Editing Cowpox (section)

==Origin==
[[File:Cowpox Engraving (detail).png|right|thumb|Cowpox (variola vaccina) pustules on a cow's udder]]

===Discovery===
In the years from 1770 to 1790, at least six people who had contact with a cow had independently tested the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Among them were the English farmer [[Benjamin Jesty]], in [[Dorset]] in 1774 and the German teacher [[Peter Plett]] in 1791.<ref>{{cite journal |last1=Plett |first1=Peter C. |last2=Schmidt |first2=J. G. |title=Peter Plett und die übrigen Entdecker der Kuhpockenimpfung vor Edward Jenner |trans-title=Peter Plett and other discoverers of cowpox vaccination before Edward Jenner |language=de |journal=Sudhoffs Archiv |date=2006 |volume=90 |issue=2 |pages=219–232 |jstor=20778029 |pmid=17338405 }}</ref> Jesty inoculated his wife and two young sons with cowpox, in a successful effort to immunize them to smallpox, an epidemic of which had arisen in their town. His patients who had contracted and recovered from the similar but milder cowpox (mainly milkmaids), seemed to be [[immune]] not only to further cases of cowpox, but also to smallpox. By scratching the fluid from cowpox lesions into the skin of healthy individuals, he was able to immunize those people against smallpox.<ref>{{cite journal | vauthors = Williams N | title = Pox precursors | journal = Current Biology | volume = 17 | issue = 5 | pages = R150–R151 | date = March 2007 | pmid = 17387780 | doi = 10.1016/j.cub.2007.02.024 | doi-access = free | bibcode = 2007CBio...17.R150W }}</ref>

Reportedly, farmers and people working regularly with cattle and horses were often spared during smallpox outbreaks. Investigations by the [[British Army]] in 1790 showed that [[cavalry|horse-mounted troops]] were less infected by smallpox than [[infantry]], due to probable exposure to the similar [[horsepox]] virus (''Variola equina''). By the early 19th century, more than 100,000 people in Great Britain had been vaccinated. The arm-to-arm method of transfer of the cowpox vaccine was also used to distribute Jenner's vaccine throughout the Spanish Empire. Spanish king  [[Charles IV of Spain|Charles IV]]'s daughter had been stricken with smallpox in 1798, and after she recovered, he arranged for the rest of his family to be vaccinated.<ref>{{Cite web | vauthors = Patowary K |date=2020-12-09 |title=Balmis Expedition - How Orphans Took The Smallpox Vaccine Around The World |url=https://www.amusingplanet.com/2020/12/balmis-expedition-how-orphans-took.html |access-date=2021-08-11 |website=Amusing Planet}}</ref>

In 1803, the king, convinced of the benefits of the vaccine, ordered his personal physician Francis Xavier de Balmis, to deliver it to the Spanish dominions in North and South America. To maintain the vaccine in an available state during the voyage, the physician recruited 22 young boys who had never had cowpox or smallpox before, aged three to nine years, from the orphanages of Spain. During the trip across the Atlantic, de Balmis vaccinated the orphans in a living chain. Two children were vaccinated immediately before departure, and when cowpox pustules had appeared on their arms, material from these lesions was used to vaccinate two more children.<ref>{{cite book | vauthors = Tucker JB |title=Scourge: The Once and Future Threat of Smallpox |year=2001 |location=New York |publisher=Atlantic Monthly Press |page=[https://archive.org/details/scourgeoncefu00tuck/page/31 31] |isbn=978-0-87113-830-9 |url=https://archive.org/details/scourgeoncefu00tuck/page/31 }}</ref>

In 1796, English medical practitioner [[Edward Jenner]] tested the theory that cowpox could protect someone from being infected by smallpox. There had long been speculation regarding the origins of Jenner's variolae vaccinae, until DNA sequencing data showed close similarities between horsepox and cowpox viruses. Jenner noted that [[farrier]]s sometimes milked cows and that material from the equine disease could produce a vesicular disease in cows from which variolae vaccinae was derived.  Contemporary accounts provide support for Jenner's speculation that the vaccine probably originated as an equine disease called "grease".<ref>{{cite journal | vauthors = Noyce RS, Lederman S, Evans DH | title = Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments | journal = PLOS ONE | volume = 13 | issue = 1 | pages = e0188453 | date = 2018-01-19 | pmid = 29351298 | pmc = 5774680 | doi = 10.1371/journal.pone.0188453 | doi-access = free | bibcode = 2018PLoSO..1388453N | veditors = Thiel V }}</ref>
Although cowpox originates on the udder of cows, Jenner took his sample from a milkmaid, Sarah Nelmes.{{citation needed|date=November 2022}}

