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The Virus of Smallpox and Vaccination

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Intro, Genome, Structure, and Lifecycle

Smallpox has affected humans for centuries causing scars, blindness, and even death. Although it is not exactly known when the first case of smallpox appeared, it is believed that smallpox has been around since the Egyptian empire. This conclusion was made upon investigating three mummies that had markings on their body similar to the scars left behind by smallpox. Smallpox is a highly contagious variola virus from the poxviridae family. It has a dsDNA genome and encodes its own polymerase. Because poxvirus’ genome does not have telomeres it replicates the end of its genome by using a terminal loop. Compared to other viruses, smallpox is quite large at 230-300nm. It can be visualized under a microscope which is abnormal for viruses because they are usually much smaller. The dsDNA is bound to proteins forming a dumbbell shaped nucleoprotein complex located in the center of the virus.

The virus replicates in the cytoplasm and uses DNA-dependent RNA-polymerase. Smallpox is interesting in that it has enveloped and non-enveloped virions. Both types of virions are infectious. These different virions are called Intracellular Mature Virus (IMV) and Extracellular Enveloped Virus (EEV). The lifecycle of poxvirus is similar to the lifecycle of other viruses as it follows the flow of binding to the cell surface, entering the cell via fusion, and trafficking to the replication site. The virus enters the body when infected droplets enter into the patient’s respiratory tract such as through the nose or mouth. The virus then attaches via surface tubules to the respiratory endothelial cells. The virus can also attach to immune cells or it can enter the body through the skin and in turn cause skin lesions. When the virus has finally attached to the immune cells or respiratory epithelial cells the outer envelope fuses with the host cell membrane. At this point the genetic material is released into the cytoplasm of the cell. Without the release of the genetic material replication would not be accomplished. Poxvirus DNA replication occurs in the cytoplasm. The early messenger RNA is translated into proteins that code for the uncoating and replication of the genome which leads to the intermediate messenger RNA. This mRNA encodes for factors that enable transcription of the late messenger RNA genes. Finally, the late mRNA can be translated into proteins that make up the structural and enzymatic components of the virions. The newly replicated genome is then incorporated into the new virions. The virions leave the cell via lysis of the host cell or sometimes via exocytosis from the host. These virions then go on to infect neighboring cells.

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Host Immune Response

Smallpox is a potentially deadly virus and it is highly contagious. It can be spread by prolonged face to face contact. Individuals first become contagious when sores appear in the throat or on the outside of the mouth. The virus can then be passed when a person coughs or sneezes because the droplets can be transferred to other people. Smallpox is not necessarily airborne as it does not spread through the air in a closed building. The virus is contagious through bedding or clothing if fluid from one of the sores touches it. Healthcare staff treating these patients have to wear gloves and other personal protective equipment when handling the bedding or clothing of these patients in order to not contract the disease. After all of the scabs have fallen off the virus is no longer infectious.

There are several stages that a person with smallpox undergoes. The first stage is the incubation period. It lasts seven to ten days and at this time the person is not contagious and usually continues to feel normal. The virus is present in the body but has yet to affect the individual. The second stage is plagued with the initial symptoms of high fever, body aches, and sometimes vomiting. At this point the individual is feeling unwell and cannot continue daily activities. This stage lasts about two to four days. Individuals are usually not contagious at this point. The third stage is the early rash. This stage lasts for about four days and this is when the individual is highly contagious. The rash originates in the mouth or on the tongue. It starts as small red bumps that then grows and bursts open releasing the virus in the mouth and throat. This occurs simultaneously with the individual experiencing a high fever. Once the sores burst within the mouth a rash begins on the outside of the body including the face, arms, hands, and legs. Within twenty-four hours the rash has spread to the entire body. At this point the fever begins to drop and the person may start to feel better. Within four days the sores on the outside of the body become filled with a thick opaque liquid. When the sores fill with fluid it may trigger the fever to rise again and if it does then the fever will not drop until the sores have scabbed over. The next stage is the pustular rash and scab stage. At this time the sores will become pustules meaning they are hard, raised bumps on the skin. This stage lasts about ten days and the individual is still contagious. About five days into this phase the pustules begin to scab over. About 14 days after the rash first appeared most of the sores-turned-pustules should be scabbed over. The second to last stage is when the scabs fall off. The individual is still contagious. About twenty-one days after the rash first appeared most of the scabs have fallen off leaving behind marks on the skin. The last stage is when there are no more scabs on the individual. Only after all of the scabs have fallen off is the individual no longer considered contagious.

The entirety of smallpox lasts about one month from infection to no longer suffering from the illness. As mild as these symptoms may seem, people experience different severity of the virus depending on the infection. Three out of every ten people infected died from this virus.

Pathogenesis

Infection of smallpox via the variola virus occurs through the respiratory tract. This is the primary route of entry but the virus may also enter through the skin. The virus rapidly enters the lymph nodes after infecting the respiratory tract. About three to four days into the infection the virus begins to also enter the blood, bone marrow, and additional lymph nodes. During days eight to twelve the virus is now causing fever and toxemia. This is also around the time when the rash is appearing in the mouth and skin. The virus has now spread to the blood vessels of the dermis and the oral mucosa. At two weeks the virus is in full swing and can be detected in the kidney, liver, and spleen as well as the bone marrow and blood.

