View source for Medicine:Smallpox

{{Short description|Eradicated viral disease}}
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{{Infobox medical condition (new)
| synonyms        = variola,<ref>{{cite book |last1=Barton |first1=Leslie L. |last2=Friedman |first2=Neil R. |title=The Neurological Manifestations of Pediatric Infectious Diseases and Immunodeficiency Syndromes|date=2008|publisher=Springer Science & Business Media|isbn=978-1-59745-391-2|page=151|url=https://books.google.com/books?id=GaIyKkRBqIQC&pg=PA151|language=en}}</ref> variola vera,<ref>{{cite book |last1=Schaller |first1=Karl F. |title=Colour Atlas of Tropical Dermatology and Venerology|date=2012|publisher=Springer Science & Business Media|isbn=978-3-642-76200-0|page=Chapter 1|url=https://books.google.com/books?id=Bw8yBwAAQBAJ&pg=PP21|language=en}}</ref> pox,<ref name="Fenner_1988"/> red plague<ref name=Peg2017/>
| image           = Child with Smallpox Bangladesh.jpg
| image_size      = 225px
| caption         = A child with smallpox in Bangladesh in 1973. The bumps filled with thick fluid and a depression or dimple in the center are characteristic.
| field           = [[Medicine:Infectious disease (medical specialty)|Infectious disease]]
| symptoms        = {{plainlist|
* '''Early''': Fever, vomiting, mouth sores<ref name=CDC2016Sym/>
* '''Later''': Fluid filled blisters which [[Biology:Wound healing#Proliferative phase|scab]] over<ref name=CDC2016Sym/>}}
| complications   = Scarring of the skin, blindness<ref name=CDC2016What/>
| onset           = 1 to 3 weeks following exposure<ref name=CDC2016Sym/>
| duration        = About 4 weeks<ref name=CDC2016Sym/>
| causes          = ''variola major virus'', ''variola minor virus'' (spread between people)<ref name=CDC2016What/><ref name=She2004/>
| risks           =
| diagnosis       = Based on symptoms and confirmed by [[Biology:Polymerase chain reaction|PCR]]<ref name=CDC2017Diag/>
| differential    = [[Medicine:Chickenpox|Chickenpox]], [[Medicine:Impetigo|impetigo]], [[Medicine:Molluscum contagiosum|molluscum contagiosum]], [[Medicine:Monkeypox|monkeypox]]<ref name=CDC2017Diag>{{cite web|title=Diagnosis & Evaluation|url=https://www.cdc.gov/smallpox/clinicians/diagnosis-evaluation.html|website=CDC|access-date=14 December 2017|language=en-us|date=25 July 2017|archive-date=9 December 2017|archive-url=https://web.archive.org/web/20171209185420/https://www.cdc.gov/smallpox/clinicians/diagnosis-evaluation.html|url-status=live}}</ref>
| prevention      = [[Medicine:Smallpox vaccine|Smallpox vaccine]]<ref name=CDC2017Tx/>
| treatment       = Supportive care<ref name=WHO2007Fact/>
| medication      = [[Chemistry:Brincidofovir|Brincidofovir]]
| prognosis       = 30% risk of death<ref name=CDC2016Sym/>
| frequency       = [[Biology:Eradication of infectious diseases|Eradicated]] (last wild case in 1977)
| deaths          =
|name=|alt=}}

'''Smallpox''' was an [[Medicine:Infectious disease|infectious disease]] caused by variola virus (often called smallpox virus)  which belongs to the genus [[Biology:Orthopoxvirus|Orthopoxvirus]].<ref name=She2004>{{cite book | veditors = Ryan KJ, Ray CG | title = Sherris Medical Microbiology | edition = 4th | pages = 525–28 | publisher = McGraw Hill | year = 2004 |isbn = 978-0-8385-8529-0 |url=https://archive.org/details/sherrismedicalmi0000unse_q1i3/page/525/mode/2up}}</ref><ref name=Viruses2015>{{cite journal | vauthors = Babkin,I, Babkina,I | title = The Origin of the variola Virus | journal = Viruses | pages = 1100–1112 | date = March 2015 | volume = 7 | issue = 3 | pmid = 25763864 | pmc = 4379562 | doi = 10.3390/v7031100 | doi-access = free }}</ref> The last naturally occurring case was diagnosed in October 1977, and the [[Organization:World Health Organization|World Health Organization]] (WHO) certified the [[Biology:Eradication of infectious diseases|global eradication]] of the disease in 1980,<ref name=WHO2007Fact>{{cite web | title=Smallpox | work=WHO Factsheet | url=https://www.who.int/mediacentre/factsheets/smallpox/en/ | archive-url=https://web.archive.org/web/20070921235036/http://www.who.int/mediacentre/factsheets/smallpox/en/ | archive-date = 21 September 2007 }}</ref> making smallpox the only human disease to be eradicated.<ref>{{cite web |title=Smallpox - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/smallpox/symptoms-causes/syc-20353027 |access-date=2022-04-27 |website=Mayo Clinic |language=en |archive-date=20 April 2022 |archive-url=https://web.archive.org/web/20220420010332/https://www.mayoclinic.org/diseases-conditions/smallpox/symptoms-causes/syc-20353027 |url-status=live }}</ref>

The initial symptoms of the disease included [[Medicine:Fever|fever]] and vomiting.<ref name=CDC2016Sym/> This was followed by formation of ulcers in the mouth and a skin rash.<ref name=CDC2016Sym/> Over a number of days, the skin rash turned into the characteristic fluid-filled [[Medicine:Blister|blister]]s with a dent in the center.<ref name=CDC2016Sym/> The bumps then [[Biology:Wound healing#Proliferative phase|scabbed]] over and fell off, leaving scars.<ref name=CDC2016Sym>{{cite web|title=Signs and Symptoms|url=https://www.cdc.gov/smallpox/symptoms/index.html|website=CDC|access-date=14 December 2017|language=en-us|date=7 June 2016|archive-date=7 June 2020|archive-url=https://web.archive.org/web/20200607083501/https://www.cdc.gov/smallpox/symptoms/index.html|url-status=live}}</ref> The disease was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person or (rarely) via [[Medicine:Fomite|contaminated objects]].<ref name=CDC2016What>{{cite web|title=What is Smallpox?|url=https://www.cdc.gov/smallpox/about/index.html|website=CDC|access-date=14 December 2017|language=en-us|date=7 June 2016|archive-date=7 June 2020|archive-url=https://web.archive.org/web/20200607000819/https://www.cdc.gov/smallpox/about/index.html|url-status=live}}</ref><ref name=Leb2013>{{cite book|url=https://books.google.com/books?id=hRryAAAAQBAJ&pg=PA89|title=Treatment of Skin Disease E-Book: Comprehensive Therapeutic Strategies|last1=Lebwohl|first1=Mark G.|last2=Heymann|first2=Warren R.|last3=Berth-Jones|first3=John|last4=Coulson|first4=Ian |date=2013|publisher=Elsevier Health Sciences|isbn=978-0-7020-5236-1|page=89|language=en}}</ref><ref name="2012Spread"/> Prevention was achieved mainly through the [[Medicine:Smallpox vaccine|smallpox vaccine]].<ref name=CDC2017Tx/> Once the disease had developed, certain antiviral medications could potentially have helped, but such medications did not become available until after the disease was eradicated.<ref name=CDC2017Tx>{{cite web|title=Prevention and Treatment|url=https://www.cdc.gov/smallpox/prevention-treatment/index.html|website=CDC|access-date=14 December 2017|language=en-us|date=13 December 2017|archive-date=15 December 2017|archive-url=https://web.archive.org/web/20171215110657/https://www.cdc.gov/smallpox/prevention-treatment/index.html|url-status=live}}</ref> The risk of death was about 30%, with higher rates among babies.<ref name=CDC2016What/><ref name=Rie2005>{{cite journal | vauthors = Riedel S | title = Edward Jenner and the history of smallpox and vaccination | journal = Proceedings | volume = 18 | issue = 1 | pages = 21–25 | date = January 2005 | pmid = 16200144 | pmc = 1200696 | doi = 10.1080/08998280.2005.11928028 }}</ref> Often, those who survived had extensive scarring of their skin, and some were left blind.<ref name=CDC2016What/>

The earliest evidence of the disease dates to around 1500 BC in Egyptian mummies.<ref name=CDC2017His>{{cite web|title=History of Smallpox|url=https://www.cdc.gov/smallpox/history/history.html|website=CDC|access-date=14 December 2017|language=en-us|date=25 July 2017|archive-date=14 June 2020|archive-url=https://web.archive.org/web/20200614213232/https://www.cdc.gov/smallpox/history/history.html|url-status=live}}</ref><ref>{{cite journal |last1=Thèves |first1=Catherine |last2=Crubézy |first2=Eric |last3=Biagini |first3=Philippe |date=2016 |title=History of Smallpox and Its Spread in Human Populations |url=https://pubmed.ncbi.nlm.nih.gov/27726788 |journal=Microbiology Spectrum |volume=4 |issue=4 |doi=10.1128/microbiolspec.PoH-0004-2014 |issn=2165-0497 |pmid=27726788 |access-date=11 September 2022 |archive-date=8 October 2022 |archive-url=https://web.archive.org/web/20221008092824/https://pubmed.ncbi.nlm.nih.gov/27726788/ |url-status=live }}</ref> The disease historically occurred in [[Medicine:Disease outbreak|outbreaks]].<ref name=WHO2007Fact/> In 18th-century Europe, it is estimated that 400,000 people died from the disease per year, and that one-third of all cases of blindness were due to smallpox.<ref name=WHO2007Fact/><ref name=Hays2005>{{cite book| vauthors = Hays JN |title=Epidemics and Pandemics: Their Impacts on Human History|date=2005|publisher=ABC-CLIO|isbn=978-1-85109-658-9|pages=[https://archive.org/details/epidemicspandemi0000hays/page/151 151]–52|url=https://archive.org/details/epidemicspandemi0000hays|url-access=registration|language=en}}</ref> Smallpox is estimated to have killed up to 300&nbsp;million people in the 20th century<ref>{{cite book | first1 = Hilary | last1 = Koprowski | first2 = Michael B. A. | last2 = Oldstone |title=Microbe hunters, then and now|publisher=Medi-Ed Press | year= 1996 |isbn=978-0-936741-11-6|page=23}}</ref><ref>{{cite journal | vauthors = Henderson DA | title = The eradication of smallpox – an overview of the past, present, and future | journal = Vaccine | volume = 29 | pages = D7–9 | date = December 2011 | issue = Suppl 4 | pmid = 22188929 | doi = 10.1016/j.vaccine.2011.06.080 }}</ref> and around 500&nbsp;million people in the last 100 years of its existence.<ref>{{cite book |url= https://books.google.com/books?id=1u7Xw5i7Ky0C&pg=PA12 |title=Smallpox : the death of a disease| vauthors = Henderson D |date=2009 |publisher=Prometheus Books |isbn=978-1-61592-230-7 |page=12 }}</ref> Earlier deaths included six European [[Social:Monarch|monarch]]s.<ref name="WHO2007Fact" /><!-- Quote = Smallpox killed Queen Mary II of England, Emperor Joseph I of Austria, King Luis I of Spain, Tsar Peter II of Russia, Queen Ulrika Elenora of Sweden, and King Louis XV of France. --><ref name="Hays2005" /> As recently as 1967, 15&nbsp;million cases occurred a year.<ref name=WHO2007Fact/>

[[Biology:Inoculation|Inoculation]] for smallpox appears to have started in China around the 1500s.<ref>{{cite book |last1=Needham |first1=Joseph |title=Science and Civilisation in China: Volume 6, Biology and Biological Technology, Part 6, Medicine |date=2000 |publisher=Cambridge University Press |isbn=978-0-521-63262-1 |page=134 |url=https://books.google.com/books?id=6bEZ8Hp8h5sC&q=Smallpox&pg=PA134 |access-date=30 March 2020 |language=en}}</ref><ref>{{cite book |title=A History of Immunology |first=Arthur M. |last=Silverstein |pages=293 |publisher=Academic Press |year=2009 |edition=2nd |url=https://books.google.com/books?id=2xNYjigte14C&q=Smallpox&pg=PA293 |isbn=978-0080919461 }}.</ref> Europe adopted this practice from Asia in the first half of the 18th century.<ref name="strathern179">{{cite book | last=Strathern | first=Paul | year=2005 | title=A Brief History of Medicine | publisher=Robinson | location=London | isbn=978-1-84529-155-6 | page=179 }}</ref> In 1796, Edward Jenner introduced the modern smallpox vaccine.<ref name=Wolfe2002>{{cite journal | vauthors = Wolfe RM, Sharp LK | title = Anti-vaccinationists past and present | journal = BMJ | volume = 325 | issue = 7361 | pages = 430–32 | date = August 2002 | pmid = 12193361 | pmc = 1123944 | doi = 10.1136/bmj.325.7361.430 }}</ref><ref>{{cite web |title=Smallpox vaccines |url=https://www.who.int/csr/disease/smallpox/vaccines/en/ |website=WHO |access-date=27 March 2020 |archive-date=30 September 2020 |archive-url=https://web.archive.org/web/20200930033132/https://www.who.int/csr/disease/smallpox/vaccines/en/ |url-status=live }}</ref> In 1967, the WHO intensified efforts to eliminate the disease.<ref name=WHO2007Fact/> Smallpox is one of two infectious diseases to have been eradicated, the other being [[Biology:Rinderpest|rinderpest]] (a disease of [[Biology:Even-toed ungulate|even-toed ungulate]]s) in 2011.<ref>{{cite book|last1=Guidotti|first1=Tee L. |title=Health and Sustainability: An Introduction|date=2015|publisher=Oxford University Press|isbn=978-0-19-932568-9|page=T290|url=https://books.google.com/books?id=hPRgBwAAQBAJ&pg=PT290|language=en}}</ref><ref>{{cite book|last1=Roossinck|first1=Marilyn J. |title=Virus: An Illustrated Guide to 101 Incredible Microbes|date=2016|publisher=Princeton University Press|isbn=978-1-4008-8325-7|page=126|url=https://books.google.com/books?id=gTH9CwAAQBAJ&pg=PA126|language=en}}</ref> The term "smallpox" was first used in England in the 16th century to distinguish the disease from [[Medicine:Syphilis|syphilis]], which was then known as the "great pox".<ref>{{OEtymD|Smallpox}}</ref><ref name=Bar1997>{{cite journal | vauthors = Barquet N, Domingo P | title = Smallpox: the triumph over the most terrible of the ministers of death | journal = Annals of Internal Medicine | volume = 127 | issue = 8 Pt 1 | pages = 635–42 | date = October 1997 | pmid = 9341063 | doi = 10.7326/0003-4819-127-8_Part_1-199710150-00010 | citeseerx = 10.1.1.695.883 | s2cid = 20357515 }}</ref> Other historical names for the disease include pox, speckled monster, and red plague.<ref name="Fenner_1988">{{cite book |vauthors=Fenner F, Henderson DA, Arita I, Ježek Z, Ladnyi ID |chapter=The History of Smallpox and its Spread Around the World |title=Smallpox and its eradication |series=History of International Public Health |volume=6 |date=1988 |publisher=World Health Organization |location=Geneva |isbn=978-92-4-156110-5 |hdl=10665/39485 |pages=209–44 |chapter-url=https://biotech.law.lsu.edu/blaw/bt/smallpox/who/red-book/9241561106_chp5.pdf |access-date=14 December 2017 |archive-date=12 December 2019 |archive-url=https://web.archive.org/web/20191212171449/https://biotech.law.lsu.edu/blaw/bt/smallpox/who/red-book/9241561106_chp5.pdf |url-status=live }}</ref><ref name=Peg2017>{{cite book |title=Medicine: The Definitive Illustrated History |date=2016 |publisher=Pengui |isbn=978-1-4654-5893-3 |page=100 |url=https://books.google.com/books?id=dicCDQAAQBAJ&pg=PA100 }}</ref><ref name=Bar1997/>

