Basic Information
As an eradicated disease, Smallpox seems to be an unlikely bioweapon. However, around World War II, many nations such as the USA, the UK, Russia, and Japan, were all looking into weaponized forms of the virus. At the time, the projects were shelved before being utilized due to the wide availability and use of Smallpox vaccines. Since eradication, vaccination against Smallpox has become less common, which potentially leaves the majority of the population susceptible again. Another threat comes from the possibility of any undocumented samples, which could be used by various people or groups to cause new infections.
The Smallpox disease is caused by Variola virus, a member of the Orthopoxvirus genus. Variola comes in two very similar strains. Variola major is the more lethal strain, with an average of about 30% fatality. Variola minor has a fatality rate of about 1%. Variola major can come in two rare forms which are nearly always fatal: Malignant, which occurs more in children, and Hemorrhagic, which occurs more in adults. The cause of these specific forms is currently unknown. Exposure to any version of Variola confers immunity to all strains, as well as immunity to all other Orthopoxvirus diseases: Vaccinia, Monkeypox, and Cowpox. Due to the genus level immunity, the Vaccinia virus is used in the current Smallpox vaccine.
The Smallpox disease is caused by Variola virus, a member of the Orthopoxvirus genus. Variola comes in two very similar strains. Variola major is the more lethal strain, with an average of about 30% fatality. Variola minor has a fatality rate of about 1%. Variola major can come in two rare forms which are nearly always fatal: Malignant, which occurs more in children, and Hemorrhagic, which occurs more in adults. The cause of these specific forms is currently unknown. Exposure to any version of Variola confers immunity to all strains, as well as immunity to all other Orthopoxvirus diseases: Vaccinia, Monkeypox, and Cowpox. Due to the genus level immunity, the Vaccinia virus is used in the current Smallpox vaccine.
Mechanism
Variola virus is most often transmitted through the aerosolized particles created when an infected individual coughs or sneezes. The droplets can sometimes be transmitted from one person to another through infected objects such as bedsheets, but this is rare. Smallpox viral particles most often infect cells in the mouth, throat, and lungs. As the virus multiplies, it migrates to the lymph nodes, where reproduction increases. After approximately 12 days, significant numbers of infected cells lyse and the virus is found in the bloodstream. At this point, another major wave of replication happens, primarily in the spleen and bone marrow. Variola then targets skin cells, which causes the characteristic symptoms of Smallpox.
Variola enters the cells binding to receptors on the exterior of the cell membrane. It is currently believed that all poxviruses use the glycosaminoglycans for this. Unlike most DNA viruses, Smallpox does not need to enter the nucleus. Instead, it replicates in the host cell cytoplasm, using its own DNA dependent RNA polymerase.
The viral genes are expressed in two phases through replication, followed by virus assembly. The first phase of gene expression consists mainly of nonstructural proteins, especially those necessary for genome replication. The second phase is primarily the structural proteins used to form the viral particle. As these proteins rebuild the structure, the virus exits the cell. The host cell dies shortly after, believed to be caused by an excess of viral mRNA, which inhibits proper cell translation. The cycle within one cell takes approximately 12 hours.
While inside the host, Variola also releases a compliment-regulatory protein (CRP). This inhibits the compliment system of the host immune response, protecting the infected cell from destruction from compliment-mediated attack. CRP inhibits the compliment response by acting as a cofactor for serine protease factor I.
Variola enters the cells binding to receptors on the exterior of the cell membrane. It is currently believed that all poxviruses use the glycosaminoglycans for this. Unlike most DNA viruses, Smallpox does not need to enter the nucleus. Instead, it replicates in the host cell cytoplasm, using its own DNA dependent RNA polymerase.
The viral genes are expressed in two phases through replication, followed by virus assembly. The first phase of gene expression consists mainly of nonstructural proteins, especially those necessary for genome replication. The second phase is primarily the structural proteins used to form the viral particle. As these proteins rebuild the structure, the virus exits the cell. The host cell dies shortly after, believed to be caused by an excess of viral mRNA, which inhibits proper cell translation. The cycle within one cell takes approximately 12 hours.
