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Smallpox is the infectious disease produced by Variola major. It was the first infection for which a preventive measure, vaccination, was introduced; it is the first infectious disease that has been eradicated from the wild. A new case of smallpox would almost certainly be a use of a biological weapon, probably as terrorism, and constitute a major worldwide emergency.

By world agreement, only two stocks of the smallpox pathogen exist: in high-security government laboratories in Russia and the United States. There are concerns, however, that there may be cultures elsewhere, and, since it is transmissible from human to human and has substantial morbidity and mortality, there are worldwide preparations for containing and treating an outbreak. The vaccine, while having significant side effects, can reduce the severity of an active case as well as prevent the disease. At least one antiviral drug, cidofovir, is believed active against it, but has not been used in humans.


Smallpox is believed to have originated in Africa from a rodent that lived along the south Nile River in the crescent green forests.[1] From Africa it then spread to china and India thousands of years ago. During the Egyptian-Hittite war in 1350 B.C. was the first recorded epidemic of Smallpox.[2] Almost Two Thousand years later this disease reached Europe where it plagued the countries from the fifth century until the nineteenth century. From Europe the disease spread to major cities all around the world including the American colonies in the seventeenth and eighteenth centuries.

Smallpox has played a major role in shaping the way western civilization prospered and grew during the middle ages and into modern times. From the tenth century until the eighteenth century Smallpox accounted for more the four-hundred thousand deaths per year. The estimated death toll ranges from 300 to 500 million.[3]


The demise of smallpox came about with the realization that survivors of the illness were immune for the rest of their life.[4] This brought about the practice of Variolation. Variolation is the process of exposing a healthy person to infected substance in chance that the healthy person would develop a milder form of the disease and then receive immunity. The first known practice of variolation records a Buddhist nun grinding up the scabs taken from a smallpox victim into a fine powder and then blowing them into the nostrils of a healthy patient.[5]

After centuries of this type of inoculation eventually it was refined by professional doctors and turned into a very effective and “safe” process. A study was done in Boston where 12,000 people contracted the disease. Of these fourteen percent that were not inoculated died. Of those who had variolation performed only two percent died from naturally contracted the disease. These statistics dramatically increase the number of people who had variolation performed on themselves.

After centuries of the practice of inoculation by variolation had developed it was time for a new era to come about. It all started when a young boy name Edward Jenner’s was inoculated with the virus along with thousands of other boys. Some say that this experience inspired young Edward to follow a career of science. However that is mere speculation. Edward spent his life studying many different fields of science and was very successful. He developed new ways of thinking and new forms of scientific method. However his most meaningful study came from his interest in the idea that cowpox brings immunity to smallpox. He had heard many rumors that dairy maids, after being infected with cowpox, a lesser virus similar to smallpox, received immunity from both diseases. After studying a dairy made with fresh cowpox lesions on her hand he saw that she was immune to smallpox. After much thought and careful planning he decided to inoculate a boy with fresh cowpox lesions. After a mild case of cowpox occurred he decided to take fresh smallpox and place it on an open wound on the boy. After a few weeks no smallpox had shown up and Edward Jenner concluded that immunity was complete. This discovery paved the way for the eventual eradication of this disease from the world.[6]


Smallpox was named from the small lesions that form on the victims skin. The lesions are much smaller than the larger lesions formed from the common disease syphilis. These two diseases in the beginning and in the Middle Ages were commonly mistaken.

Smallpox Infection

The virus normally enters the body through the respiratory mucosal surfaces. It can also enter through the skin and rarely enters through the placenta[7]. Relatively few particles (10-100) are needed to infect[8] people with the virus. Once infected, the virus concentrates in the lymph nodes. The primary viremia lasts from the 3rd day from exposure to the 8th or 12th days since infection. During the primary infection, the patient does not have symptoms. After this initial period, the secondary viremia begins and the patient begins to display symptoms. After about the 14th day, the lesions begin to form, at this point the patient is contagious. Eventually the patient dies from toxemia, or blood poisoning, from the amount of infected cells[7].


Smallpox is caused by the variola virus. The variola virus is a member of the genus Orthopoxvirus, which also includes cowpox, monkeypox, orf and molluscum contagiosum. Among animal viruses, poxviruses are some of the largest, rivaling the size of bacteria and have DNA strands that are, on average, 200,000 base pairs (200 kbp). The smallpox virus is a brick shaped virion that is 250 to 300nm long and 250nm high with a diameter of 200nm. [8][7]


The poxviruses are unique in the fact that they are able to reproduce in the cytoplasm of a cell, with no need for the nucleus[7]. In fact, poxviruses are the only known virus to be able to do this[8]. Due to natural defenses that allow smallpox to circumvent the first and secondary levels of general immune response it can infect areas with high concentrations of Lymphocytes. The virus replicates in the major organs and uses the filtering organs (lymph nodes, kidneys, spleen and liver) to reproduce and spread rapidly[9].