== Classification ==
{| class="wikitable" style="text-align:center"
|+ [[Medicine:Case fatality rate|Case fatality rate]] and frequency of smallpox by type and vaccination status according to Rao case study<ref>Fenner, Frank, Henderson, Donald A, Arita, Isao, Jezek, Zdenek, Ladnyi, Ivan Danilovich. et al. (1988). Smallpox and its eradication / F. Fenner ... [et al.]. World Health Organization. https://apps.who.int/iris/handle/10665/39485 {{Webarchive|url=https://web.archive.org/web/20200526044554/https://apps.who.int/iris/handle/10665/39485 |date=26 May 2020 }}</ref>
!rowspan="2"| Type of disease
!colspan="2"| Case fatality rate (%) !!colspan="2"| Frequency (%)
|-
! {{abbr|Unvac.|unvaccinated}} !! {{abbr|Vac.|vaccinated}} !! {{abbr|Unvac.|unvaccinated}} !! {{abbr|Vac.|vaccinated}}
|-
|{{left}} Ordinary discrete
| 9.3 || 0.7 || 42.1 || 58.4
|-
|{{left}} Ordinary confluent
| 62 || 26.3 || 22.8 || 4.6
|-
|{{left}} Ordinary semiconfluent
| 37 || 8.4 || 23.9 || 7
|-
|{{left}} Modified
| 0 || 0 || 2.1 || 25.3
|-
|{{left}} Malignant aka Flat
| 96.5 || 66.7 || 6.7 || 1.3
|-
|{{left}} Early hemorrhagic
| 100 || 100 || 0.7 || 1.4
|-
|{{left}} Late hemorrhagic
| 96.8 || 89.8 || 1.7 || 2.0
|}
There are two forms of the smallpox. ''Variola major'' is the severe and most common form, with a more extensive rash and higher fever. Variola minor is a less common presentation, causing less severe disease, typically discrete smallpox, with historical death rates of 1% or less.<ref name=FactSheet>{{cite web|url=http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp |title=CDC Smallpox |access-date=26 December 2007 |work=Smallpox Overview |url-status=dead |archive-url=https://web.archive.org/web/20130402220850/http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp |archive-date=2 April 2013 }}</ref> Subclinical ([[Medicine:Asymptomatic|asymptomatic]]) infections with variola virus were noted but were not common.<ref name= PinkBook /> In addition, a form called ''variola sine eruptione'' <!-- Do not capitalize "variola". -->(smallpox without rash) was seen generally in vaccinated persons. This form was marked by a fever that occurred after the usual [[Medicine:Incubation period|incubation period]] and could be confirmed only by [[Biology:Antibody|antibody]] studies or, rarely, by [[Biology:Viral culture|viral culture]].<ref name= PinkBook /> In addition, there were two very rare and fulminating types of smallpox, the malignant (flat) and hemorrhagic forms, which were usually fatal.

== Signs and symptoms ==
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The initial symptoms were similar to other viral diseases that are still extant, such as [[Medicine:Influenza|influenza]] and the [[Medicine:Common cold|common cold]]: fever of at least {{convert|38.3|°C|°F|0}}, [[Medicine:Myalgia|muscle pain]], malaise, headache and fatigue. As the [[Biology:Gastrointestinal tract|digestive tract]] was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called ''enanthem'' – appeared on mucous membranes of the mouth, tongue, palate, and throat, and the temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva.<ref name="AFIP" />

Variola virus tended to attack skin cells, causing the characteristic pimples, or macules, associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared.<ref name="AFIP" /> At this point, variola major disease could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification:<ref name=":0">{{cite book | vauthors = Rao AR | date = 1972 | title = Smallpox | edition = 1st | location = Bombay | publisher = Kothari Book Depot | oclc = 723806 }}</ref> ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and the malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed.<ref name="eMedicine_Smallpox">{{cite journal | vauthors=Hogan CJ, Harchelroad F | title=CBRNE – Smallpox | journal=EMedicine | url=http://www.emedicine.com/emerg/topic885.htm | access-date=23 September 2006 | date=2018-08-22 | archive-date=17 October 2008 | archive-url=https://web.archive.org/web/20081017170330/http://www.emedicine.com/emerg/topic885.htm | url-status=live }}</ref> The [[Medicine:Incubation period|incubation period]] between contraction and the first obvious symptoms of the disease was 7–14 days.<ref name="pmid25490691">{{cite journal |vauthors=Payne DC, Parashar UD, Lopman BA |title=Developments in understanding acquired immunity and innate susceptibility to norovirus and rotavirus gastroenteritis in children |journal=Current Opinion in Pediatrics |volume=27 |issue=1 |pages=105–109 |date=February 2015 |pmid=25490691 |pmc=4618547 |doi=10.1097/MOP.0000000000000166 |url=}}</ref>

=== Ordinary ===
[[File:Smallpox child.jpg|thumb|upright|A child showing rash due to ordinary-type smallpox (variola major)]]
At least 90% of smallpox cases among unvaccinated persons were of the ordinary type.<ref name= PinkBook /> In this form of the disease, by the second day of the rash the macules had become raised ''papules''. By the third or fourth day, the papules had filled with an opalescent fluid to become ''vesicles''. This fluid became [[Physics:Opacity (optics)|opaque]] and turbid within 24–48 hours, resulting in pustules.

By the sixth or seventh day, all the skin lesions had become pustules. Between seven and ten days the pustules had matured and reached their maximum size. The pustules were sharply raised, typically round, tense, and firm to the touch. The pustules were deeply embedded in the dermis, giving them the feel of a small bead in the skin. Fluid slowly leaked from the pustules, and by the end of the second week, the pustules had deflated and began to dry up, forming crusts or scabs. By day 16–20 scabs had formed over all of the lesions, which had started to flake off, leaving depigmented scars.<ref name=training1>{{cite web |url=http://emergency.cdc.gov/agent/smallpox/training/overview/pdf/diseasemgmt.pdf |title=Smallpox Disease and Its Clinical Management |access-date=26 December 2007 |work=From the training course titled "Smallpox: Disease, Prevention, and Intervention" (www.bt.cdc.gov/agent/smallpox/training/overview) |archive-url=https://web.archive.org/web/20160510161935/http://emergency.cdc.gov/agent/smallpox/training/overview/pdf/diseasemgmt.pdf |archive-date=10 May 2016 |url-status=dead }}</ref>

Ordinary smallpox generally produced a discrete rash, in which the pustules stood out on the skin separately. The distribution of the rash was most dense on the face, denser on the extremities than on the trunk, and denser on the distal parts of the extremities than on the proximal. The palms of the hands and soles of the feet were involved in most cases.<ref name="PinkBook" />

====Confluent====
Sometimes, the blisters merged into sheets, forming a confluent rash, which began to detach the outer layers of skin from the underlying flesh. Patients with confluent smallpox often remained ill even after scabs had formed over all the lesions. In one case series, the case-fatality rate in confluent smallpox was 62%.<ref name="PinkBook" />

=== Modified ===
[[File:Modified smallpox2.png|thumb|Modified smallpox in a vaccinated 4 year old in [[Place:Cardiff|Cardiff]], Wales, 1962]]
Referring to the character of the eruption and the rapidity of its development, modified smallpox occurred mostly in previously vaccinated people. It was rare in unvaccinated people, with one case study showing 1–2% of modified cases compared to around 25% in vaccinated people. In this form, the prodromal illness still occurred but may have been less severe than in the ordinary type. There was usually no fever during the evolution of the rash. The skin lesions tended to be fewer and evolved more quickly, were more superficial, and may not have shown the uniform characteristic of more typical smallpox.<ref name=training1 /> Modified smallpox was rarely, if ever, fatal. This form of variola major was more easily confused with [[Medicine:Chickenpox|chickenpox]].<ref name= PinkBook />

=== Malignant ===
[[File:Malignant smallpox (cropped).jpg|thumb|Malignant hemorrhagic smallpox in a baker during an 1896 epidemic in Gloucester, {{wipe|England}}. Died 8 days after admission.]]
In malignant-type smallpox (also called flat smallpox) the lesions remained almost flush with the skin at the time when raised vesicles would have formed in the ordinary type. It is unknown why some people developed this type. Historically, it accounted for 5–10% of cases, and most (72%) were children.<ref name="Fenner_1988" /> Malignant smallpox was accompanied by a severe prodromal phase that lasted 3–4 days, prolonged high fever, and severe symptoms of [[Medicine:Viremia|viremia]]. The prodromal symptoms continued even after the onset of the rash.<ref name="Fenner_1988" /> The rash on the mucous membranes (enanthem) was extensive. Skin lesions matured slowly, were typically confluent or semi-confluent, and by the seventh or eighth day, they were flat and appeared to be buried in the skin. Unlike ordinary-type smallpox, the vesicles contained little fluid, were soft and velvety to the touch, and may have contained hemorrhages. Malignant smallpox was nearly always fatal and death usually occurred between the 8th and 12th day of illness. Often, a day or two before death, the lesions turned ashen gray, which, along with abdominal distension, was a bad prognostic sign.<ref name="Fenner_1988" /> This form is thought to be caused by deficient [[Biology:Cell-mediated immunity|cell-mediated immunity]] to smallpox. If the person recovered, the lesions gradually faded and did not form scars or scabs.<ref name="CDC"/>

=== Hemorrhagic ===
[[Medicine:Viral hemorrhagic fever|Hemorrhagic]] smallpox is a severe form accompanied by extensive bleeding into the skin, mucous membranes, gastrointestinal tract, and [[Biology:Organ (anatomy)|viscera]]. This form develops in approximately 2% of infections and occurs mostly in adults.<ref name="PinkBook" /> Pustules do not typically form in hemorrhagic smallpox. Instead, bleeding occurs under the skin, making it look charred and black,<ref name="PinkBook" /> hence this form of the disease is also referred to as variola nigra or "black pox".<ref name="PrestonNY" /> Hemorrhagic smallpox has very rarely been caused by variola minor virus.<ref name="Downie 619–629" /> While bleeding may occur in mild cases and not affect outcomes,<ref name="Dixon_1962" /> hemorrhagic smallpox is typically fatal.<ref name="Lane_2011" /> Vaccination does not appear to provide any immunity to either form of hemorrhagic smallpox and some cases even occurred among people that were revaccinated shortly before. It has two forms.<ref name="Fenner_1988" />

==== Early ====
[[File:Hemorrhagic smallpox 2 (cropped).jpg|thumb|An unvaccinated person with probable hemorrhagic smallpox in a 1925 Milwaukee, Wisconsin epidemic. He later died of the disease.]]

The early or [[Medicine:Fulminant|fulminant]] form of hemorrhagic smallpox (referred to as ''purpura variolosa'') begins with a prodromal phase characterized by a high fever, severe headache, and abdominal pain.<ref name="CDC">{{cite web |url=https://www.cdc.gov/smallpox/clinicians/clinical-disease.html |title=Clinical Disease {{!}} Smallpox |date=2019-02-15 |publisher=CDC |language=en-us |access-date=2020-02-06 |archive-date=21 December 2021 |archive-url=https://web.archive.org/web/20211221191749/https://www.cdc.gov/smallpox/clinicians/clinical-disease.html |url-status=live }}</ref> The skin becomes dusky and erythematous, and this is rapidly followed by the development of petechiae and bleeding in the skin, [[Medicine:Subconjunctival bleeding|conjunctiva]] and mucous membranes. Death often occurs suddenly between the fifth and seventh days of illness, when only a few insignificant skin lesions are present. Some people survive a few days longer, during which time the skin detaches and fluid accumulates under it, rupturing at the slightest injury. People are usually conscious until death or shortly before.<ref name="Lane_2011" /> Autopsy reveals petechiae and bleeding in the spleen, kidney, serous membranes, skeletal muscles, pericardium, liver, gonads and bladder.<ref name="Downie 619–629" /> Historically, this condition was frequently misdiagnosed, with the correct diagnosis made only at autopsy.<ref name="Downie 619–629">{{cite journal | vauthors = Downie AW, Fedson DS, Saint Vincent L, Rao AR, Kempe CH | title = Haemorrhagic smallpox | journal = The Journal of Hygiene | volume = 67 | issue = 4 | pages = 619–629 | date = December 1969 | pmid = 4311573 | pmc = 2130761 | doi = 10.1017/S0022172400042078 }}</ref> This form is more likely to occur in pregnant women than in the general population (approximately 16% of cases in unvaccinated pregnant women were early hemorrhagic smallpox, versus roughly 1% in nonpregnant women and adult males).<ref name="Lane_2011">{{cite journal | vauthors = Lane JM | title = Remaining questions about clinical variola major | journal = Emerging Infectious Diseases | volume = 17 | issue = 4 | pages = 676–680 | date = April 2011 | pmid = 21470458 | pmc = 3377426 | doi = 10.3201/eid1704.101960 }}</ref> The case fatality rate of early hemorrhagic smallpox approaches 100%.<ref name="Lane_2011" />

==== Late ====
There is also a later form of hemorrhagic smallpox (referred to late hemorrhagic smallpox, or ''variolosa pustula hemorrhagica''). The prodrome is severe and similar to that observed in early hemorrhagic smallpox, and the fever persists throughout the course of the disease.<ref name="Fenner_1988" /> Bleeding appears in the early eruptive period (but later than that seen in ''purpura variolosa''), and the rash is often flat and does not progress beyond the vesicular stage. Hemorrhages in the mucous membranes appear to occur less often than in the early hemorrhagic form.<ref name="PinkBook" /> Sometimes the rash forms pustules which bleed at the base and then undergo the same process as in ordinary smallpox. This form of the disease is characterized by a decrease in all of the elements of the coagulation cascade and an increase in circulating antithrombin.<ref name="AFIP" /> This form of smallpox occurs anywhere from 3% to 25% of fatal cases, depending on the virulence of the smallpox strain.<ref name="eMedicine_Smallpox" /> Most people with the late-stage form die within eight to 10 days of illness. Among the few who recover, the hemorrhagic lesions gradually disappear after a long period of convalescence.<ref name="Fenner_1988" /> The case fatality rate for late hemorrhagic smallpox is around 90–95%.<ref name=":0" /> Pregnant women are slightly more likely to experience this form of the disease, though not as much as early hemorrhagic smallpox.<ref name="Fenner_1988" />

== Cause ==
{{Virusbox
| image = Smallpox virus virions TEM PHIL 1849.JPG
| image_alt = This transmission electron micrograph depicts a number of smallpox virions. The "dumbbell-shaped" structure inside the virion is the viral core, which contains the viral DNA; Mag. = ~370,000×
| image_caption = This [[Engineering:Transmission electron microscopy|transmission electron micrograph]] depicts a number of smallpox virions. The "dumbbell-shaped" structure inside the virion is the viral core, which contains the viral DNA; Mag. = ~370,000×
| taxon = Variola virus
| extinct = yes
| synonyms = 
| synonyms_ref = 
}}

Smallpox is caused by infection with variola virus, which belongs to the family ''[[Biology:Poxviridae|Poxviridae]]'', subfamily ''[[Biology:Chordopoxvirinae|Chordopoxvirinae]]'', genus ''[[Biology:Orthopoxvirus|Orthopoxvirus]]''.

