Editing Smallpox vaccine (section)

== Origin ==
The origin of the modern smallpox vaccine has long been unclear,<ref name="smithson2014">{{cite journal | vauthors = Smithson C, Kampman S, Hetman BM, Upton C |title=Incongruencies in Vaccinia Virus Phylogenetic Trees |journal=Computation |date=2014 |volume=2 |issue=4 |pages=182–98 |doi=10.3390/computation2040182 |doi-access = free | title-link = doi |hdl=1828/7374 |hdl-access=free }}</ref> but [[horsepox]] was identified in the 2010s as the most likely ancestor.<ref name="virology5e">{{cite book |vauthors=Flint J, Racaniello VR, Rall GF, Hatziioannou T, Skalka AM |title=Principles of Virology |date=7 August 2020 |publisher=John Wiley & Sons |isbn=978-1-68367-033-9 |edition=5th |url=https://books.google.com/books?id=rEL2DwAAQBAJ |access-date=13 June 2022 |archive-date=8 July 2022 |archive-url=https://web.archive.org/web/20220708045919/https://www.google.com/books/edition/Principles_of_Virology/rEL2DwAAQBAJ |url-status=live }}</ref>{{rp|9}} [[Edward Jenner]] had obtained his vaccine from a cow, so he named the virus ''[[vaccinia]]'', after the Latin word for cow. Jenner believed that both cowpox and smallpox were viruses that originated in the horse and passed to the cow,<ref name="jenner1798">{{cite book |url=https://en.wikisource.org/wiki/An_Inquiry_Into_the_Causes_and_Effects_of_the_Variol%C3%A6_Vaccin%C3%A6 |title=An Inquiry into the Causes and Effects of the Variolæ Vaccinæ |vauthors=Jenner E |date=1798 |publisher=Self-published |location=London |access-date=11 July 2022 |archive-date=11 July 2022 |archive-url=https://web.archive.org/web/20220711220735/https://en.wikisource.org/wiki/An_Inquiry_Into_the_Causes_and_Effects_of_the_Variol%C3%A6_Vaccin%C3%A6 |url-status=live }}</ref>{{rp|52–53}} and some doctors followed his reasoning by inoculating their patients directly with [[horsepox]].<ref name="esparza2017">{{cite journal | vauthors = Esparza J, Schrick L, Damaso CR, Nitsche A | title = Equination (inoculation of horsepox): An early alternative to vaccination (inoculation of cowpox) and the potential role of horsepox virus in the origin of the smallpox vaccine | journal = Vaccine | volume = 35 | issue = 52 | pages = 7222–7230 | date = December 2017 | pmid = 29137821 | doi = 10.1016/j.vaccine.2017.11.003 | doi-access = free | title-link = doi }}</ref> The situation was further muddied when Louis Pasteur developed techniques for creating vaccines in the laboratory in the late 19th century. As medical researchers subjected viruses to [[serial passage]], inadequate recordkeeping resulted in the creation of laboratory strains with unclear origins.<ref name="baxby1981"/>{{rp|4}} By the late 19th century, it was unknown whether the vaccine originated from cowpox, horsepox, or an attenuated strain of smallpox.<ref>{{cite journal | vauthors = Taylor HH |title=What is Vaccinia? |journal=British Medical Journal |date=October 1889 |volume=2 |issue=1504 |pages=951–52 |pmc=2155820 |issn=0007-1447}}</ref>

