Smallpox

Disease/Drug of interest: Smallpox/Smallpox Vaccine (ACAM2000) Motivation and Background: Few diseases have had as much of an impact on history as smallpox. While it is famed as the disease which accounts for the highest number of fatalities, it is also the only human disease to be eliminated (in its natural form) by vaccination, the first vaccination ever manufactured, in fact. Although the exact origin of smallpox is unknown, evidence of smallpox-like symptoms have been found on three different mummies from the Egyptian Empire (particularly around the 3rd century BCE). Another early account of a disease that is thought to be smallpox was discovered in China, found in a written report in the 4th century BCE [1]. However, a recent paper, “17th Century Variola Virus Reveals the Recent History of Smallpox,” casts doubt on the earlier instances (like the two just mentioned) being smallpox, rather than another pustular disease. A 17th century mummy was found with an ancient strain of smallpox, and by using molecular-clock analyses (a technique that uses mutation rate to determine when life forms diverged) discovered that the timescale of the disease is much more recent than previously believed to have been. Regardless of the time period the disease, it is not known what could have contributed to the disease in its early stages. Smallpox spread within groups of people through trade, exploration, and expansion, not particularly showing an affinity for a certain race, lifestyle, or class, rather infecting the many in its path, transmitting person-to-person. As expected, over the years, smallpox exposure in those communities led to an immunity that built up (survivors also became immune) and caused the inhabitants to become less susceptible to the disease. During the colonization of the Americas, the disease spread and almost wiped out the indigenous peoples that had no natural immunity built up. Initial symptoms involved fever, aches, and possible vomiting. The next stage of the disease exhibited early rashes which evolved into telltale pustular rashes (shown in Figure 1) that scab over. Next the scabs fell off, and once all were gone, the infected person was no longer contagious [2]. It is estimated that 30 percent of those infected were killed by the virus, with a death count estimated at 300 million people in the 20th century alone, and left most survivors with marring pox scars [6]. **Figure 1:** The progression of skin pustules characteristic of smallpox. While it may seem to be a tragic thing of the past, the dangers of smallpox are returning. The possibility of major threats using smallpox as a biological weapon, the use of which is referred to as “bioterrorism,” led to a possible mass vaccination and stockpile of vaccines in the United States and United Kingdom in the early 2000s, but the deal eventually fell through. However, this led to the beginning of exploring safer options due to the major threat smallpox poses—most of the current population has never had the vaccine. The Food and Drug Administration released their briefing information from 2007 detailing how they voted unanimously to produce a new live virus vaccine, a second-generation smallpox vaccine, ACAM2000, produced by Sanofi Pasteur Biologics LLC, a biotechnology company, to use for people at high risk of becoming infected with smallpox [4]. This new vaccine has only had small amounts produced to add to the Strategic National Stockpile, the United States' repository of medical supplies to use in case of a public health emergency. With the ever-increasing threat of warfare around the world, money is needed to produce more vaccines to stock for the public's safety. While many in the government and media focus on the nuclear threat posed, a biological threat could go unnoticed. An epidemic could occur before more are produced, causing the disease to spread and add to the hundreds of millions already killed. The largess of the threat is demonstrated in the FDA's unanimous vote to create such a vaccine. At least a couple hundred million doses should be added to the stockpile to effectively address a possible emergency. Every country should be focused on protecting the livelihood of their citizens.

[1] Centers for Disease Control. History of Smallpox. https://www.cdc.gov/smallpox/history/history.html (accessed Feb 3rd, 2017). [2] Centers for Disease Control. Smallpox Signs and Symptoms. https://www.cdc.gov/smallpox/symptoms/index.html (accessed Feb 3rd, 2017). [3] Nature. A schematic representation of the orthopoxvirus genome. http://www.nature.com/nri/journal/v2/n7/fig_tab/nri845_F2.html#figure-title (accessed Feb 18th, 2017). [4] U.S. Food and Drug Administration. Highlights of Prescribing Information (ACAM2000). https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM142572.pdf (accessed Feb 19th, 2017). [5] Moss, B., Smallpox vaccines: targets of protective immunity. Immunol Rev 2011, **239** (1), 8-26. [6] National Geographic. Smallpox: Conquered Killer. http://science.nationalgeographic.com/science/health-and-human-body/human-diseases/smallpox-article/ (accessed Feb 3rd, 2017). [7] Riedel, S., Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent) 2005, **18** (1), 21-5. [8] Greenburg, R.N., Kennedy, J.S., ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccin  e. Expert Opin Investig Drugs 2008, **17** (4), 555-64.
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External link:
<span style="font-family: Arial,Helvetica,sans-serif;">http://www.sanofipasteur.us/vaccines/ACAM2000 =<span style="font-family: Arial,Helvetica,sans-serif; text-align: justify;"> = =<span style="font-family: Arial,Helvetica,sans-serif; text-align: justify;">Target Information: Smallpox =