=== Evolution ===
The date of the appearance of smallpox is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago.<ref name=Esposito2006>{{cite journal | vauthors = Esposito JJ, Sammons SA, Frace AM, Osborne JD, Olsen-Rasmussen M, Zhang M, Govil D, Damon IK, Kline R, Laker M, Li Y, Smith GL, Meyer H, Leduc JW, Wohlhueter RM | title = Genome sequence diversity and clues to the evolution of variola (smallpox) virus | journal = Science | volume = 313 | issue = 5788 | pages = 807–12 | date = August 2006 | pmid = 16873609 | doi = 10.1126/science.1125134 | type = Submitted manuscript | bibcode = 2006Sci...313..807E | s2cid = 39823899 | url = https://zenodo.org/record/1230868 |  access-date = 23 August 2020 | archive-date = 8 October 2022 | archive-url = https://web.archive.org/web/20221008190305/https://zenodo.org/record/1230868 | url-status = live }}</ref> The wide range of dates is due to the different records used to calibrate the [[Biology:Molecular clock|molecular clock]]. One [[Biology:Clade|clade]] was the variola major strains (the more clinically severe form of smallpox) which spread from Asia between 400 and 1,600 years ago. A second clade included both alastrim (a phenotypically mild smallpox) described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago.<ref name=Li2007>{{cite journal | vauthors = Li Y, Carroll DS, Gardner SN, Walsh MC, Vitalis EA, Damon IK | title = On the origin of smallpox: correlating variola phylogenics with historical smallpox records | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 40 | pages = 15787–92 | date = October 2007 | pmid = 17901212 | pmc = 2000395 | doi = 10.1073/pnas.0609268104 | bibcode = 2007PNAS..10415787L | doi-access = free }}</ref>

A second estimate has placed the separation of variola  virus from Taterapox (an [[Biology:Orthopoxvirus|Orthopoxvirus]] of some African rodents including [[Biology:Gerbillinae|gerbil]]s) at 3,000 to 4,000 years ago.<ref name=Hughes2010>{{cite journal | vauthors = Hughes AL, Irausquin S, Friedman R | title = The evolutionary biology of poxviruses | journal = Infection, Genetics and Evolution | volume = 10 | issue = 1 | pages = 50–59 | date = January 2010 | pmid = 19833230 | pmc = 2818276 | doi = 10.1016/j.meegid.2009.10.001 }}</ref> This is consistent with archaeological and historical evidence regarding the appearance of smallpox as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses, the divergence date of variola virus from Taterapox has been estimated to be 50,000 years ago.<ref name="Hughes2010" /> While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed.

Examination of a strain that dates from {{circa|1650}} found that this strain was [[Biology:Basal (phylogenetics)|basal]] to the other presently sequenced strains.<ref name=Duggan2016>{{cite journal | vauthors = Duggan AT, Perdomo MF, Piombino-Mascali D, Marciniak S, Poinar D, Emery MV, Buchmann JP, Duchêne S, Jankauskas R, Humphreys M, Golding GB, Southon J, Devault A, Rouillard JM, Sahl JW, Dutour O, Hedman K, Sajantila A, Smith GL, Holmes EC, Poinar HN | title =17th Century variola Virus Reveals the Recent History of Smallpox | journal = Current Biology | volume = 26 | issue = 24 | pages = 3407–12 | date = December 2016 | pmid = 27939314 | pmc = 5196022 | doi = 10.1016/j.cub.2016.10.061 | }}</ref> The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries.

=== Virology ===
Variola virus is  large and brick-shaped and is approximately 302 to 350 nanometers by 244 to 270&nbsp;nm,<ref>{{cite journal | vauthors = Dubochet J, Adrian M, Richter K, Garces J, Wittek R | title = Structure of intracellular mature vaccinia virus observed by cryoelectron microscopy | journal = Journal of Virology | volume = 68 | issue = 3 | pages = 1935–41 | date = March 1994 | pmid = 8107253 | pmc = 236655 | doi = 10.1128/JVI.68.3.1935-1941.1994 }}</ref> with a single linear double stranded DNA [[Biology:Genome|genome]] 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end.<ref name=Moss>{{cite book | vauthors = Moss B| chapter=Poxviridae: the viruses and their replication | veditors= Fields BN, Knipe DM, Howley PM |display-editors=etal| title=Fields Virology | volume=2 | edition=5th |location=Philadelphia, PA | publisher=Lippincott-Raven | year=2006 |isbn=978-0-7817-6060-7 | pages=2905–46}}</ref><ref name=Damon>{{cite book | vauthors = Damon I| chapter=Poxviruses | veditors= Fields BN, Knipe DM, Howley PM |display-editors=etal | title=Fields Virology | volume=2 | edition=5th |location=Philadelphia, PA | publisher=Lippincott-Raven | year=2006 |isbn=978-0-7817-6060-7 | pages=2947–76}}</ref>

Four orthopoxviruses cause infection in humans: variola, [[Medicine:Vaccinia|vaccinia]], [[Medicine:Cowpox|cowpox]], and [[Biology:Monkeypox virus|monkeypox]]. Variola virus infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature.<ref name = PinkBook>{{cite book | veditors = Atkinson W, Hamborsky J, McIntyre L, Wolfe S | chapter = Smallpox | title = Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) | edition = 9th | pages = 281–306 | publisher = Public Health Foundation | location =Washington DC |year = 2005 | chapter-url = https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/smallpox.pdf | archive-url =https://web.archive.org/web/20100306053203/http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/smallpox.pdf | archive-date=6 March 2010}}</ref>

The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among human DNA viruses in that they replicate in the [[Biology:Cytoplasm|cytoplasm]] of the cell rather than in the [[Biology:Cell nucleus|nucleus]]. To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase.

Both [[Biology:Viral envelope|enveloped]] and unenveloped virions are infectious. The viral envelope is made of modified [[Biology:Golgi apparatus|Golgi]] membranes containing viral-specific polypeptides, including [[Medicine:Hemagglutinin|hemagglutinin]].<ref name=Moss /> Infection with either variola major virus or variola minor virus confers immunity against the other.<ref name=AFIP>{{cite web |url=http://www.afip.org/Departments/infectious/sp/text/1_1.htm |archive-url=https://web.archive.org/web/20071009141639/http://www.afip.org/Departments/infectious/sp/text/1_1.htm |archive-date=9 October 2007 |title=Smallpox |access-date=28 October 2008 |work=Armed Forces Institute of Pathology: Department of Infectious and Parasitic Diseases}}</ref>

==== Variola major ====
The more common, infectious form of the disease was caused by the variola major virus strain.

==== Variola minor ====
Variola minor virus, also called alastrim, was a less common form of the virus, and much less deadly. Although variola minor had the same incubation period and pathogenetic stages as smallpox, it is believed to have had a mortality rate of less than 1%, as compared to smallpox's 30%. Like variola major, variola minor was spread through inhalation of the virus in the air, which could occur through face-to-face contact or through fomites. Infection with variola minor virus conferred immunity against the more dangerous variola major virus.

Because variola minor was a less debilitating disease than smallpox, people were more frequently ambulant and thus able to infect others more rapidly. As such, variola minor swept through the United States, Great Britain, and South Africa in the early 20th century, becoming the dominant form of the disease in those areas and thus rapidly decreasing mortality rates. Along with variola major, the minor form has now been totally eradicated from the globe. The last case of indigenous variola minor was reported in a Somali cook, Ali Maow Maalin, in October 1977, and smallpox was officially declared eradicated worldwide in May 1980.<ref>{{cite web|url=https://www.cdc.gov/smallpox/history/history.html|title=History of Smallpox - Smallpox - CDC|date=15 February 2019|website=www.cdc.gov|access-date=21 March 2019|archive-date=14 June 2020|archive-url=https://web.archive.org/web/20200614213232/https://www.cdc.gov/smallpox/history/history.html|url-status=live}}</ref> Variola minor was also called white pox, kaffir pox, Cuban itch, West Indian pox, milk pox, and pseudovariola.

==== Genome composition ====
The [[Biology:Genome|genome]] of variola major virus is about 186,000 base pairs in length.<ref>{{cite journal |date=2020-12-20 |title=Variola virus, complete genome |url=http://www.ncbi.nlm.nih.gov/nuccore/NC_001611.1 |language=en-US |access-date=11 May 2022 |archive-date=11 May 2022 |archive-url=https://web.archive.org/web/20220511074355/https://www.ncbi.nlm.nih.gov/nuccore/NC_001611.1 |url-status=live }}</ref> It is made from linear double stranded [[Biology:DNA|DNA]] and contains the [[Biology:Coding region|coding sequence]] for about 200 [[Biology:Gene|gene]]s.<ref name=":1">{{cite journal |last1=Thèves |first1=C. |last2=Biagini |first2=P. |last3=Crubézy |first3=E. |date=2014-03-01 |title=The rediscovery of smallpox |journal=Clinical Microbiology and Infection |language=en |volume=20 |issue=3 |pages=210–218 |doi=10.1111/1469-0691.12536 |pmid=24438205 |issn=1198-743X |doi-access=free }}</ref> The genes are usually not overlapping and typically occur in blocks that point towards the closer terminal region of the genome.<ref name=":2">{{cite book |url=https://www.worldcat.org/oclc/825740706 |title=Fields virology |date=2013 |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins |others=Bernard N. Fields, David M. Knipe, Peter M. Howley |isbn=978-1-4511-0563-6 |edition=6th |location=Philadelphia |oclc=825740706}}</ref> The coding sequence of the central region of the genome is highly consistent across [[Biology:Orthopoxvirus|orthopoxvirus]]es, and the arrangement of genes is consistent across chordopoxviruses<ref name=":1" /><ref name=":2" />

The center of the variola virus genome contains the majority of the essential viral genes, including the genes for structural [[Biology:Protein|protein]]s, [[Biology:DNA replication|DNA replication]], [[Biology:Transcription|transcription]], and [[Biology:Messenger RNA|mRNA]] synthesis.<ref name=":1" /> The ends of the genome vary more across strains and species of [[Biology:Orthopoxvirus|orthopoxvirus]]es.<ref name=":1" /> These regions contain proteins that [[Biology:Immunomodulation|modulate]] the hosts' immune systems, and are primarily responsible for the variability in [[Biology:Virulence|virulence]] across the [[Biology:Orthopoxvirus|orthopoxvirus]] family.<ref name=":1" /> These terminal regions in poxviruses are [[Biology:Inverted repeat|inverted terminal repetitions]] (ITR) sequences.<ref name=":2" /> These sequences are identical but oppositely oriented on either end of the genome, leading to the genome being a continuous loop of DNA<ref name=":2" /> Components of the ITR sequences include an incompletely base paired A/T rich [[Biology:Stem-loop|hairpin loop]], a region of roughly 100 base pairs necessary for resolving [[Biology:Concatemer|concatomeric]] DNA (a stretch of DNA containing multiple copies of the same sequence), a few [[Biology:Open reading frame|open reading frame]]s, and [[Biology:Microsatellite|short tandemly repeating sequences]] of varying number and length.<ref name=":2" /> The ITRs of [[Biology:Poxviridae|poxviridae]] vary in length across strains and species.<ref name=":2" /> The coding sequence for most of the viral proteins in variola major virus have at least 90% similarity with the genome of [[Medicine:Vaccinia|vaccinia]], a related virus used for [[Biology:Vaccination|vaccination]] against smallpox.<ref name=":2" />

==== Gene expression ====
[[Biology:Gene expression|Gene expression]] of variola virus occurs entirely within the [[Biology:Cytoplasm|cytoplasm]] of the host [[Biology:Cell|cell]], and follows a distinct progression during infection.<ref name=":2" /> After entry of an infectious [[Biology:Virus|virion]] into a host cell, synthesis of viral [[Biology:Messenger RNA|mRNA]] can be detected within 20 minutes.<ref name=":2" /> About half of the viral genome is [[Biology:Transcription|transcribed]] prior to the [[Biology:DNA replication|replication]] of viral DNA.<ref name=":2" /> The first set of expressed genes are transcribed by pre-existing viral machinery packaged within the infecting virion.<ref name=":2" /> These genes encode the factors necessary for viral DNA synthesis and for transcription of the next set of expressed genes.<ref name=":2" /> Unlike most DNA viruses, [[Biology:DNA replication|DNA replication]] in variola virus and other poxviruses takes place within the cytoplasm of the infected cell.<ref name=":2" /> The exact timing of DNA replication after infection of a host cell varies across the [[Biology:Poxviridae|poxviridae]].<ref name=":2" /> [[Biology:Recombinant DNA|Recombination]] of the genome occurs within actively infected cells.<ref name=":2" /> Following the onset of viral DNA replication, an intermediate set of genes codes for [[Biology:Transcription factor|transcription factor]]s of late gene expression.<ref name=":2" /> The [[Biology:Gene product|products]] of the later genes include transcription factors necessary for transcribing the early genes for new virions, as well as viral [[Biology:RNA polymerase|RNA polymerase]] and other essential enzymes for new viral particles.<ref name=":2" /> These proteins are then packaged into new infectious virions capable of infecting other cells.<ref name=":2" />