In 1939, [[Allan Watt Downie]] showed that the vaccinia virus was [[serology|serologically]] distinct from the "spontaneous" cowpox virus.<ref name="downie1939">{{cite journal | vauthors = Downie AW |title=The Immunological Relationship of the Virus of Spontaneous Cowpox to Vaccinia Virus |journal=British Journal of Experimental Pathology |date=April 1939 |volume=20 |issue=2 |pages=158–76 |pmc=2065307 |issn=0007-1021}}</ref> This work established [[vaccinia]] and cowpox as two separate viral species. The term ''[[vaccinia]]'' now refers only to the smallpox vaccine,<ref>{{cite encyclopedia | vauthors = Smith GL, Vanderplasschen A |title=Extracellular Enveloped Vaccinia virus: Entry, Egress, and Evasion | veditors = Enjuanes L, Siddel SG, Spaan W |encyclopedia=Coronaviruses and Arteriviruses |date=1998 |volume=440 |publisher=Springer Science & Business Media |isbn=978-0-306-45910-8 |page=396|pmid=9782308 }}</ref> while cowpox no longer has a Latin name.<ref>{{cite encyclopedia |title=ICTV Taxonomy history: Cowpox virus |url=https://ictv.global/taxonomy/taxondetails?taxnode_id=201904769 |date=14 April 2021 |quote=Varidnaviria > Bamfordvirae > Nucleocytoviricota > Pokkesviricetes > Chitovirales > Poxviridae > Chordopoxvirinae > Orthopoxvirus > Cowpox virus |access-date=15 April 2021 |archive-date=15 April 2021 |archive-url=https://web.archive.org/web/20210415161543/https://talk.ictvonline.org/taxonomy/p/taxonomy-history?taxnode_id=201904769 |url-status=live }}</ref> The development of [[whole genome sequencing]] in the 1990s made it possible to compare [[orthopoxvirus]] genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to ''vaccinia''.<ref>{{cite journal | vauthors = Tulman ER, Delhon G, Afonso CL, Lu Z, Zsak L, Sandybaev NT, Kerembekova UZ, Zaitsev VL, Kutish GF, Rock DL | title = Genome of horsepox virus | journal = Journal of Virology | volume = 80 | issue = 18 | pages = 9244–9258 | date = September 2006 | pmid = 16940536 | doi = 10.1128/JVI.00945-06 | pmc = 1563943 }}</ref> In a [[phylogenetic tree]] of the [[orthopoxvirus]]es, horsepox forms a [[clade]] with ''vaccinia'' strains, and cowpox strains form a different clade.<ref name="carroll2011"/>

Horsepox is extinct in the wild, and the only known sample was collected in 1976.<ref>{{cite journal | vauthors = Esparza J | title = Has horsepox become extinct? | journal = The Veterinary Record | volume = 173 | issue = 11 | pages = 272–273 | date = September 2013 | pmid = 24057497 | doi = 10.1136/vr.f5587 | s2cid = 36975171 | doi-access = free | title-link = doi }}</ref> Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of ''vaccinia'' that had escaped into the wild.<ref name="duggan2020"/> However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern ''vaccinia'' strains. A smallpox vaccine manufactured by [[H. K. Mulford Company|Mulford]] in 1902 is 99.7% similar to horsepox, closer than any previously known strain of ''vaccinia''.<ref>{{cite journal | vauthors = Schrick L, Tausch SH, Dabrowski PW, Damaso CR, Esparza J, Nitsche A | title = An Early American Smallpox Vaccine Based on Horsepox | journal = The New England Journal of Medicine | volume = 377 | issue = 15 | pages = 1491–1492 | date = October 2017 | pmid = 29020595 | doi = 10.1056/NEJMc1707600 | doi-access = free | title-link = doi }}</ref> Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of ''vaccinia''.<ref name="damaso2017">{{cite journal |vauthors=Damaso CR |title=Revisiting Jenner's mysteries, the role of the Beaugency lymph in the evolutionary path of ancient smallpox vaccines |journal=The Lancet Infectious Diseases |date=February 2018 |volume=18 |issue=2 |pages=e55–e63 |doi=10.1016/S1473-3099(17)30445-0 |pmid=28827144 |url=https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30445-0/fulltext |access-date=13 June 2022 |archive-date=21 May 2020 |archive-url=https://web.archive.org/web/20200521124915/https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30445-0/fulltext |url-status=live }}</ref> Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox,<ref name="duggan2020">{{cite journal | vauthors = Duggan AT, Klunk J, Porter AF, Dhody AN, Hicks R, Smith GL, Humphreys M, McCollum AM, Davidson WB, Wilkins K, Li Y, Burke A, Polasky H, Flanders L, Poinar D, Raphenya AR, Lau TT, Alcock B, McArthur AG, Golding GB, Holmes EC, Poinar HN | title = The origins and genomic diversity of American Civil War Era smallpox vaccine strains | journal = Genome Biology | volume = 21 | issue = 1 | pages = 175 | date = July 2020 | pmid = 32684155 | doi = 10.1186/s13059-020-02079-z | pmc = 7370420 | doi-access = free | title-link = doi }}</ref> as well as the 1902 Mulford vaccine.<ref name="brinkmann2020"/> One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in ''vaccinia''.<ref name="brinkmann2020">{{cite journal | vauthors = Brinkmann A, Souza AR, Esparza J, Nitsche A, Damaso CR | title = Re-assembly of nineteenth-century smallpox vaccine genomes reveals the contemporaneous use of horsepox and horsepox-related viruses in the USA | journal = Genome Biology | volume = 21 | issue = 1 | pages = 286 | date = December 2020 | pmid = 33272280 | doi = 10.1186/s13059-020-02202-0 | pmc = 7716468 | doi-access = free | title-link = doi }}</ref>