Jenner extracted the pus of one of the lesions formed by cowpox on Nelmes to [[James Phipps]], an eight-year-old boy who had never had smallpox. He eventually developed a scab and fever that was manageable. Approximately six weeks later, Jenner then introduced an active sample of the smallpox virus into Phipps to test the theory. After being observed for an extended amount of time, it was recorded that Phipps did not receive a reaction from it. Although Jenner was not the first person to conceive the notion of cowpox protecting against the smallpox virus, his experiment proved the theory.{{fact|date=March 2025}}

In later years, Jenner popularized the experiment, calling it a vaccination from the Latin for cow, ''vacca''. The number of vaccinations among people of that era increased drastically. It was widely considered to be a relatively safer procedure compared to the [[variolation|mainstream inoculation]]. Although Jenner was propelled into the spotlight from the vaccination popularity, he mainly focused on science behind why the cowpox allowed persons to not be infected by smallpox. The honour of the discovery of the vaccination is often attributed to [[Benjamin Jesty]], but he was no scientist and did not repeat or publish his findings. He is considered to be the first to use cowpox as a vaccination, though the term vaccination was not invented yet.{{citation needed|date=January 2023}}

During the midst of the smallpox outbreak, Jesty transferred pieces of cow udder which he knew had been infected with cowpox into the skin of his family members in the hopes of protecting them. Jesty did not publicize his findings, and Jenner, who performed his first inoculation 22 years later and publicized his findings, assumed credit. It is said that Jenner made this discovery by himself, possibly without knowing previous accounts 20 years earlier. Although Jesty may have been the first to discover it, Jenner made vaccination widely accessible and has therefore been credited for its invention.<ref>{{cite book |last1=Bynum |first1=W. F. |title=Science and the Practice of Medicine in the Nineteenth Century |date=1994 |publisher=Cambridge University Press |isbn=978-0-521-27205-6 }}{{pn|date=March 2025}}</ref>

=== Life cycle ===
The genome for the CPXV is over 220kbp. This makes it the largest genome in the Orthopoxviral species. It can be divided into three different regions. There are two end regions called R1 and R2 and a main central region that is roughly half of the size of the genome. There are also inverted terminal repeats that are located at the terminal sites of the genome and measure around 10kbp. These inverted terminal repeats can then be divided into two more distinct regions. The first section is around 7.5kbp long and includes a coding region. The other section includes a terminal region that can be repeated up to as many times as thirty and is composed of 50 nucleotides.<ref>{{cite journal | vauthors = Pickup DJ, Ink BS, Parsons BL, Hu W, Joklik WK | title = Spontaneous deletions and duplications of sequences in the genome of cowpox virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 21 | pages = 6817–6821 | date = November 1984 | pmid = 6093123 | pmc = 392023 | doi = 10.1073/pnas.81.21.6817 | bibcode = 1984PNAS...81.6817P | doi-access = free }}</ref> The CPXV genome encodes only 30-40% of products of which are involved in the pathogenesis of the virus.<ref>{{cite journal | vauthors = Carroll DS, Emerson GL, Li Y, Sammons S, Olson V, Frace M, Nakazawa Y, Czerny CP, Tryland M, Kolodziejek J, Nowotny N, Olsen-Rasmussen M, Khristova M, Govil D, Karem K, Damon IK, Meyer H | display-authors = 6 | title = Chasing Jenner's vaccine: revisiting cowpox virus classification | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23086 | date = 2011-08-08 | pmid = 21858000 | pmc = 3152555 | doi = 10.1371/journal.pone.0023086 | bibcode = 2011PLoSO...623086C | doi-access = free }}</ref> The CPXV genome has the most complete set of genes out of all of the orthopoxviruses. This unique feature of CPXV makes it ideal to be able to mutate into different strains of the virus.<ref>{{cite journal | vauthors = Xu Z, Zikos D, Osterrieder N, Tischer BK | title = Generation of a complete single-gene knockout bacterial artificial chromosome library of cowpox virus and identification of its essential genes | journal = Journal of Virology | volume = 88 | issue = 1 | pages = 490–502 | date = January 2014 | pmid = 24155400 | pmc = 3911729 | doi = 10.1128/JVI.02385-13 }}</ref> It is a double stranded DNA virus. The virus does have an envelope that surrounds the virion.<ref>{{cite journal |last1=Payne |first1=L. G. |title=The existence of an envelope on extracellular cowpox virus and its antigenic relationship to the vaccinia envelope |journal=Archives of Virology |date=March 1986 |volume=90 |issue=1–2 |pages=125–133 |doi=10.1007/BF01314150 |pmid=3729722 |doi-access=free }}</ref> The cowpox's genome allows the virus to encode its own transcription machinery along with its own DNA replication machinery. The replication then takes place in the cytoplasm after the virus is in the cell and the virion is uncoated. The virion is then assembled and released from the host cell.<ref>{{cite journal | vauthors = Alzhanova D, Früh K | title = Modulation of the host immune response by cowpox virus | journal = Microbes and Infection | volume = 12 | issue = 12–13 | pages = 900–909 | date = November 2010 | pmid = 20673807 | pmc = 3500136 | doi = 10.1016/j.micinf.2010.07.007 }}</ref>