=== Research ===
Two live samples of variola major virus remain, one in the United States at the CDC in Atlanta, and one at the Vector Institute in Koltsovo, Russia.<ref name=":3">{{cite journal |last=Vogel |first=Gretchen |date=2004-11-19 |title=WHO Gives a Cautious Green Light to Smallpox Experiments |url=https://www.science.org/doi/10.1126/science.306.5700.1270a |journal=Science |language=en |volume=306 |issue=5700 |pages=1270–1271 |doi=10.1126/science.306.5700.1270a |pmid=15550627 |s2cid=28863021 |issn=0036-8075 |access-date=11 May 2022 |archive-date=11 May 2022 |archive-url=https://web.archive.org/web/20220511074356/https://www.science.org/doi/10.1126/science.306.5700.1270a |url-status=live }}</ref> Research with the remaining virus samples is tightly controlled, and each research proposal must be approved by the [[Organization:World Health Organization|WHO]] and the [[Organization:World Health Assembly|World Health Assembly]] (WHA).<ref name=":3" /> Most research on poxviruses is performed using the closely related ''[[Medicine:Vaccinia|Vaccinia virus]]'' as a model organism.<ref name=":2" /> Vaccinia virus, which is used to vaccinate for smallpox, is also under research as a viral vector for [[Biology:Vaccine|vaccine]]s for unrelated diseases.<ref>{{cite journal |last1=Kaynarcalidan |first1=Onur |last2=Moreno Mascaraque |first2=Sara |last3=Drexler |first3=Ingo |date=26 November 2021 |title=Vaccinia Virus: From Crude Smallpox Vaccines to Elaborate Viral Vector Vaccine Design |journal=Biomedicines |language=en |volume=9 |issue=12 |pages=1780 |doi=10.3390/biomedicines9121780 |pmid=34944596 |pmc=8698642 |issn=2227-9059|doi-access=free }}</ref>

The genome of variola major virus was first [[Biology:DNA sequencing|sequenced]] in its entirety in the 1990s.<ref name=":1" /> The complete coding sequence is publicly available online. The current [[Biology:Reference genome|reference sequence]] for variola major virus was sequenced from a strain that circulated in India in 1967. In addition, there are sequences for samples of other strains that were collected during the WHO eradication campaign.<ref name=":1" /> A [[Biology:Genome browser|genome browser]] for a complete database of annotated sequences of variola virus and other poxviruses is publicly available through the [[Biology:Viral Bioinformatics Resource Center|Viral Bioinformatics Resource Center]].<ref>{{cite web |title=Home |url=https://4virology.net/ |access-date=2022-05-11 |website=Viral Bioinformatics Research Centre |language=en-US |archive-date=24 March 2023 |archive-url=https://web.archive.org/web/20230324214038/https://4virology.net/ |url-status=live }}</ref>

==== Genetic engineering ====
The [[Organization:World Health Organization|WHO]] currently bans [[Biology:Genetic engineering|genetic engineering]] of the variola virus.<ref name=":4">{{cite journal |last=Check |first=Erika |date=2004-11-01 |title=Unanimous vote approves tweak to smallpox genome |journal=Nature |language=en |volume=432 |issue=7015 |pages=263 |doi=10.1038/432263a |pmid=15549065 |bibcode=2004Natur.432..263C |s2cid=70459338 |issn=1476-4687 |doi-access=free }}</ref> However, in 2004, a committee advisory to the WHO voted in favor of allowing editing of the genome of the two remaining samples of variola major virus to add a [[Biology:Marker gene|marker gene]].<ref name=":4" /> This gene, called [[Biology:Green fluorescent protein|GFP]], or green fluorescent protein, would cause live samples of the virus to glow green under fluorescent light.<ref name=":5">{{cite news |last=Altman |first=Lawrence K. |date=2004-11-11 |title=W.H.O. Panel Backs Gene Manipulation in Smallpox Virus |language=en-US |work=The New York Times |url=https://www.nytimes.com/2004/11/11/health/who-panel-backs-gene-manipulation-in-smallpox-virus.html |access-date=2022-05-11 |issn=0362-4331 |archive-date=11 May 2022 |archive-url=https://web.archive.org/web/20220511075252/https://www.nytimes.com/2004/11/11/health/who-panel-backs-gene-manipulation-in-smallpox-virus.html |url-status=live }}</ref> The insertion of this gene, which would not influence the [[Biology:Virulence|virulence]] of the virus, would be the only allowed modification of the genome.<ref name=":5" /> The committee stated the proposed modification would aid in research of treatments by making it easier to assess whether a potential treatment was effective in killing viral samples.<ref name=":5" /> The recommendation could only take effect if approved by the [[Organization:World Health Assembly|WHA]].<ref name=":5" /> When the WHA discussed the proposal in 2005, it refrained from taking a formal vote on the proposal, stating that it would review individual research proposals one at a time.<ref>{{cite web |date=June 1, 2005 |title=WHO smallpox vaccine reserve gains support |url=https://www.cidrap.umn.edu/news-perspective/2005/06/who-smallpox-vaccine-reserve-gains-support |access-date=2022-05-11 |website=CIDRAP |language=en |archive-date=11 May 2022 |archive-url=https://web.archive.org/web/20220511074406/https://www.cidrap.umn.edu/news-perspective/2005/06/who-smallpox-vaccine-reserve-gains-support |url-status=live }}</ref> Addition of the GFP gene to the ''[[Medicine:Vaccinia|Vaccinia]]'' genome is routinely performed during research on the closely related ''[[Medicine:Vaccinia|Vaccinia virus]]''.<ref>{{cite journal |last1=Daian e Silva |first1=D. S. O. |last2=Pinho |first2=T. M. G. |last3=Rachid |first3=M. A. |last4=Barbosa-Stancioli |first4=D. F. |last5=Da Fonseca |first5=F. G. |date=2019-03-15 |title=The Perennial Use of the Green Fluorescent Protein Marker in a Live Vaccinia Virus Ankara Recombinant Platform Shows No Acute Adverse Effects in Mice |journal=Brazilian Journal of Microbiology |volume=50 |issue=2 |pages=347–355 |doi=10.1007/s42770-019-00067-5 |issn=1517-8382 |pmc=6863200 |pmid=30877662}}</ref>

==== Controversies ====
The public availability of the variola virus complete sequence has raised concerns about the possibility of illicit synthesis of infectious virus.<ref name=":6">{{cite web |title=A paper showing how to make a smallpox cousin just got published. Critics wonder why |url=https://www.science.org/content/article/paper-showing-how-make-smallpox-cousin-just-got-published-critics-wonder-why |access-date=2022-05-11 |website=www.science.org |language=en |archive-date=11 May 2022 |archive-url=https://web.archive.org/web/20220511074405/https://www.science.org/content/article/paper-showing-how-make-smallpox-cousin-just-got-published-critics-wonder-why |url-status=live }}</ref> ''[[Medicine:Vaccinia|Vaccinia]]'', a cousin of the variola virus, was artificially synthesized in 2002 by [[Organization:National Institutes of Health|NIH]] scientists.<ref name=":7">{{cite journal |last1=Domi |first1=Arban |last2=Moss |first2=Bernard |date=2002-09-17 |title=Cloning the vaccinia virus genome as a bacterial artificial chromosome in Escherichia coli and recovery of infectious virus in mammalian cells |journal=Proceedings of the National Academy of Sciences |language=en |volume=99 |issue=19 |pages=12415–12420 |doi=10.1073/pnas.192420599 |issn=0027-8424 |pmc=129459 |pmid=12196634|bibcode=2002PNAS...9912415D |doi-access=free }}</ref> They used a previously established method that involved using a [[Biology:Recombinant DNA|recombinant]] viral genome to create a self-replicating bacterial [[Biology:Plasmid|plasmid]] that produced viral particles.<ref name=":7" />

In 2016, another group synthesized the horsepox virus using publicly available sequence data for horsepox.<ref name=":8">{{cite web |title=How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA |url=https://www.science.org/content/article/how-canadian-researchers-reconstituted-extinct-poxvirus-100000-using-mail-order-dna |access-date=2022-05-11 |website=www.science.org |language=en |archive-date=16 May 2022 |archive-url=https://web.archive.org/web/20220516140933/https://www.science.org/content/article/how-canadian-researchers-reconstituted-extinct-poxvirus-100000-using-mail-order-dna |url-status=live }}</ref> The researchers argued that their work would be beneficial to creating a safer and more effective [[Biology:Vaccine|vaccine]] for smallpox, although an effective vaccine is already available.<ref name=":8" /> The horsepox virus had previously seemed to have gone extinct, raising concern about potential revival of variola major and causing other scientists to question their motives.<ref name=":6" /> Critics found it especially concerning that the group was able to recreate viable virus in a short time frame with relatively little cost or effort.<ref name=":8" /> Although the WHO bans individual laboratories from [[Biology:Artificial gene synthesis|synthesizing]] more than 20% of the genome at a time, and purchases of smallpox genome fragments are monitored and regulated, a group with [[Social:Bioterrorism|malicious intentions]] could compile, from multiple sources, the full synthetic genome necessary to produce viable virus.<ref name=":8" />

=== Transmission ===
Smallpox was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of smallpox infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year.<ref name= PinkBook /> Age distribution of smallpox infections depended on acquired immunity. [[Biology:Vaccination|Vaccination]] [[Medicine:Immunity (medical)|immunity]] declined over time and was probably lost within thirty years.<ref name=AFIP /> Smallpox was not known to be transmitted by insects or animals and there was no [[Medicine:Asymptomatic carrier|asymptomatic carrier]] state.<ref name= PinkBook />

Transmission occurred through inhalation of airborne variola virus, usually droplets expressed from the oral, nasal, or [[Biology:Pharynx|pharyngeal]] mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person.<ref name="2012Spread">{{cite journal |author1=Donald K. Milton |title=What was the primary mode of smallpox transmission? Implications for biodefense |journal=Front Cell Infect Microbiol |date=November 29, 2012 |volume=2 |issue=150 |page=150 |doi=10.3389/fcimb.2012.00150 |pmid=23226686 |pmc=3509329 |quote=the rarity of smallpox transmission via fomites suggests that mucosal exposure was not the primary means of transmission and is consistent with a preference for infection via the lower respiratory tract. The rarity of transmission on crowded buses and trains could be evidence that airborne transmission was not important. However, Fenner et al. (1988) state that transmission on public transport was rare because patients seldom traveled after becoming ill.|doi-access=free }}</ref>

Some infections of laundry workers with smallpox after handling contaminated bedding suggested that smallpox could be spread through direct contact with contaminated objects ([[Medicine:Fomite|fomite]]s), but this was found to be rare.<ref name="2012Spread"/><ref name=":0"/> Also rarely, smallpox was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains.<ref name= FactSheet /> The virus can cross the [[Biology:Placenta|placenta]], but the incidence of congenital smallpox was relatively low.<ref name=AFIP /> Smallpox was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by [[Medicine:Lesion|lesion]]s in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact.<ref name= PinkBook /> Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last smallpox scab fell off.<ref name="pmid10367824">{{cite journal | vauthors = Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Eitzen E, Jahrling PB, Hauer J, Layton M, McDade J, Osterholm MT, O'Toole T, Parker G, Perl T, Russell PK, Tonat K | title = Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense | journal = JAMA | volume = 281 | issue = 22 | pages = 2127–37 | date = June 1999 | pmid = 10367824 | doi = 10.1001/jama.281.22.2127 }}</ref>

== Mechanism ==
Once inhaled, the variola virus invaded the mucus membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread [[Biology:Lysis|lysis]] of infected cells occurred and the virus could be found in the bloodstream in large numbers, a condition known as [[Medicine:Viremia|viremia]]. This resulted in the second wave of multiplication in the [[Biology:Spleen|spleen]], [[Biology:Bone marrow|bone marrow]], and lymph nodes.

== Diagnosis ==
The clinical definition of ordinary smallpox is an illness with acute onset of fever equal to or greater than {{convert|38.3|°C|°F|0}} followed by a rash characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause.<ref name= PinkBook /> When a clinical case was observed, smallpox was confirmed using laboratory tests.

[[Engineering:Microscope|Microscopically]], poxviruses produce characteristic cytoplasmic [[Biology:Inclusion bodies|inclusion bodies]], the most important of which are known as Guarnieri bodies, and are the sites of [[Biology:Viral replication|viral replication]]. Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies could not be used to rule out smallpox.<ref>{{cite journal | vauthors = Riedel S | title = Smallpox and biological warfare: a disease revisited | journal = Proceedings | volume = 18 | issue = 1 | pages = 13–20 | date = January 2005 | pmid = 16200143 | pmc = 1200695 | doi = 10.1080/08998280.2005.11928026 }}</ref> The diagnosis of an orthopoxvirus infection can also be made rapidly by [[Physics:Electron microscopy|electron microscopic]] examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy.<ref name=AFIP /> If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections.