Vaccine

The smallpox vaccine was the first vaccine ever developed and remains to this day the only human disease eradicated from the world because of the vaccine. It was introduced by Edward Jenner in 1796. In 1790 Jenner realized that the milkmaids that had contracted cowpox were protected against smallpox. This is where he came up with vaccination by first doing variolation with cowpox so the symptoms were milder and there was protection from smallpox. This is how we get the term vaccination because in Latin vaca means cow. Jenner saw that inoculated vaccinia virus protected against inoculated variola virus. Smallpox vaccines used during the intense eradication program are called first generation vaccines. The vaccinations developed at the end of this eradication period or later on were developed with modern cell culture technology. Second generation vaccines utilize the same smallpox vaccine strains as first-generation vaccines. However, third generation vaccines use the more attenuated virus strains specifically developed to provide a safer vaccine. Second and third generation vaccines were developed with modern cell culture technology. The vaccine currently available is not made with the variola virus. Instead it is made with the vaccinia virus, which still protects humans from smallpox. On occasion this vaccine can cause serious side effects which in extreme cases may even be fatal. After smallpox was eradicated in 1979 it was decided that all remaining stocks of variola virus should be destroyed or transferred to one of the two secure laboratories in the United States and the Russian Federation. This process occurred in 1980 and no other laboratory has official access to the disease. Because smallpox has been eradicated it is not currently part of routine immunizations. It was recognized that in case there ever is another outbreak there needs to be a vaccine available. There is currently a physical stockpile of smallpox vaccine located in the World Health Organization headquarters in Switzerland. It is estimated that there are enough doses to vaccinate 2.4 million people. There is also a stock of vaccines held in France, Germany, Japan, New Zealand, and the United States. Together all of these countries can treat an additional 30.01 million cases of smallpox. Currently scientists are working on new forms of the vaccine should smallpox ever resurface. These new vaccines will hopefully cause less harmful, potentially fatal side effects and be more effective. The vaccine is administered by puncturing the skin multiple times with a bifurcated needle that contains the vaccine.

Viral Evolution

It has been speculated that the variola virus that causes smallpox outbreaks and epidemics in Europe and the United States may be a slightly different strain than those seen in ancient remains. It is also speculated that during the time when vaccinations were coming out in full force it may have caused the variola virus to evolve and force the split between variola major and variola minor. There are several poxviridae viruses that are closely related to variola virus, however, in terms of direct viral evolution from the variola virus itself not much is known at this time.

Interesting Facts about Smallpox

The day before Abraham Lincoln was to deliver the Gettysburg Address he told his private secretary that he did not feel well. The next day, when he gave that fateful speech, he developed a severe headache and high fever. Within a weeks’ time he had sores full of pus, a telltale sign of smallpox. Lincoln’s doctor assured him that he had a mild form of smallpox. However, it is believed his sickness was much more severe but, in an attempt, to not worry the American people it was merely brushed off. Luckily, at day ten Lincoln’s fever broke and his rash began to scab over. If President Lincoln had succumbed to smallpox at that point in American history can you imagine how different life might be? According to Lincoln’s physician, during the height of his illness when he was the most contagious he cheerfully remarked, “Now I have something I can give everybody.”

Elizabeth I, so says one of the greatest monarchs, was also a famous person who contracted smallpox. At first, she thought it was just a cold but she later realized that it was a fairly severe case of smallpox. The disease left her with scars but luckily, she still had her life. Josef Stalin is also a famous survivor of smallpox. He contracted the disease at age seven and was left with severe scars, to the point that he would have his photographs touched up to make the scars less noticeable. It is said that his disfigurement may have been a cause for his ruthlessness. Whether that is factually accurate or not it would be interesting to know how different history may have been if he were not scarred from the illness or if he had not been able to fight it off.

Another notable figure who unfortunately did succumb to smallpox was Pocahontas. Considering relationships were already strained between Native Americans and English settlers this only increased tensions. In terms of horrible things English settlers did to Native Americans, giving them blankets infected with smallpox was probably at the top of the list. Not only did the colonists purposefully use biological warfare to rid the land of their enemies the only way they knew they could achieve such a goal was by realizing the Native Americans did not have the immune systems that the colonists have. The first outbreak of smallpox on the northwest coast directly coincides to the Native American’s first direct contact with the English settlers. Of all the disease brought over by the settlers, smallpox was the deadliest. It has been estimated that during this smallpox epidemic the Native American population in Western Washington was reduced by eleven thousand.

In conclusion, smallpox is a virus that has touched the lives of hundreds of thousands of individuals all across the globe. Smallpox has transcended decades and has brought death knocking on too many people’s doors. Thankfully this virus has been eradicated and the vaccine is still available and being improved. As detrimental as this virus was it did give us the key to open the door to vaccinations which has truly helped change the history of humans.

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