The genome is arranged so that both of the ends contain the genes responsible for evading the defenses from the immune system of the host which is only activated in the extracellular portion. These receptors are able to be stopped by cytokine and chemokine secretion by blocking the cytokine and chemokine found extracellularly. This is the process responsible for attachment and entry of the virion into the host cell.<ref>{{cite journal | vauthors = Soares JA, Leite FG, Andrade LG, Torres AA, De Sousa LP, Barcelos LS, Teixeira MM, Ferreira PC, Kroon EG, Souto-Padrón T, Bonjardim CA | display-authors = 6 | title = Activation of the PI3K/Akt pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication | journal = Journal of Virology | volume = 83 | issue = 13 | pages = 6883–6899 | date = July 2009 | pmid = 19386722 | pmc = 2698574 | doi = 10.1128/JVI.00245-09 }}</ref> Because of the large size of the genome, it makes the virus more likely and capable to fight back against the immunes system defenses. Out of all of the poxviruses, CPXV has the most cytokine responses that fight back against the immune system. It encodes cytokine receptors such as TNF, CrmB, CrmC, CrmD, and CrmE proteins. Another set of receptors that CPXV have are lymphotoxins such as IL-1ß, IFN-y, IFN 1, β-chemokines, and IL-18. However, not all of the receptors of CPXV are still not known. CPXV also encodes four tumor necrosis factors (TNF) and lymphotoxin which are the biggest group of homologous receptors for the virus. These receptors play a crucial role that are involved with the immune system.<ref>{{cite journal | vauthors = Panus JF, Smith CA, Ray CA, Smith TD, Patel DD, Pickup DJ | title = Cowpox virus encodes a fifth member of the tumor necrosis factor receptor family: a soluble, secreted CD30 homologue | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 8348–8353 | date = June 2002 | doi = 10.1073/pnas.122238599 | pmid = 12034885 | pmc = 123070 | doi-access = free }}</ref>