Definitive laboratory identification of variola virus involved growing the virus on [[Biology:Chorioallantoic membrane|chorioallantoic membrane]] (part of a chicken [[Biology:Embryo|embryo]]) and examining the resulting pock lesions under defined temperature conditions.<ref>{{cite web |url=http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/biofacts/smllpx-summary.html#_Criteria_for_Determining |title=Smallpox: Current, comprehensive information on pathogenesis, microbiology, epidemiology, diagnosis, treatment, and prophylaxis |access-date=27 December 2007 |work=Center for Infectious Disease Research & Policy |archive-date=4 January 2008 |archive-url=https://web.archive.org/web/20080104115535/http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/biofacts/smllpx-summary.html#_Criteria_for_Determining |url-status=live }}</ref> Strains were characterized by [[Biology:Polymerase chain reaction|polymerase chain reaction]] (PCR) and [[Biology:Restriction fragment length polymorphism|restriction fragment length polymorphism]] (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measured variola virus-specific immunoglobulin and antigen were also developed to assist in the diagnosis of infection.<ref>{{cite journal | vauthors = LeDuc JW, Jahrling PB | title = Strengthening national preparedness for smallpox: an update | journal = Emerging Infectious Diseases | volume = 7 | issue = 1 | pages = 155–57 | year = 2001 | pmid = 11266310 | pmc = 2631676 | doi = 10.3201/eid0701.010125 }}</ref>

[[Medicine:Chickenpox|Chickenpox]] was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox could be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods were available for detecting chickenpox in the evaluation of suspected smallpox cases.<ref name= PinkBook />

<gallery widths="200px" heights="200px">
File:Smallpox CAM.png|Smallpox virus lesions on the [[Biology:Chorioallantoic membrane|chorioallantoic membrane]] of a developing chick
File:Smallpox versus chickenpox english plain.svg|In contrast to the rash in smallpox, the rash in [[Medicine:Chickenpox|chickenpox]] occurs mostly on the torso, spreading less to the limbs.
File:Female smallpox patient -- late-stage confluent maculopapular scarring.jpg|An Italian female smallpox patient whose skin displayed the characteristics of late-stage confluent maculopapular scarring, 1965
</gallery>

== Prevention ==
{{Main|Medicine:Smallpox vaccine}}
[[File:Smallpox vaccine (cropped).jpg|thumb|Components of a modern smallpox vaccination kit including the diluent, a vial of Dryvax vaccinia vaccine, and a bifurcated needle]]
The earliest procedure used to prevent smallpox was [[Biology:Inoculation|inoculation]] with variola minor virus (a method later known as ''[[Biology:Variolation|variolation]]'' after the introduction of [[Medicine:Smallpox vaccine|smallpox vaccine]] to avoid possible confusion), which likely occurred in India, Africa, and China well before the practice arrived in Europe.<ref name=Rie2005/> The idea that inoculation originated in India has been challenged, as few of the ancient [[Social:Sanskrit|Sanskrit]] medical texts described the process of inoculation.<ref>{{cite book | last = Wujastyk | first = Dominik | date= 1995 | chapter = Medicine in India | title = Oriental Medicine: An Illustrated Guide to the Asian Arts of Healing | pages = 19–38, 29 | location = London | publisher = Serindia Publications | isbn = 0-906026-36-9}}</ref> Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure was widely practiced by the 16th century, during the Ming dynasty.<ref name= Temple>{{cite book | last = Temple | first = Robert | date = 1986 | title = The Genius of China: 3,000 Years of Science, Discovery, and Invention | quote = With a foreword by Joseph Needham | location = New York | publisher = Simon and Schuster, Inc. | isbn = 0-671-62028-2 | pages = 135–37 }}</ref> If successful, inoculation produced lasting [[Medicine:Immunity (medical)|immunity]] to smallpox. Because the person was infected with variola virus, a severe infection could result, and the person could transmit smallpox to others. Variolation had a 0.5–2 percent mortality rate, considerably less than the 20–30 percent mortality rate of the disease.<ref name= PinkBook /> Two reports on the Chinese practice of [[Biology:Inoculation|inoculation]] were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.<ref>{{cite book|title=A History of Immunology|first=Arthur M. |last=Silverstein |page=293|publisher=Academic Press|year=2009|edition=2nd|url=https://books.google.com/books?id=2xNYjigte14C|isbn=978-0-08-091946-1 }}</ref>

[[Biography:Lady Mary Wortley Montagu|Lady Mary Wortley Montagu]] observed smallpox inoculation during her stay in the [[Place:Ottoman Empire|Ottoman Empire]], writing detailed accounts of the practice in her letters, and enthusiastically promoted the procedure in England upon her return in 1718.<ref>{{cite web |url=http://www.fordham.edu/Halsall/mod/montagu-smallpox.html |title=Modern History Sourcebook: Lady Mary Wortley Montagu (1689–1762): Smallpox Vaccination in Turkey |publisher=Fordham.edu |access-date=15 October 2010 |archive-date=4 December 2010 |archive-url=https://web.archive.org/web/20101204010824/http://www.fordham.edu/halsall/mod/montagu-smallpox.html |url-status=dead }}</ref> According to [[Biography:Voltaire|Voltaire]] (1742), the Turks derived their use of inoculation from neighbouring [[Place:Circassia|Circassia]]. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years".<ref name="Voltaire 1742">{{cite book|author=Voltaire|year=1742|title=Letters on the English|chapter=Letter XI|chapter-url=http://www.bartleby.com/34/2/11.html|access-date=6 July 2017|archive-date=16 October 2018|archive-url=https://web.archive.org/web/20181016221306/https://www.bartleby.com/34/2/11.html|url-status=live}}</ref> In 1721, [[Biography:Cotton Mather#Advocacy for smallpox inoculation|Cotton Mather]] and colleagues provoked controversy in Boston by inoculating hundreds. After publishing ''The present method of inoculating for the small-pox'' in 1767, Dr Thomas Dimsdale was invited to Russia to variolate the Empress Catherine the Great of Russia and her son, Grand Duke Paul, which he successfully did in 1768. In 1796, Edward Jenner, a doctor in Berkeley, Gloucestershire, rural England, discovered that immunity to smallpox could be produced by inoculating a person with material from a cowpox lesion. Cowpox is a poxvirus in the same family as variola. Jenner called the material used for inoculation vaccine from the [[Social:Root (linguistics)|root word]] ''vacca'', which is Latin for cow. The procedure was much safer than variolation and did not involve a risk of smallpox transmission. Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus used for smallpox vaccination was replaced by the vaccinia virus. Vaccinia is in the same family as cowpox and variola virus but is genetically distinct from both. The origin of the vaccinia virus and how it came to be in the vaccine are not known.<ref name= PinkBook />

[[File:The cow pock.jpg|thumb|upright=1.4|left|An 1802 cartoon by James Gillray of the early controversy surrounding Edward Jenner's vaccination procedure, showing using his cowpox-derived smallpox vaccine causing cattle to emerge from patients]]
The current formulation of the smallpox vaccine is a live virus preparation of the infectious vaccinia virus. The vaccine is given using a [[Biology:Bifurcated needle|bifurcated (two-pronged) needle]] that is dipped into the vaccine solution. The needle is used to prick the skin (usually the upper arm) several times in a few seconds. If successful, a red and itchy bump develops at the vaccine site in three or four days. In the first week, the bump becomes a large blister (called a "Jennerian vesicle") which fills with pus and begins to drain. During the second week, the blister begins to dry up, and a scab forms. The scab falls off in the third week, leaving a small scar.<ref>{{cite web |url=http://www.bt.cdc.gov/agent/smallpox/vaccination/faq.asp |title=Frequently Asked Questions About Smallpox Vaccine |publisher=Centers for Disease Control and Prevention |date=7 February 2007 |access-date=28 December 2010 |url-status=dead |archive-url=https://web.archive.org/web/20151116152008/http://www.bt.cdc.gov/agent/smallpox/vaccination/faq.asp |archive-date=16 November 2015 }}</ref>

The [[Biology:Antibodies|antibodies]] induced by the vaccinia vaccine are cross-protective for other orthopoxviruses, such as monkeypox, cowpox, and variola (smallpox) viruses. Neutralizing antibodies are detectable 10 days after first-time vaccination and seven days after revaccination. Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated.<ref name= CDCvac /> Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter. If a person is vaccinated again later, the immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was 1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated 20 or more years before infection. By contrast, 52 percent of unvaccinated persons died.<ref>{{cite journal | vauthors = Mack TM | title = Smallpox in Europe, 1950–1971 | journal = The Journal of Infectious Diseases | volume = 125 | issue = 2 | pages = 161–69 | date = February 1972 | pmid = 5007552 | doi = 10.1093/infdis/125.2.161 }}</ref>

[[File:Smallpox vaccine injection.jpg|thumb|A demonstration by medical personnel on use of a bifurcated needle to deliver the smallpox vaccine, 2002]]
There are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic reaction at the site of the vaccination (erythema multiforme), spread of the vaccinia virus to other parts of the body, and spread to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1&nbsp;million people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1&nbsp;million (0.000198 percent) who receive the vaccine may die as a result, most often the result of postvaccinial [[Medicine:Encephalitis|encephalitis]] or severe [[Biology:Necrosis|necrosis]] in the area of vaccination (called [[Medicine:Progressive vaccinia|progressive vaccinia]]).<ref name= CDCvac />

Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United States in 1972 and was abandoned in most European countries in the early 1970s.<ref name=WHO2007Fact /><ref>{{cite journal | vauthors = Pütz MM, Alberini I, Midgley CM, Manini I, Montomoli E, Smith GL | title = Prevalence of antibodies to Vaccinia virus after smallpox vaccination in Italy | journal = The Journal of General Virology | volume = 86 | issue = Pt 11 | pages = 2955–2960 | date = November 2005 | pmid = 16227216 | doi = 10.1099/vir.0.81265-0 |  doi-access = free }}</ref> Routine vaccination of health care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel deploying to the Middle East and Korea still receive the vaccination<ref>{{cite web | url = http://www.smallpox.mil/resource/qaAll.asp?cID=364 | title = Questions and Answers | archive-url = https://web.archive.org/web/20080916201159/http://smallpox.mil/resource/qaAll.asp?cID=364 |archive-date=16 September 2008 | work = DoD Smallpox Vaccination Program (SVP) }}</ref>). By 1986, routine vaccination had ceased in all countries.<ref name=WHO2007Fact /> It is now primarily recommended for laboratory workers at risk for occupational exposure.<ref name= PinkBook /> However, the possibility of variola virus being used as a biological weapon has rekindled interest in the development of newer vaccines.<ref name = "Metzger_2007">{{cite journal | vauthors = Metzger W, Mordmueller BG | title = Vaccines for preventing smallpox | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD004913 | date = July 2007 | volume = 2007 | pmid = 17636779 | pmc = 6532594 | doi = 10.1002/14651858.CD004913.pub2 | collaboration = Cochrane Infectious Diseases Group }}</ref> The smallpox vaccine is also effective in, and therefore administered for, the prevention of [[Medicine:Monkeypox|monkeypox]].<ref name="pmid36179973">{{cite journal |vauthors=Aljabali AA, Obeid MA, Nusair MB, Hmedat A, Tambuwala MM |title=Monkeypox virus: An emerging epidemic |journal=Microbial Pathogenesis |volume= 173|issue= Pt A|pages=105794 |date=September 2022 |pmid=36179973 |doi=10.1016/j.micpath.2022.105794 |pmc=9534103 |s2cid=252612981 |url=}}</ref>

== Treatment ==
Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of the disease.<ref name=CDCvac>{{cite web|url=http://www.bt.cdc.gov/agent/smallpox/vaccination/pdf/vaccine-overview.pdf |title=Vaccine Overview |access-date=2 January 2008 |work=Smallpox Fact Sheet |url-status=dead |archive-url=https://web.archive.org/web/20080102234114/http://www.bt.cdc.gov/agent/smallpox/vaccination/pdf/vaccine-overview.pdf |archive-date=2 January 2008 }}</ref> Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible [[Engineering:Ventilator|ventilator]] assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat [[Medicine:Shock (circulatory)|shock]], such as [[Medicine:Fluid replacement|fluid resuscitation]]. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin [[Physics:Burn|burn]]s.<ref name= Fenner4 />

In July 2018, the [[Organization:Food and Drug Administration|Food and Drug Administration]] approved [[Chemistry:Tecovirimat|tecovirimat]], the first drug approved for treatment of smallpox.<ref>{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613496.htm|title=Press Announcements – FDA approves the first drug with an indication for treatment of smallpox|author=Office of the Commissioner|website=www.fda.gov|language=en|access-date=2018-07-28|archive-date=23 April 2019|archive-url=https://web.archive.org/web/20190423072008/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613496.htm|url-status=live}}</ref> [[Biology:Antiviral drug|Antiviral]] treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug [[Chemistry:Cidofovir|cidofovir]] might be useful as a therapeutic agent. The drug must be administered intravenously, and may cause serious kidney toxicity.<ref>{{cite journal | vauthors = Bray M, Roy CJ | title = Antiviral prophylaxis of smallpox | journal = The Journal of Antimicrobial Chemotherapy | volume = 54 | issue = 1 | pages = 1–5 | date = July 2004 | pmid = 15163655 | doi = 10.1093/jac/dkh286 | doi-access = free }}</ref>

[[Biology:ACAM2000|ACAM2000]] is a [[Medicine:Smallpox vaccine|smallpox vaccine]] developed by Acambis. It was approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live [[Medicine:Vaccinia|vaccinia]] virus, cloned from the same strain used in an earlier [[Biology:Vaccine|vaccine]], Dryvax. While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells ([[Biology:Vero cell|Vero cell]]s) from an African green monkey. Efficacy and adverse reaction incidence are similar to Dryvax.<ref name = "Metzger_2007" /> The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the [[Social:Strategic National Stockpile|Strategic National Stockpile]].<ref>{{cite web | title = Smallpox Preparedness and Response Updates from FDA | url = https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/smallpox-preparedness-and-response-updates-fda | work = U.S. Food and Drug Administration | date = 4 June 2021 | access-date = 12 April 2020 | archive-date = 30 July 2020 | archive-url = https://web.archive.org/web/20200730163515/https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/smallpox-preparedness-and-response-updates-fda | url-status = live }}</ref>

In June 2021, [[Chemistry:Brincidofovir|brincidofovir]] was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus.<ref name="FDA Tembexa">{{cite web | title=FDA approves drug to treat smallpox | publisher=[[Organization:Food and Drug Administration|U.S. Food and Drug Administration (FDA)]] | date=4 June 2021 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-drug-treat-smallpox | access-date=7 June 2021 | archive-date=8 June 2021 | archive-url=https://web.archive.org/web/20210608011633/https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-drug-treat-smallpox | url-status=live }} {{PD-notice}}</ref><ref name="FDA appeoval letter">{{cite web|title=NDA Appoval – Animal Efficacy|publisher=[[Organization:Food and Drug Administration|U.S. Food and Drug Administration (FDA)]]|date=4 June 2021|access-date=7 June 2021|url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214460Origs000,214461Orig1s000ltr.pdf|archive-date=8 June 2021|archive-url=https://web.archive.org/web/20210608005721/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214460Origs000,214461Orig1s000ltr.pdf|url-status=live}}</ref>

== Prognosis ==
[[File:Man with facial scarring and blindness due to smallpox, 1972 (cropped).jpg|thumb|upright|Smallpox survivor with facial scarring, blindness and white [[Medicine:Corneal opacity|corneal scar]] in his left eye, 1972]]