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">Size: molecular weight of the protein
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The molecular weight is not known.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">Location:
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The disease spreads around the body, but symptoms are physically shown as skin lesions.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The vaccine is used as a preventative measure. When the weakened or dead version of the disease enters the body, antibodies fight it, thus making them equipped to fight smallpox. After contraction, the faster the vaccine is given the better the chance is that it will succeed. If smallpox does invade cells, it will multiply in the cytoplasm and continue to spread. = = <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;">Drug Information: ACAM2000 <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Schematic figure of drug: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">**Figure 2:** Chordopoxvirinae's gene conservation. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Chordopoxvirinae include vertebrate pox viruses (smallpox and cowpox included). This schematic, figure 2, from Nature.com shows the genes of these pox viruses and how strains differ due to variable genes on the terminal loops [3]. It is fitting because vaccines are weakened or dead versions of the disease it is used to prevent. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Formula: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">At the beginning of smallpox vaccinations, cowpox was used to immunize, then it was changed to a dead version of smallpox, and currently, a live version. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Molecular weight: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">The molecular weight for the smallpox vaccine is not known.

<span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">CAS Number: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">There is no CAS number for the smallpox vaccine. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Delivery method: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">A droplet of ACAM2000 is administered by jabbing the skin (percutaneous route application) 15 times using a bifurcated needle [4]. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Maker or company: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Sanofi Pasteur Biologies LLC is the biotechnology company that produces the vaccine [4]. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Is it patented? <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Strains of second generation smallpox vaccines, including ACAM2000, have been patented. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Clinical Trials Info: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">The studies with ACAM2000 indicate that it closely matches the safety of the previous smallpox vaccine in both non-clinical and clinical trials. ACAM2000 met two of the four primary surrogate efficacy end point criteria established for the Phase III clinical trials [8]. There is concern of heart problems with both ACAM2000 and the older smallpox vaccine. The evidence towards the betterment of the older vaccine through ACAM2000 was sufficient enough to sway the FDA--the drug was approved unanimously. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Origin: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">The vaccine for smallpox was contrived in 1798 by Edward Jenner, an English physician located in the countryside [5]. Jenner had noticed that milkmaids in his county tended not to become infected with smallpox unlike many others he knew. Jenner also noticed that a common infection for milkmaids, cowpox, created pustules much like smallpox. He then deduced that being infected with cowpox gave its host immunity against smallpox. Deciding to test it, Jenner experimented with an 8-year-old boy, infecting him with cowpox and subsequently inoculating him with smallpox. The boy did not contract smallpox. Jenner did many more experiments with others before he submitted his paper; he had made the first vaccination, even creating the name himself (vaccinia is Latin for cowpox) [7]. News spread of a cure and in many places around the world citizens were required by law to take the vaccine. Later it was discovered that revaccination was needed (every 5 years) and more measures were put in during the 1950s (the vaccine was altered to contain a virus related to cowpox and smallpox) to eradicate the disease, with the last case recorded in Somalia in 1977 [7]. In 2008, the FDA approved a new version of the vaccine, ACAM2000. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Alternatives to this drug: <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">The earlier version of the vaccine or different strains of it could be used as an alternative. <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">Other uses: can this drug be used to treat other diseases/conditions? <span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 11pt; text-align: justify;">No, vaccines are used to prevent its specific disease. **Figure 3:** Modern smallpox vaccine.