CPXV has two different types of inclusion bodies. All of the poxviruses have basophilic inclusions also called B-type inclusion bodies. The B-type inclusion bodies contain the factory where the virus produces necessary elements for the replication and maturation of the virion. CPXV has another inclusion body that is unique to only some chordopoxviruses called acidophilic inclusion bodies also called A-type inclusion bodies (ATIs). The ATIs are encoded by the cpxv158 gene and is then made the protein ATIP which is a late protein. However, the importance of these ATIs in the life cycle are still not well known or understood and research is still being done to better understand them. It is known that replication can still continue without the cpxv158 gene, and that the replication cycle shows no difference between a fully encoded virion versus the virion that had deleted cwpx158 gene. However, with studies done on mice, the lesions that were caused by the CPXV-BR△ati were able to heal faster due to less tissue that was lost than the CPXV-BR lesions that took longer to heal and lost more tissue. This suggests that this gene helps supports the idea that ATIs are partly involved in how the host responds to the virus infection.<ref>{{cite journal | vauthors = Leite JA, da Fonseca FG, de Souza Trindade G, Abrahão JS, Arantes RM, de Almeida-Leite CM, dos Santos JR, Guedes MI, Ribeiro BM, Bonjardim CA, Ferreira PC, Kroon EG | display-authors = 6 | title = A-type inclusion bodies: a factor influencing cowpox virus lesion pathogenesis | journal = Archives of Virology | volume = 156 | issue = 4 | pages = 617–628 | date = April 2011 | doi = 10.1007/s00705-010-0900-0 | pmid = 21212997 }}</ref>

Another way that the virus is able to control and infect the host is by regulating cellular signaling pathways. During the infection, CPXV is known to use MEK/ERK/1/2/Egr-1, JNK1/2, and PI3K/Akt pathways. Some of these pathways are not unique only to CPXV, but how they function in response to the host is unique to this virus.<ref>{{cite journal | vauthors = Salgado AP, Soares-Martins JA, Andrade LG, Albarnaz JD, Ferreira PC, Kroon EG, Bonjardim CA | title = Study of vaccinia and cowpox viruses' replication in Rac1-N17 dominant-negative cells | journal = Memórias do Instituto Oswaldo Cruz | volume = 108 | issue = 5 | pages = 554–562 | date = August 2013 | pmid = 23903969 | pmc = 3970603 | doi = 10.1590/s0074-02762013000500004 }}</ref>

One notable protein in the CPXV is the p28 protein. It is made up of 242 amino acids and contains two domains, and N terminal KilA-N and a C-terminal RING domain. One of those domains, the N-terminal [[KilA-N domain]], allows for DNA to bind to it. The KilA-N domain facilitates this p28 protein that is translated early in the replication cycle in the cytoplasm and is then located in the cytoplasm for the rest of the life cycle of the virus. There is current research still being done to determine if the p28 protein could be a requital for an essential macrophage factor that is needed for the DNA replication.<ref>{{cite journal | vauthors = Bourquain D, Schrick L, Tischer BK, Osterrieder K, Schaade L, Nitsche A | title = Replication of cowpox virus in macrophages is dependent on the host range factor p28/N1R | journal = Virology Journal | volume = 18 | issue = 1 | pages = 173 | date = August 2021 | doi = 10.1186/s12985-021-01640-x | pmid = 34425838 | pmc = 8381512 | doi-access = free }}</ref>

===Opposition to vaccination===
The majority of the population at the time accepted the up-and-coming vaccination. However, there was still opposition from individuals who were reluctant to change from the inoculations. In addition, there became a growing concern from parties who were worried about the unknown repercussions of infecting a human with an animal disease. One way individuals expressed their discontent was to draw comics that sometimes depicted small cows growing from the sites of vaccination. Others publicly advocated for the continuance of the inoculations; however, this was not because of their discontent for the vaccinations. Some of their reluctance had to do with an apprehensiveness for change. They had become so familiar with the process, outcome, positives, and negatives of inoculations that they did not want to be surprised by the outcome or effects of the vaccinations. Jenner soon eased their minds after extensive trials. However, others advocated against vaccinations for different reason. Because of the high price of inoculation, Jenner experienced very few common folk who were not willing to accept the vaccination. Due to this, Jenner found many subjects for his tests. He was able to publish his results in a pamphlet in 1798: ''An Inquiry into the Causes and Effects of Variolae Vaccinae, a Disease, Discovered in some of the Western Counties of England particularly Gloucestershire, and known by the Name of Cow Pox.''<ref>{{Cite book|title=Medicine and Society in Early Modern Europe| vauthors = Lindemann M  }}</ref><ref>{{Cite book|title=An inquiry into the causes and effects of the variolae vaccinae: a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of the cow pox| vauthors = Jenner E |url= https://collections.nlm.nih.gov/catalog/nlm:nlmuid-2559001R-bk}}</ref>