The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%.<ref name=WHOSmallpox>{{cite web|title=Smallpox|work=Biologicals:Vaccines and Immunization|publisher=[[Organization:World Health Organization|World Health Organization]]|location=Geneva, Switzerland|date=January 13, 2014|url=https://www.who.int/biologicals/vaccines/smallpox/en/#:~:text=Two%20forms%20of%20the%20disease,most%20prominent%20on%20the%20face.|archive-url=https://web.archive.org/web/20130325084234/http://www.who.int/biologicals/vaccines/smallpox/en/#:~:text=Two%20forms%20of%20the%20disease,most%20prominent%20on%20the%20face.|url-status=dead|archive-date=25 March 2013|access-date=December 26, 2020}}</ref>

Ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the case-fatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat or late hemorrhagic type smallpox is 90% or greater and nearly 100% is observed in cases of early hemorrhagic smallpox.<ref name="Lane_2011" /> The case-fatality rate for variola minor is 1% or less.<ref name="training1" /> There is no evidence of chronic or recurrent infection with variola virus.<ref name="training1" /> In cases of flat smallpox in vaccinated people, the condition was extremely rare but less lethal, with one case series showing a 66.7% death rate.<ref name="Fenner_1988" />

In fatal cases of ordinary smallpox, death usually occurs between days 10-16 of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating [[Biology:Immune complex|immune complex]]es, overwhelming viremia, or an uncontrolled [[Biology:Immune response|immune response]] may be contributing factors.<ref name=PinkBook /> In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. The cause of death in early hemorrhagic cases is commonly due to heart failure and [[Medicine:Pulmonary edema|pulmonary edema]]. In late hemorrhagic cases, high and sustained viremia, severe [[Medicine:Thrombocytopenia|platelet loss]] and poor immune response were often cited as causes of death.<ref name= "Fenner_1988" /> In flat smallpox modes of death are similar to those in burns, with [[Medicine:Hypovolemic shock|loss of fluid]], protein and [[Physics:Electrolyte|electrolyte]]s, and fulminating [[Medicine:Sepsis|sepsis]].<ref name=Fenner4>{{cite book |vauthors=Fenner F, Henderson DA, Arita I, Ježek Z, Ladnyi ID |chapter=Chapter 9: Development of the Global Smallpox Eradication Programme, 1958–1966 |title=Smallpox and Its Eradication |series=History of International Public Health |volume=6 |publisher=World Health Organization |location=Geneva |year=1988 |chapter-url=http://whqlibdoc.who.int/smallpox/9241561106_chp9.pdf |pages=31, 125 |isbn=978-92-4-156110-5 |df=dmy-all |access-date=2 January 2008 |archive-date=15 January 2011 |archive-url=https://web.archive.org/web/20110115065733/http://whqlibdoc.who.int/smallpox/9241561106_chp9.pdf |url-status=dead }}</ref>

=== Complications ===
Complications of smallpox arise most commonly in the respiratory system and range from simple [[Medicine:Bronchitis|bronchitis]] to fatal [[Medicine:Pneumonia|pneumonia]]. Respiratory complications tend to develop on about the eighth day of the illness and can be either viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively uncommon complication of smallpox. When this occurs, the fever usually remains elevated.<ref name=PinkBook />

Other complications include [[Medicine:Encephalitis|encephalitis]] (1 in 500 patients), which is more common in adults and may cause temporary disability; permanent pitted scars, most notably on the face; and complications involving the eyes (2% of all cases). Pustules can form on the eyelid, [[Medicine:Conjunctiva|conjunctiva]], and [[Medicine:Cornea|cornea]], leading to complications such as [[Medicine:Conjunctivitis|conjunctivitis]], [[Medicine:Keratitis|keratitis]], corneal ulcer, iritis, iridocyclitis, and atrophy of the optic nerve. Blindness results in approximately 35-40% of eyes affected with keratitis and corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and [[Biology:Retina|retina]]l hemorrhages. In 2-5% of young children with smallpox, virions reach the joints and bone, causing ''[[Medicine:Osteomyelitis|osteomyelitis]] variolosa''. Bony lesions are symmetrical, most common in the elbows, legs, and characteristically cause separation of the [[Biology:Epiphysis|epiphysis]] and marked [[Biology:Periosteum|periosteal]] reactions. Swollen joints limit movement, and arthritis may lead to limb deformities, ankylosis, malformed bones, flail joints, and stubby fingers.<ref name=AFIP />

Between 65 and 80% of survivors are marked with deep pitted scars (pockmarks), most prominent on the face.

== History ==
{{Main|Biology:History of smallpox}}

=== Disease emergence ===
[[File:Sopona.jpg|thumb|upright|Statue of Sopona, the Yoruba god thought to cause the disease]]
The earliest credible clinical evidence of smallpox is found in the descriptions of smallpox-like disease in medical writings from ancient India (as early as 1500 BCE),<ref name=Shchelkunov2011>{{cite journal | vauthors = Shchelkunov SN | title = Emergence and reemergence of smallpox: the need for development of a new generation smallpox vaccine | journal = Vaccine | volume = 29 | pages = D49–53 | date = December 2011 | issue = Suppl 4 | pmid = 22185833 | doi = 10.1016/j.vaccine.2011.05.037 }}</ref><ref name="Serum Evils p. 5">''Vaccine and Serum Evils'', by Herbert M. Shelton, p. 5</ref> and China (1122 BCE),<ref name=Hopkins_2002>{{cite book | vauthors = Hopkins DR | title = The Greatest Killer: Smallpox in history | publisher = University of Chicago Press | year = 2002 | isbn = 978-0-226-35168-1 | url-access = registration | url = https://archive.org/details/greatestkillersm0000hopk }} Originally published as {{cite book | title = Princes and Peasants: Smallpox in History | date = 1983 | isbn = 0-226-35177-7 | last1 = Hopkins | first1 = Donald R. | publisher = University of Chicago Press }}</ref> as well as a study of the Egyptian mummy of Ramses V, who died more than 3000 years ago (1145 BCE).<ref name="Serum Evils p. 5"/><ref name=Ramses>{{cite web|last=Hopkins |first=Donald |title=Ramses V: Earliest known victim?|url=http://whqlibdoc.who.int/smallpox/WH_5_1980_p22.pdf|archive-url=https://web.archive.org/web/20070919181605/http://whqlibdoc.who.int/smallpox/WH_5_1980_p22.pdf|url-status=dead|archive-date=19 September 2007|publisher=WHO|access-date=6 July 2010}}</ref> It has been speculated that Egyptian traders brought smallpox to India during the 1st millennium BCE, where it remained as an [[Medicine:Endemic (epidemiology)|endemic]] human disease for at least 2000 years. Smallpox was probably introduced into China during the 1st century CE from the southwest, and in the 6th century was carried from China to Japan.<ref name= "Fenner_1988" /> In Japan, the epidemic of 735–737 is believed to have killed as much as one-third of the population.<ref name=Hays2005/><ref>{{cite book | vauthors = Thieme HR | date = 2003 | url = https://books.google.com/books?id=cHcjnkrMweYC | title = Mathematics in population biology | publisher = Princeton University Press | page = 285 | isbn = 0-691-09291-5 }}</ref> At least seven religious deities have been specifically dedicated to smallpox, such as the god Sopona in the [[Religion:Yoruba religion|Yoruba religion]] in West Africa. In India, the Hindu goddess of smallpox, [[Religion:Shitala|Shitala]], was worshipped in temples throughout the country.<ref>{{cite book | vauthors = Henderson DA, Preston R |   title = Smallpox- the Death of a Disease: The Inside Story of Eradicating a Worldwide Killer | publisher = Prometheus Books | year = 2009 | edition = 1st | page = 334 | url = https://www.amazon.com/o/ASIN/1591027225/sciencefriday/#reader_1591027225 | isbn = 978-1-59102-722-5 | access-date = 12 September 2017 | archive-date = 21 July 2020 | archive-url = https://web.archive.org/web/20200721010501/https://www.amazon.com/o/ASIN/1591027225/sciencefriday/#reader_1591027225 | url-status = live }}</ref>

A different viewpoint is that smallpox emerged 1588&nbsp;CE and the earlier reported cases were incorrectly identified as smallpox.<ref>{{cite web |url=https://news.nationalgeographic.com/2016/12/mummies-smallpox-virus-dna-lithuania-health-science |title=Child Mummy Found With Oldest Known Smallpox Virus |last=McKenna |first=Maryn |date=8 December 2016 |website=National Geographic |publisher=National Geographic Society |archive-url=https://web.archive.org/web/20181107014904/https://news.nationalgeographic.com/2016/12/mummies-smallpox-virus-dna-lithuania-health-science/ |archive-date=7 November 2018 |url-status=dead}}</ref><ref>{{cite journal | vauthors = Duggan AT, Perdomo MF, Piombino-Mascali D, Marciniak S, Poinar D, Emery MV, Buchmann JP, Duchêne S, Jankauskas R, Humphreys M, Golding GB, Southon J, Devault A, Rouillard JM, Sahl JW, Dutour O, Hedman K, Sajantila A, Smith GL, Holmes EC, Poinar HN | title = th Century Variola Virus Reveals the Recent History of Smallpox | journal = Current Biology | volume = 26 | issue = 24 | pages = 3407–12 | date = December 2016 | pmid = 27939314 | pmc = 5196022 | doi = 10.1016/j.cub.2016.10.061 | url = }}</ref>

The timing of the arrival of smallpox in Europe and south-western Asia is less clear. Smallpox is not clearly described in either the [[Religion:Old Testament|Old]] or [[Religion:New Testament|New Testament]]s of the Bible or in the literature of the Greeks or Romans. While some have identified the [[Unsolved:Plague of Athens|Plague of Athens]]&nbsp;– which was said to have originated in "Ethiopia" and Egypt&nbsp;– or the plague that lifted Carthage's 396 BCE siege of Syracuse&nbsp;– with smallpox,<ref name="Fenner_1988" /> many scholars agree it is very unlikely such a serious disease as variola major would have escaped being described by [[Biography:Hippocrates|Hippocrates]] if it had existed in the Mediterranean region during his lifetime.<ref name = "Dixon_1962">{{cite book | vauthors = Dixon CW |title=Smallpox |location=London |publisher=Churchill |year=1962 }}</ref>

While the Antonine Plague that swept through the Roman Empire in 165{{ndash}}180 CE may have been caused by smallpox,<ref>{{cite web | first = Verity | last = Murphy | url = http://news.bbc.co.uk/2/hi/health/4381924.stm | title = Past pandemics that ravaged Europe | work = BBC News | date = 7 November 2005 | access-date = 22 February 2009 | archive-date = 7 October 2017 | archive-url = https://web.archive.org/web/20171007210210/http://news.bbc.co.uk/2/hi/health/4381924.stm | url-status = live }}</ref> Saint Nicasius of Rheims became the patron saint of smallpox victims for having supposedly survived a bout in 450,<ref name="Fenner_1988"/> and Saint Gregory of Tours recorded a similar outbreak in France and Italy in 580, the first use of the term ''variola''.<ref name="Fenner_1988" /> Other historians speculate that Arab armies first carried smallpox from Africa into Southwestern Europe during the 7th and 8th centuries.<ref name= "Fenner_1988" /> In the 9th century the Persian physician, Rhazes, provided one of the most definitive descriptions of smallpox and was the first to differentiate smallpox from [[Medicine:Measles|measles]] and [[Medicine:Chickenpox|chickenpox]] in his ''Kitab fi al-jadari wa-al-hasbah'' (''The Book of Smallpox and Measles'').<ref>{{cite journal | vauthors = Otri AM, Singh AD, Dua HS | title = Abu Bakr Razi | journal = British Journal of Ophthalmology | date = October 2008 | volume = 92 | issue = 10 | pages = 1324 }}</ref> During the [[History:Middle Ages|Middle Ages]] several smallpox outbreaks occurred in Europe. However, smallpox had not become established there until the population growth and mobility marked by the [[Religion:Crusades|Crusades]] allowed it to do so. By the 16th century, smallpox had become entrenched across most of Europe,<ref name= "Fenner_1988" /> where it had a mortality rate as high as 30 percent. This endemic occurrence of smallpox in Europe is of particular historical importance, as successive exploration and colonization by Europeans tended to spread the disease to other nations. By the 16th century, smallpox had become a predominant cause of morbidity and mortality throughout much of the world.<ref name= "Fenner_1988" />

[[File:FlorentineCodex BK12 F54 smallpox.jpg|thumb|left|Drawing accompanying text in Book XII of the 16th-century ''Florentine Codex'' (compiled 1555–1576), showing Nahuas of conquest-era central Mexico with smallpox]]

There were no credible descriptions of smallpox-like disease in the [[Earth:Americas|Americas]] before the westward exploration by Europeans in the 15th century CE.<ref name=Li2007 /> Smallpox was introduced into the Caribbean island of Hispaniola in 1507, and into the mainland in 1520, when Spanish settlers from Hispaniola arrived in Mexico, inadvertently carrying smallpox with them. Because the native Amerindian population had no acquired immunity to this new disease, their peoples were decimated by epidemics. Such disruption and population losses were an important factor in the Spanish achieving conquest of the Aztecs and the Incas.<ref name= "Fenner_1988" /> Similarly, English settlement of the east coast of North America in 1633 in Plymouth, Massachusetts was accompanied by devastating outbreaks of smallpox among Native American populations,<ref>{{cite book | url = https://books.google.com/books?id=o-BNU7QuJkYC&pg=PA164 | title = Encyclopedia of North American Indians | first = Frederick E. | last = Hoxie | date = 1996 | page = 164 | isbn = 0-395-66921-9 }}{{Dead link|date=December 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and subsequently among the native-born colonists.<ref>{{cite web|url=http://www.ucpress.edu/books/pages/9968/9968.ch01.html |first=David A. |last=Koplow |title=Smallpox The Fight to Eradicate a Global Scourge |publisher=University of California Press |year=2003 |access-date=22 February 2009 |url-status=dead |archive-url=https://web.archive.org/web/20080907093641/http://www.ucpress.edu/books/pages/9968/9968.ch01.html |archive-date=7 September 2008 }}</ref> Case fatality rates during outbreaks in Native American populations were as high as 90%.<ref>{{cite book | url = https://books.google.com/books?id=qubTdDk1H3IC&pg=PA205 | title = The Cambridge Encyclopedia of Human Paleopathology | first1 = Arthur C. | last1 = Aufderheide | first2 = Conrado | last2 = Rodríguez-Martín | first3 = Odin | last3 = Langsjoen | date = 1998 | publisher = {{wipe|Cambridge University Press}} | page = 205 | isbn = 0-521-55203-6 }}</ref> Smallpox was introduced into {{wipe|Australia}} in 1789 and again in 1829,<ref name= "Fenner_1988" /> though colonial surgeons, who by 1829 were attempting to distinguish between smallpox and [[Medicine:Chickenpox|chickenpox]] (which could be almost equally fatal to Aborigines), were divided as to whether the 1829–1830 epidemic was chickenpox or smallpox.<ref>Peter J Dowling, [https://openresearch-repository.anu.edu.au/bitstream/1885/7529/1/02Whole_Dowling.pdf ''"A Great Deal of Sickness": Introduced diseases among the Aboriginal People of colonial Southeast Australia 1788–1900''] {{Webarchive|url=https://web.archive.org/web/20200610090118/https://openresearch-repository.anu.edu.au/bitstream/1885/7529/1/02Whole_Dowling.pdf |date=10 June 2020 }}, 1997 ANU PhD thesis. pp. 60–62, 89.</ref> Although smallpox was never endemic on the continent,<ref name= "Fenner_1988" /> it has been described as the principal cause of death in Aboriginal populations between 1780 and 1870.<ref name = "Glynn_2004">{{cite book | last1 = Glynn | first1 = Ian | last2 = Glynn | first2 = Jenifer | title = The life and death of smallpox | url = https://archive.org/details/lifedeathofsmall00glyn | url-access = registration | publisher = Cambridge University Press | year = 2004 | page = [https://archive.org/details/lifedeathofsmall00glyn/page/n160 145] | isbn = 978-0-521-84542-7 }}</ref>