Immune System Evasion

Two major devices that smallpox use to prevent immune system response have been discovered.

Interlukin-18 blocking

Interlukin-18 (IL-18) is a protein that is produced by macrophages to activate natural killer (NK) and natural killer T cells (NKT). Smallpox, and other poxviruses, block this protein from activating the NK and NKT cells. When the IL-18 protein is not blocked, it causes the production of Interferon-gamma or IFN-&gamma. This research accompanied research revealing how proteins communicate, giving the possibility to create drugs that disable the blocking mechanism for smallpox as there are no drugs that effectively combat smallpox[10]

Interferon-gamma (IFN-γ) binding protein

Recent research has revealed the reason that the poxvirues and the variola virus in particular are so efficient at infecting the patient with very few particles of virus and why it is able to resist immune response in the early stages of infection. Research at Saint Louis University has revealed that mousepox, a type of poxvirus, contains a protein that binds to the IFN-γ molecule that is produced by natural killer cells and natural killer T cells. Its main role is to prevent virus replication directly by altering the genome of affected cells and activating natural killer responses. The protein binds to the IFN-γ molecule and neutralizes it, rendering one of the first levels of immune system useless[11]. This gives the virus time to reproduce with little restriction and spread until a secondary immune response is activated.


There are two types of the variola virus, variola major and variola minor. Variola major is the deadlier version of the virus with a general fatality rate of 30%, whereas variola minor has a fatality rate of less than 1%. Variola major has three different presentations in victims.

Type of infection Occurrence Fatality rate Principal Factors Symptoms Summary
Classic High 30% (variola major) Infection with variola major
  • Prodrome Symptoms (lasting 3-4 days)- organized by rate of occurrence in large case series [12]
    • Fever, 100%
    • Headache, 90%
    • Backache, 90%
    • Vomiting, 50%
    • Chills, 60%
    • Pharyngitis, 15%
    • Abdominal pain, 13%
    • Diarrhea, 10%
The most common reaction to the smallpox virus
Hemorrhagic Very Low Extremely high, about 96% [12]: Usually death occurs in less than a week after incubation period (same as classic) Thought to be caused by abnormal immune system response or lack thereof, not a variant of the variola virus [8]
  • Early-onset form (Sudden onset, hemorrhagic symptoms occur within 2 days of onset)
  • Late-onset form (typical prodrome lasting 3-4 days)[8]
    • Prodrome stage (see classic smallpox symptoms)
    • Rash (similar to classic smallpox, except for indicated)
      • Lesion development is accelerated
      • Bleeding occurs at base of lesions
    • General Hemorrhagic Symptoms
One of the more severe reactions to the smallpox virus, it is the second deadliest
Flat (malignant) Very Low Extremely high; approaches 100% [8] Unknown
  • Prodrome (Same symptoms of classic smallpox except as noted, lasting 2-4 days)
  • Rash [13] [14]
    • Lesions develop much slower
    • Rarely develop into pustules; remain flattened
    • Lesions "velvety" by 4th or 5th day
    • Normally confluent
    • Heals without scarring
The most severe reaction to smallpox

Timeline of Infection

Timeline of the classic presentation of the disease and a description as reported by the CDC's Emergency Response and Preparedness page on Smallpox[15]

Stage Duration Contagious Desription
Incubation Period 7 to 17 days Not contagious Exposure to the virus is followed by an incubation period during which people do not have any symptoms and may feel fine. This incubation period averages about 12 to 14 days but can range from 7 to 17 days. During this time, people are not contagious.
Initial Symptoms (Prodrome) 2 to 4 days Sometimes contagious* The first symptoms of smallpox include fever, malaise, head and body aches, and sometimes vomiting. The fever is usually high, in the range of 101 to 104 degrees Fahrenheit. At this time, people are usually too sick to carry on their normal activities. This is called the prodrome phase and may last for 2 to 4 days.
Early Rash About 4 Days Most Contagious A rash emerges first as small red spots on the tongue and in the mouth.

These spots develop into sores that break open and spread large amounts of the virus into the mouth and throat. At this time, the person becomes most contagious. Around the time the sores in the mouth break down, a rash appears on the skin, starting on the face and spreading to the arms and legs and then to the hands and feet. Usually the rash spreads to all parts of the body within 24 hours. As the rash appears, the fever usually falls and the person may start to feel better. By the third day of the rash, the rash becomes raised bumps. By the fourth day, the bumps fill with a thick, opaque fluid and often have a depression in the center that looks like a bellybutton. (This is a major distinguishing characteristic of smallpox.) Fever often will rise again at this time and remain high until scabs form over the bumps.

Pustular Rash About 5 Days Contagious The bumps become pustules—sharply raised, usually round and firm to the touch as if there’s a small round object under the skin. People often say the bumps feel like BB pellets embedded in the skin.
Pustules and Scabs About 5 Days Contagious The pustules begin to form a crust and then scab.

