual, but it does not infect it. Then it will travel the skin and present lesions, rashes, pustules, and scabs. In some cases such as with the severe - variola major, it can present mild symptoms or more serious problems, as associated with the hemorrhagic and malignant forms. The hemorrhagic form of the variola major can lead to destruction of the entire skin surface and mucous membranes of the body, leading to fatality within 5 to 7 days. The malignant form will lead to excessive bleeding of both the skin and the intestinal tract, leading to fatality (Mayo, 2002). Due to the bleeding, and unable to clot the blood, it can result in cardiovascular collapse, intravascular coagulation, hypotention, swelling of the liver, or hyperplasia in bone marrow and spleen (IOM, 1999). Infected individuals who survive the less damaging strains often have excessive scaring all over their body, and in some cases, may cause a person to go blind (Mayo, 2002).



Smallpox has been mistaken with chickenpox, but several observations can differentiate the two. The lesions from chickenpox mainly occur on the outside surface of the skin, but mainly toward the lower extremities and less on the face. Also, chickenpox can readily be contagious prior to experiences symptoms of the infection.
There is no known cure for a smallpox infection, but if treatment with Cidofovir, an antiviral medication used to treat cytomegalovirus (CMV), is given within day 2 of exposure, may prevent an infection (during the non-symptomatic incubation period). The only other choice is prevention through the use of the vaccine (Mayo, 2002).
The smallpox vaccine is a live vaccine, derived from the vaccinia virus. The vaccine does not contain or cause a variola infection. It provides an individual with immunity for 3 to 5 years, which decreases from after that period of time. The vaccine has provided protection to 95% of the vaccinated individuals. It is administered using a bifurcated (two-pronged) needle. The needles are dipped in the vaccine and once wet, are used to prick the skin a few times in the upper arm (CDC overview2). This process creates a sore spot, which becomes a bump, then a blister with pus, and eventually falls off as a scab after 3 weeks.
The vaccine will provide protection after 2 days of its administration. It offers the best possible protection against a possible exposure to smallpox. The side effects to the vaccine are usually mild, which include a sore arm, fever, and general body aches. The people who are likely to get serious side effects are those who have conditions, symptoms or illnesses, for which the vaccine is not to be administered. These individuals include those who have eczema or any skim problem or conditions such as burns, atopic dermatitis, herpes, those individuals who have a weakened immune system due so events such as an organ transplant or diseases like HIV, and also to pregnant or planning to be pregnant within 1 month after administration of the vaccine. It is not recommended to women who are breast-feeding, to children under 12 years of age. (CDC, vaccine).


Barquet, Nicolau, MD and Domingo, Pere, MD. "Smallpox: The Triumph Over the Most Terrible of the Ministers of Death." Annals of Internal Medicine. 1997; 127:635- 42.
Ellner, P.D. "Smallpox: Gone but Not Forgotten." Infection. 1998; 26 (5); 263-9.
CDC overview:
CDC overview2:
Koplow, David. "Smallpox: The Fight to Eradicate a Global Scourge. 2003
IOM(Institute of Medicine): "Live Variola Virus – committee on the assessment of future
Scientific needs for live variola virus. National Academy Press; 1999.
Mayo Foundation for Medical Education and Research (MFMER). October 1, 2002
Nature Reviews Immunology 2, 544 (2002); doi:10.1038/nri868


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