[[File:Global number of reported smallpox cases (1920-2016).svg|thumb|right|Global number of reported smallpox cases from 1920 to 2016]]
[[File:Friedhof Rastede - Kindergrab von 1711.jpg|thumb|left|Gravestone from 1711 for 4 children who died of smallpox (Rastede, Germany)]]
By the mid-18th century, smallpox was a major [[Medicine:Endemic (epidemiology)|endemic disease]] everywhere in the world except in Australia and small islands untouched by outside exploration. In 18th century Europe, smallpox was a leading cause of death, killing an estimated 400,000 Europeans each year.<ref>{{cite web | first1 = Stanley A | last1 = Plotkin | first2 = Walter A | last2 = Orenstein | first3 = Donald A. | last3 = Henderson | first4 = Bernard | last4 = Moss |url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=vacc.chapter.3 |title=Smallpox and Vaccinia |access-date=15 October 2010 |url-status=dead |archive-url=https://web.archive.org/web/20090601172056/http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=vacc.chapter.3 |archive-date=1 June 2009 |df=dmy-all }}</ref> Up to 10 percent of Swedish infants died of smallpox each year,<ref name=Hays2005/> and the death rate of infants in {{wipe|Russia}} might have been even higher.<ref name=Hopkins_2002 /> The widespread use of [[Biology:Variolation|variolation]] in a few countries, notably Great Britain, its North American colonies, and China, somewhat reduced the impact of smallpox among the wealthy classes during the latter part of the 18th century, but a real reduction in its incidence did not occur until vaccination became a common practice toward the end of the 19th century. Improved vaccines and the practice of re-vaccination led to a substantial reduction in cases in Europe and North America, but smallpox remained almost unchecked everywhere else in the world. By the mid-20th century, variola minor occurred along with variola major, in varying proportions, in many parts of Africa. Patients with variola minor experience only a mild systemic illness, are often ambulant throughout the course of the disease, and are therefore able to more easily spread disease. Infection with variola minor virus induces immunity against the more deadly variola major form. Thus, as variola minor spread all over the US, into Canada, the South American countries, and Great Britain, it became the dominant form of smallpox, further reducing mortality rates.<ref name= "Fenner_1988" />

=== Eradication ===
{{Anchor|Eradiction}}
[[File:Decade-in-which-smallpox-ceased-to-be-endemic-by-country.svg|thumb|upright=1.6|left|Decade in which smallpox ceased to be endemic by country]]

The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his {{lang|zh-Latn|Dòuzhěn xīnfǎ}} ({{lang|zh|痘疹心法}}, "Pox Rash Teachings") published in 1549,<ref>{{cite book | vauthors = Needham J | year=1999 | title=Science and Civilization in China: Volume 6, Biology and Biological Technology | chapter= Part 6, Medicine | location=Cambridge|publisher= Cambridge University Press | page=134}}</ref> with earliest hints of the practice in China during the 10th century.<ref name="needham volume 6 part 6 154">{{cite book |last1=Needham |first1=Joseph |title=Science and Civilisation in China: Volume 6, Biology and Biological Technology, Part 6, Medicine |date=2000 |publisher=Cambridge University Press |isbn=978-0521632621 |page=154 |url=https://books.google.com/books?id=6bEZ8Hp8h5sC |language=en}}</ref> In China, powdered smallpox scabs were blown up the noses of the healthy. People would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of [[Biology:Inoculation|inoculation]] were received by the Royal Society in London in 1700: one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.<ref>{{cite book|title=A History of Immunology|first=Arthur M. |last=Silverstein |page=293|publisher=Academic Press|year=2009|edition=2nd|url=https://books.google.com/books?id=2xNYjigte14C|isbn=978-0080919461 }}.</ref> [[Biography:Voltaire|Voltaire]] (1742) reports that the Chinese had practiced smallpox inoculation "these hundred years".<ref name="Voltaire 1742"/> [[Biology:Variolation|Variolation]] had also been witnessed in [[Place:Ottoman Empire|Turkey]] by [[Biography:Lady Mary Wortley Montagu|Lady Mary Wortley Montagu]], who later introduced it in the UK.<ref>{{cite book | vauthors = Montagu MW |  veditors = Grundy I | title = Selected Letters | publisher = Penguin Books | date = 1997 | isbn = 978-0-14-043490-3 }}</ref>

An early mention of the possibility of smallpox's eradication was made in reference to the work of [[Biography:Johnnie Notions|Johnnie Notions]], a self-taught inoculator from Shetland, Scotland. Notions found success in treating people from at least the late 1780s through a method devised by himself despite having no formal medical background.<ref name="Smith1998">{{cite journal | vauthors = Smith B | title = Camphor, cabbage leaves and vaccination: the career of Johnie "Notions" Williamson, of Hamnavoe, Eshaness, Shetland | journal = Proceedings of the Royal College of Physicians of Edinburgh | volume = 28 | issue = 3 | pages = 395–406 | date = July 1998 | pmid = 11620446 | url = https://www.rcpe.ac.uk/sites/default/files/vol28_3.1_10.pdf | access-date = 2019-10-12 | publisher = Royal College of Physicians of Edinburgh | doi = 10.1177/147827159802800312 | s2cid = 734446 | archive-date = 31 July 2020 | archive-url = https://web.archive.org/web/20200731014908/https://www.rcpe.ac.uk/sites/default/files/vol28_3.1_10.pdf | url-status = live }}{{rp|400}}</ref><ref name="Conacher2001">{{cite journal | vauthors = Conacher ID | title = The enigma of Johnnie "Notions" Williamson | journal = Journal of Medical Biography | volume = 9 | issue = 4 | pages = 208–12 | date = November 2001 | pmid = 11595947 | doi = 10.1177/096777200100900403 | s2cid = 41392514 }}</ref> His method involved exposing smallpox pus to [[Earth:Peat|peat]] smoke, burying it in the ground with [[Chemistry:Camphor|camphor]] for up to 8 years, and then inserting the matter into a person's skin using a knife, and covering the incision with a cabbage leaf.<ref name="Dishington1999">{{cite journal|last=Dishington|first=Andrew|date=1999|orig-year=1792|editor-last=Sinclair|editor-first=Sir John|title=United Parishes of Mid and South Yell|url=https://stataccscot.edina.ac.uk/link/osa-vol2-p569-parish-shetland-yellmid_and_south|journal=The Statistical Account of Scotland Drawn up from the Communications of the Ministers of the Different Parishes|location=University of Edinburgh, University of Glasgow|publisher=Edinburgh: William Creech|volume=2|issue=50|pages=569–71|oclc=1045293275|access-date=2019-10-10|via=The Statistical Accounts of Scotland online service|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829062124/https://stataccscot.edina.ac.uk/static/statacc/dist/viewer/osa-vol2-Parish_record_for_Yellmid_and_South_in_the_county_of_Shetland_in_volume_2_of_account_1/osa-vol2-p569-parish-shetland-yellmid_and_south|url-status=live}}</ref> He was reputed not to have lost a single patient.<ref name="Dishington1999" /> Arthur Edmondston, in writings on Notions' technique that were published in 1809, stated, "Had every practitioner been as uniformly successful in the disease as he was, the small-pox might have been banished from the face of the earth, without injuring the system, or leaving any doubt as to the fact."<ref name="Edmondston1809">{{cite book |url=https://archive.org/details/aviewancientand01edmogoog/page/n98 |title=A view of the ancient and present state of the Zetland islands |last=Edmondston |first=Arthur |publisher=John Ballantyne and Co.|year=1809|volume=II|location=Edinburgh|pages=83–91|language=en|oclc=213599237|ol=23529045M|via=archive.org}}</ref>

[[File:Fighting smallpox in Niger, 1969.jpg|thumb|Vaccination during the Smallpox Eradication and Measles Control Program in Niger, 1969]]
The English physician Edward Jenner demonstrated the effectiveness of cowpox to protect humans from smallpox in 1796, after which various attempts were made to eliminate smallpox on a regional scale. In Russia in 1796, the first child to receive this treatment was bestowed the name "Vaccinov" by Catherine the Great, and was educated at the expense of the nation.<ref>{{cite book | vauthors=Ben-Menahem A | title=Historical Encyclopedia of Natural and Mathematical Sciences | publisher=Springer | issue=v. 1 | year=2009 | isbn=978-3-540-68831-0 | url=https://books.google.com/books?id=9tUrarQYhKMC&pg=PA1497 | access-date=31 January 2017 | page=1497 | bibcode=2009henm.book.....B | archive-date=14 January 2023 | archive-url=https://web.archive.org/web/20230114064348/https://books.google.com/books?id=9tUrarQYhKMC&pg=PA1497 | url-status=live }}</ref>

The introduction of the vaccine to the New World took place in Trinity, Newfoundland in 1800 by Dr. John Clinch, boyhood friend and medical colleague of Jenner.<ref>{{cite book |last=Handcock |first=Gordon |title=The Story of Trinity |location=Trinity |publisher=The Trinity Historical Society |page=1 |isbn=978-0-9810017-0-8}}</ref> As early as 1803, the Spanish Crown organized the Balmis expedition to transport the vaccine to the [[Place:Spanish Empire|Spanish colonies]] in the Americas and the Philippines, and establish mass vaccination programs there.<ref>{{cite web | first = Willie T. | last = Ong |url= http://www.doh.gov.ph/sphh/balmis.htm |archive-url= https://web.archive.org/web/20041223112019/http://www.doh.gov.ph/sphh/balmis.htm |archive-date=23 December 2004 |title=Dr. Francisco de Balmis and his Mission of Mercy |publisher=Society of Philippine Health History |access-date=14 July 2015 }}</ref> The U.S. Congress passed the [[Biology:Vaccine Act of 1813|Vaccine Act of 1813]] to ensure that safe smallpox vaccine would be available to the American public. By about 1817, a robust state vaccination program existed in the Dutch East Indies.<ref>{{cite journal | first = Penelope | last = Shino |url=http://www.iias.nl/sites/default/files/IIAS_NL48_39.pdf|title=Against all odds: vanquishing smallpox in far-flung Japan | journal = IIAS News Letter | publisher = The International Institute for Asian Studies (IIAS) | volume = 48 |access-date=14 July 2015 |date=2007 |archive-url= https://web.archive.org/web/20150924034438/http://www.iias.nl/sites/default/files/IIAS_NL48_39.pdf |archive-date=24 September 2015 |url-status=dead }}</ref>

On August 26, 1807, [[History:Kingdom of Bavaria|Bavaria]] became the first country in the world to introduce compulsory vaccinations. Baden followed in 1809, [[History:Kingdom of Prussia|Prussia]] in 1815, Württemberg in 1818, [[History:Union between Sweden and Norway|Sweden]] in 1816 and the [[Place:German Empire|German Empire]] in 1874 through the Reichs Vaccination Act.<ref name="MeyerReiter">{{citation|surname1=C. Meyer, S. Reiter|periodical=Bundesgesundheitsblatt – Gesundheitsforschung -Gesundheitsschutz|title=Impfgegner und Impfskeptiker|volume=47|issue=12|at=pp.&nbsp;1182–1188|issn=1437-1588|date=2004-12-01|language=German|doi=10.1007/s00103-004-0953-x|pmid=15583889|s2cid=23282373|url=http://edoc.rki.de/docviews/abstract.php?id=1761|access-date=5 November 2021|archive-date=20 May 2022|archive-url=https://web.archive.org/web/20220520153523/https://edoc.rki.de/handle/176904/1107|url-status=live}}</ref><ref name=Klein>{{citation|surname1=Silvia Klein, Irene Schöneberg, Gérard Krause|periodical=Bundesgesundheitsblatt|title=Vom Zwang zur Pockenschutzimpfung zum Nationalen Impfplan|volume=55|at=pp.&nbsp;1512–1523|date=2012-10-21|language=German|doi=10.25646/1620
}}</ref> In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800.<ref>Anders Jarlert: ''Sveriges Kyrkohistoria.'' Band 6. Stockholm 2001, S. 33–54.</ref> The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.<ref>Rudolf Rheinberger: [http://www.eliechtensteinensia.li/viewer/image/000000453_76/333/ ''Zum 200. Geburtstag von Landesphysikus Gebhard Schaedler.''] {{Webarchive|url=https://web.archive.org/web/20211027101204/https://www.eliechtensteinensia.li/viewer/image/000000453_76/333/ |date=27 October 2021 }} In: ''Jahrbuch des Historischen Vereins für das Fürstentum Liechtenstein.'' Band 76. 1976, S. 337–343.</ref>

In British India a program was launched to propagate smallpox vaccination, through Indian vaccinators, under the supervision of European officials.<ref>{{cite web |url=http://www.york.ac.uk/history/research/majorprojects/smallpox-eradication/other-south-asia/ |title=The control and eradication of smallpox in South Asia |publisher=University of York |date=2015 |access-date=14 July 2015 |archive-date=14 July 2015 |archive-url=https://web.archive.org/web/20150714135334/http://www.york.ac.uk/history/research/majorprojects/smallpox-eradication/other-south-asia/ |url-status=dead }}</ref> Nevertheless, British vaccination efforts in India, and in Burma in particular, were hampered by indigenous preference for inoculation and distrust of vaccination, despite tough legislation, improvements in the local efficacy of the vaccine and vaccine preservative, and education efforts.<ref>{{cite book | chapter-url=http://indianmedicine.eldoc.ub.rug.nl/root/N2/284n/ | first = Atsuko | last = Naono | chapter = State of Vaccination: The Fight Against Smallpox in Colonial Burma | title = ABIM – An Annotated Bibliography of Indian Medicine |publisher= Orient BlackSwan | location = Hyderabad |access-date=15 October 2010 |url-status=dead |archive-url=https://web.archive.org/web/20110724165444/http://indianmedicine.eldoc.ub.rug.nl/root/N2/284n/ |archive-date=24 July 2011 }}</ref> By 1832, the federal government of the United States established a smallpox vaccination program for Native Americans.<ref>{{cite book | chapter-url = http://www.ihs.gov/ihm/index.cfm?module=dsp_ihm_pc_p1c3 | chapter = Chapter 3 – Indian Health Program | title = Indian Health Manual | location = Rockville, MD | publisher = Indian Health Service | access-date = 8 February 2012 | date = 1976 | archive-date = 14 July 2015 | archive-url = https://web.archive.org/web/20150714131027/http://www.ihs.gov/ihm/index.cfm?module=dsp_ihm_pc_p1c3 | url-status = dead }}</ref> In 1842, the United Kingdom banned inoculation, later progressing to [[Biology:Vaccination Act|mandatory vaccination]]. The British government introduced compulsory smallpox vaccination by an Act of Parliament in 1853.<ref>{{cite book |title=Bodily Matters: The Anti-Vaccination Movement in England, 1853–1907 |isbn=978-0-8223-3423-1|last1= Durbach|first1= Nadja|year= 2005|publisher=Duke University Press }}</ref>

In the United States, from 1843 to 1855, first {{wipe|Massachusetts}} and then other states required smallpox vaccination. Although some disliked these measures,<ref name=Hopkins_2002 /> coordinated efforts against smallpox went on, and the disease continued to diminish in the wealthy countries. In Northern Europe a number of countries had eliminated smallpox by 1900, and by 1914, the incidence in most industrialized countries had decreased to comparatively low levels.