By the end of the second week after the rash appears, most of the sores have scabbed over.

Resolving Scabs About 6 Days Contagious The scabs begin to fall off, leaving marks on the skin that eventually become pitted scars. Most scabs will have fallen off three weeks after the rash appears.

The person is contagious to others until all of the scabs have fallen off.

Scabs resolved n/a Not Contagious Scabs have fallen off. Person is no longer contagious.
  • Smallpox may be contagious during the prodrome phase, but is most infectious during the first 7 to 10 days following rash onset.



Modern Day

As of December 1979 the WHO declared that global eradication of Smallpox was complete. There is no known natural host for the smallpox virus which means that humans are the only reservoir of the disease, because of this it is believed that the only remaining stocks are in two WHO laboratories, one in the Russian Federation and one in the United States of America.[16] The last contraction of the virus occurred with a young girl in an accidental exposure in laboratory setting in 1978; the scientist responsible for the infection later committed suicide since the girl infected was eventually killed by the disease.[17]


Since 2001 the United States has increased its observation and preparedness for a smallpox terrorist attack. In this preparedness before and after 2001 America currently has roughly one hundred million doses of the vaccine and has purchased a contract that would ensure enough doses for the American population if there were to be a smallpox outbreak.

The threat of smallpox being used as a bio-weapon comes from the Cold War era. Both the Soviet Union and the United States were developing this disease to be used as a bio-weapon should war between the countries have broken out. At the fall of the Soviet Union it was rumored that certain weaponized stockpiles of the smallpox virus went missing and were thought to be purchased or stolen by countries such as North Korea, Afghanistan, and Iraq. Of these countries all have known terror organizations with great interest in getting their hands on this fateful virus.[18]

In the late 20th century there were many efforts to dispose of all smallpox stockpiles including in laboratory settings. However this idea was retracted with the information of the massive effort that the Soviet Union had put towards their bio-weapons program and the lack of funding they had before they fell.[19] The lack of funding made it easier for their programs to be infiltrated and also compromised the safety of the programs. During this time it is known that many samples of this disease went missing and or stolen. Since there is not a way to locate these lost stockpiles of the smallpox virus, WHO decided it best for there to be samples of this virus in order to further study its makeup in order to create a better vaccine in case another outbreak occurred.[20]

Definitions of Medical Terms

Natural Killer 
Bone marrow-derived lymphocytes that possess cytotoxic properties, classically directed against transformed and virus-infected cells. Unlike T-CELLS and B-CELLS, NK cells are not antigen specific. The cytotoxicity of natural killer cells is determined by the collective signaling of an array of inhibitory and stimulatory CELL SURFACE RECEPTORS. A subset of T-LYMPHOCYTES referred to as NATURAL KILLER T CELLS shares some of the properties of this cell type. [21]
Natural Killer T 
A specialized subset of T-LYMPHOCYTES that exhibit features of INNATE IMMUNITY similar to that of NATURAL KILLER CELLS. They are reactive to glycolipids presented in the context of the major histocompatibility complex ( MHC) class I-like molecule, CD1D ANTIGEN [22]

  7. 7.0 7.1 7.2 7.3 "CIDRAP Smallpox: Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis." CIDRAP Center for Infectious Disease Research and Policy. Web. 01 Dec. 2009. <>.
  8. 8.0 8.1 8.2 8.3 8.4 8.5 Hogan, Christopher J., and Fred Harchelroad. "CBRNE - Smallpox." EMedicine (2009). EMedicine. WebMD Health Professional Network, 12 June 2009. Web. <>
  9. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med 2002 Apr 25;346(17):1300-8
  10. Oklahoma State University (2009, January 26). Breakthrough Against Poxviruses May Lead To Medication For Smallpox and Monkeypox. ScienceDaily. Retrieved December 9, 2009, from¬ /releases/2009/01/090123111513.htm
  11. Saint Louis University (2008, February 1). How Poxviruses Such As Smallpox Evade The Immune System. ScienceDaily. Retrieved December 9, 2009, from¬ /releases/2008/01/080131122956.htm
  12. 12.0 12.1 Rao AR. Smallpox. Bombay, India: Kothari Book Depot, 1972 –Out of 85 cases of hemorrhagic smallpox, the fatality rate was 96%
  13. Fenner F, Henderson DA, Arita I, et al. Smallpox and its eradication. Geneva, Switzerland: World Health Organization, 1988
  14. Dixon CW. Smallpox in Tripolitania, 1946: an epidemiological and clinical study of 500 case, including trials of penicillin treatment. J Hygiene 1948;46(4):351-77
  15. 15.0 15.1 "Smallpox Overview." Center For Disease Control and Prevention. 30 Dec 2004. CDC Division of Bioterrorism Preparedness and Response, Web. 18 Nov 2009.