While inside the host, Variola also releases a compliment-regulatory protein (CRP). This inhibits the compliment system of the host immune response, protecting the infected cell from destruction from compliment-mediated attack. CRP inhibits the compliment response by acting as a cofactor for serine protease factor I.
Side Effects and Symptoms
Smallpox has an incubation period of 7-17 days (12 day average) between initial exposure and any symptoms, which then appear in two phases. Phase one is difficult to diagnose, often mistaken for influenza or the common cold. The second phase is much more obvious and proper diagnosis becomes significantly easier. The infection can only be spread from people in stage two of the symptomatic state.
Stage one symptoms include:
Stage two is indicated by the appearance of a rash that starts on the tongue and the inside of the mouth. The rash spreads to other sections of the body and changes appearance over the course of the infection.
Hemorrhagic Smallpox is also known as Black Pox due to the different appearance of the skin. It does not cause raised bumps of any kind. Instead, the skin remains smooth and bleeding occurs under the skin. This alters the skin to appear blackened. Eyes also appear red. Patients suffering from this variant usually die from hemorrhages of organs, often the spleen or kidneys. Death can also be caused by degradation of the skin or mucus membranes.
Stage one symptoms include:
- Body ache
- Fever of at least 101ºF
- Headache
- In some cases nausea and vomiting
Stage two is indicated by the appearance of a rash that starts on the tongue and the inside of the mouth. The rash spreads to other sections of the body and changes appearance over the course of the infection.
- Full body coverage of rash within 24 hours, generally more heavily on face and extremities.
- Over next 3 days, turns into raised papules.
- Papules fill with thick fluid.
- Harden into flat-topped pustules, usually with small depression in the center.
- Pustules turn into scabs, which fall off within 3 weeks of the initial appearance of the rash. Once the scabs fall off, the virus is no longer infectious.
Hemorrhagic Smallpox is also known as Black Pox due to the different appearance of the skin. It does not cause raised bumps of any kind. Instead, the skin remains smooth and bleeding occurs under the skin. This alters the skin to appear blackened. Eyes also appear red. Patients suffering from this variant usually die from hemorrhages of organs, often the spleen or kidneys. Death can also be caused by degradation of the skin or mucus membranes.
Treatment
Currently, no full treatment options or cure exist for Smallpox. Studies have shown that vaccination within four days of initial exposure can have an effect by reducing symptom severity. Any other treatment would be patient care while the disease runs its course. There are currently no known antiviral treatments. Since the eradication of natural Smallpox, however, antiviral medications have improved somewhat so it is slightly possible that more effective medications exist today. Research into Smallpox treatment has not been extensive since eradication, though some research is taking place for certain antiviral medications that could potentially also combat the Variola virus. Efforts pre-eradication usually focused on vaccination and limiting exposure. If a biological attack using Smallpox were to occur, the options for a response would be very limited.
Drug Design
Drug research looking at the specific treatment of viruses with a double-stranded DNA (dsDNA) genome is currently in development. Until recently, the most promising drug for this was cidofovir (CDV). This drug is currently sold under the trade name Vistide and is used primarily for retinitis and AIDS treatment. Cidofovir is activated by phosphorylation within the cells. The active form, cidofovir diphosphate (CDV-PP), selectively inhibits viral DNA polymerases. It also inhibits the human DNA polymerases, but at a significantly lesser rate. CDV is not easily absorbed when taken orally, so it is currently delivered to the body through an IV.
More recently, Chimerix has developed a prodrug to cidofovir. This drug goes by the names CMX001 or brincidofovir. This drug is synthesized from CDV by adding a long carbon chain to the molecule. This hydrophobic tail allows it to transport through the cell membrane significantly faster, lessening the extracellular concentrations and increasing the intracellular concentrations of CDV. Inside the cell, the tail is enzymatically cleaved, releasing CDV to be phosphorylated and CDV-PP to attack the viral enzymes. CMX001 appears to be a more practical choice because the long tail also increases absorption into the body, making an oral version of the medication more possible. Brincidofovir is currently in phase III clinical trial trials and has a Fast Track designation from the FDA. |