Vaccination continued in industrialized countries as protection against reintroduction until the mid to late 1970s. {{wipe|Australia}} and [[Earth:New Zealand|New Zealand]] are two notable exceptions; neither experienced endemic smallpox and never vaccinated widely, relying instead on protection by distance and strict quarantines.<ref name=Plotkin_1999>{{cite book |last1=Orenstein |first1=Walter A. |last2=Plotkin |first2=Stanley A. |title=Vaccines |url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=smallpox&rid=vacc.section.45#47 |publisher=W.B. Saunders Co |location=Philadelphia |year=1999 |format=e–book |isbn=978-0-7216-7443-8 |access-date=12 September 2017 |archive-date=12 February 2009 |archive-url=https://web.archive.org/web/20090212062827/http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=smallpox&rid=vacc.section.45#47 |url-status=live }}</ref>

[[File:Smallpox keep out of this house..JPG|thumb|left|Smallpox quarantine order, California, {{circa|1910}}]]

The first [[Earth:Western Hemisphere|hemisphere]]-wide effort to eradicate smallpox was made in 1950 by the [[Organization:Pan American Health Organization|Pan American Health Organization]].<ref>{{cite journal | vauthors = Rodrigues BA | title = Smallpox eradication in the Americas | journal = Bulletin of the Pan American Health Organization | volume = 9 | issue = 1 | pages = 53–68 | year = 1975 | pmid = 167890 }}</ref> The campaign was successful in eliminating smallpox from all countries of the Americas except Argentina, Brazil, Colombia, and Ecuador.<ref name=Plotkin_1999 /> In 1958 Professor Viktor Zhdanov, Deputy Minister of Health for the [[Place:Soviet Union|USSR]], called on the [[Organization:World Health Assembly|World Health Assembly]] to undertake a global initiative to [[Biology:Eradication of infectious diseases|eradicate]] smallpox.<ref name= Fenner2 /> The proposal (Resolution WHA11.54) was accepted in 1959.<ref name= Fenner2>{{cite book |vauthors=Fenner F, Henderson DA, Arita I, Ježek Z, Ladnyi ID |chapter=Chapter 9: Development of the Global Smallpox Eradication Programme, 1958–1966 |title=Smallpox and Its Eradication |series=History of International Public Health |volume=6 |publisher=World Health Organization |location=Geneva |year=1988 |chapter-url=http://whqlibdoc.who.int/smallpox/9241561106.pdf |pages=366–418 |isbn=978-92-4-156110-5 |access-date=7 September 2007 |archive-date=19 February 2015 |archive-url=https://web.archive.org/web/20150219005302/http://whqlibdoc.who.int/smallpox/9241561106.pdf |url-status=live }}</ref> At this point, 2&nbsp;million people were dying from smallpox every year. Overall, the progress towards eradication was disappointing, especially in Africa and in the [[Earth:Indian subcontinent|Indian subcontinent]]. In 1966 an international team, the Smallpox Eradication Unit, was formed under the leadership of an American, Donald Henderson.<ref name= Fenner3>{{cite book |vauthors=Fenner F, Henderson DA, Arita I, Ježek Z, Ladnyi ID |chapter=Chapter 10: The Intensified Smallpox Eradication Programme, 1967–1980 |title=Smallpox and Its Eradication |series=History of International Public Health |volume=6 |chapter-url=http://whqlibdoc.who.int/smallpox/9241561106.pdf |publisher=World Health Organization |location=Geneva |year=1988 |pages=422–538 |isbn=978-92-4-156110-5 |access-date=7 September 2007 |archive-date=19 February 2015 |archive-url=https://web.archive.org/web/20150219005302/http://whqlibdoc.who.int/smallpox/9241561106.pdf |url-status=live }}</ref> In 1967, the World Health Organization intensified the global smallpox eradication by contributing $2.4&nbsp;million annually to the effort, and adopted the new [[Medicine:Disease surveillance|disease surveillance]] method promoted by Czech epidemiologist Karel Raška.<ref name="pmid20586232">{{cite journal | vauthors = Zikmund V | title = Karel Raška: An active participant in the eradication program of smallpox | journal = Central European Journal of Public Health | volume = 18 | issue = 1 | pages = 55–56 | date = March 2010 | pmid = 20586232 | url = http://apps.szu.cz/svi/cejph/archiv/2010-1-10-full.pdf | access-date = 15 July 2015 | archive-date = 15 July 2015 | archive-url = https://web.archive.org/web/20150715210036/http://apps.szu.cz/svi/cejph/archiv/2010-1-10-full.pdf | url-status = live }}</ref>

[[File:Rahima Banu.jpg|thumb|upright|Three-year-old Rahima Banu of Bangladesh ''(pictured)'' was the last person infected with naturally occurring variola major, in 1975.]]
In the early 1950s, an estimated 50&nbsp;million cases of smallpox occurred in the world each year.<ref name=WHO2007Fact /> To eradicate smallpox, each outbreak had to be stopped from spreading, by isolation of cases and vaccination of everyone who lived close by.<ref>{{cite journal|last1=Metzger|first1=Wolfram G|last2=Köhler|first2=Carsten|last3=Mordmüller|first3=Benjamin|date=December 2015|title=Lessons from a modern review of the smallpox eradication files|journal=Journal of the Royal Society of Medicine|language=en|volume=108|issue=12|pages=473–477|doi=10.1177/0141076815605211|pmid=26432815|pmc=4698834|issn=0141-0768|doi-access=free}}</ref> This process is known as "ring vaccination". The key to this strategy was the monitoring of cases in a community (known as surveillance) and containment.

The initial problem the WHO team faced was inadequate reporting of smallpox cases, as many cases did not come to the attention of the authorities. The fact that humans are the only reservoir for smallpox infection and that [[Medicine:Asymptomatic carrier|carriers]] did not exist played a significant role in the eradication of smallpox. The WHO established a network of consultants who assisted countries in setting up surveillance and containment activities. Early on, donations of vaccine were provided primarily by the Soviet Union and the United States, but by 1973, more than 80 percent of all vaccine was produced in developing countries.<ref name=Plotkin_1999 /> The Soviet Union provided one and a half billion doses between 1958 and 1979, as well as the medical staff.<ref>{{cite journal|language=ru|first=Viktor|last=Zhdanov|title=Человек и вирусы (Man and viruses)|journal=Наука и человечество (Science And Mankind), 1984|location=Moscow|publisher=Знание (издательство, Москва) (Knowledge)|pages=44–55}}</ref>

The last major European outbreak of smallpox was in 1972 in Yugoslavia, after a pilgrim from Kosovo returned from the Middle East, where he had contracted the virus. The epidemic infected 175 people, causing 35 deaths. Authorities declared martial law, enforced quarantine, and undertook widespread re-vaccination of the population, enlisting the help of the WHO. In two months, the outbreak was over.<ref>{{cite journal |first=Colette |last=Flight |url=https://www.bbc.co.uk/history/british/empire_seapower/smallpox_03.shtml |title=Smallpox: Eradicating the Scourge |journal=BBC History |date=17 February 2011 |access-date=28 July 2015 |archive-date=14 February 2009 |archive-url=https://web.archive.org/web/20090214152400/http://www.bbc.co.uk/history/british/empire_seapower/smallpox_03.shtml |url-status=live }}</ref> Prior to this, there had been a smallpox outbreak in May–July 1963 in [[Place:Stockholm|Stockholm]], Sweden, brought from the [[Place:Far East|Far East]] by a Swedish sailor; this had been dealt with by quarantine measures and vaccination of the local population.<ref>{{cite journal | title = Smallpox – Stockholm, Sweden, 1963 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 45 | issue = 25 | pages = 538–45 | date = June 1996 | pmid = 9132571 | url = https://www.cdc.gov/MMWR/preview/mmwrhtml/00042757.htm | author1 = Centers for Disease Control Prevention (CDC) | access-date = 12 September 2017 | archive-date = 21 July 2020 | archive-url = https://web.archive.org/web/20200721010602/https://www.cdc.gov/MMWR/preview/mmwrhtml/00042757.htm | url-status = live }}</ref>

By the end of 1975, smallpox persisted only in the [[Place:Horn of Africa|Horn of Africa]]. Conditions were very difficult in Ethiopia and Somalia, where there were few roads. Civil war, famine, and refugees made the task even more difficult. An intensive surveillance and containment and vaccination program was undertaken in these countries in early and mid-1977, under the direction of Australian microbiologist Frank Fenner. As the campaign neared its goal, Fenner and his team played an important role in verifying eradication.<ref>{{cite news|url=https://www.nytimes.com/2010/11/26/world/26fenner.html|title=Frank Fenner Dies at 95|work={{wipe|The New York Times}}|access-date=27 November 2010|first=William|last=Grimes|date=25 November 2010|archive-date=9 March 2014|archive-url=https://web.archive.org/web/20140309041303/http://www.nytimes.com/2010/11/26/world/26fenner.html|url-status=live}}</ref> The last naturally occurring case of indigenous smallpox (variola minor) was diagnosed in Ali Maow Maalin, a hospital cook in Merca, Somalia, on 26 October 1977.<ref name= PinkBook /> The last naturally occurring case of the more deadly variola major had been detected in October 1975 in a three-year-old Bangladeshi girl, Rahima Banu.<ref name=PrestonNY>{{cite news |first=Richard |last=Preston |title=A reporter at large: Demon in the Freezer |url=http://www.newyorker.com/magazine/1999/07/12/the-demon-in-the-freezer |magazine=The New Yorker |date=12 July 1999 |access-date=3 January 2008 |archive-date=7 September 2014 |archive-url=https://web.archive.org/web/20140907095018/http://www.newyorker.com/magazine/1999/07/12/the-demon-in-the-freezer |url-status=live }}</ref>

The global eradication of smallpox was certified, based on intense verification activities, by a commission of eminent scientists on 9 December 1979 and subsequently endorsed by the World Health Assembly on 8 May 1980.<ref name=WHO2007Fact /><ref name="Fenner 2006">{{cite book | last = Fenner | first = Frank | title = Nature, Nurture and Chance: The Lives of Frank and Charles Fenner | publisher = Australian National University Press | year= 2006|location = Canberra, ACT 0200 |isbn = 978-1-920942-62-5 }}</ref> The first two sentences of the resolution read:

{{blockquote|Having considered the development and results of the global program on smallpox eradication initiated by WHO in 1958 and intensified since 1967 … Declares solemnly that the world and its peoples have won freedom from smallpox, which was a most devastating disease sweeping in epidemic form through many countries since earliest time, leaving death, blindness and disfigurement in its wake and which only a decade ago was rampant in Africa, Asia and South America.<ref name= Pennington>{{cite journal | vauthors = Pennington H | title = Smallpox and bioterrorism | journal = Bulletin of the World Health Organization | volume = 81 | issue = 10 | pages = 762–67 | year = 2003 | pmid = 14758439 | pmc = 2572332 | url=https://www.who.int/bulletin/volumes/81/10/PHR1003.pdf |archive-url=https://web.archive.org/web/20220323184833/https://www.who.int/bulletin/volumes/81/10/PHR1003.pdf |archive-date=23 March 2022 |url-status=dead}}</ref>}}

==== Costs and benefits ====
The cost of the eradication effort, from 1967 to 1979, was roughly US$300&nbsp;million. Roughly a third came from the developed world, which had largely eradicated smallpox decades earlier. The United States, the largest contributor to the program, has reportedly recouped that investment every 26 days since in money not spent on vaccinations and the costs of incidence.<ref>{{cite Q|Q99372019}}<!-- Jane Seymour: Eradicating Smallpox -->.</ref>

=== Post-eradication ===
{{Further|Biology:Smallpox virus retention debate}}
[[File:Directors of Global Smallpox Eradication Program.jpg|thumb|Three former directors of the Global Smallpox Eradication Program read the news that smallpox had been globally eradicated, 1980.]]
The last case of smallpox in the world occurred in an outbreak in the United Kingdom in 1978.<ref name= Pallen>{{cite book|last1=Pallen|first1=Mark|title=The Last Days of Smallpox: Tragedy in Birmingham|date=2018|publisher=Amazon KDP|location=UK|isbn=978-1-9804-5522-6}}</ref> A medical photographer, Janet Parker, contracted the disease at the University of Birmingham Medical School and died on 11 September 1978. Although it has remained unclear how Parker became infected, the source of the infection was established to be the variola virus grown for research purposes at the Medical School laboratory.<ref>{{cite web |last1=Rimmer |first1=Monica |title=How smallpox claimed its final victim |url=https://www.bbc.co.uk/news/uk-england-birmingham-45101091 |publisher=BBC News |access-date=8 December 2019 |date=10 August 2018 |archive-date=20 February 2020 |archive-url=https://web.archive.org/web/20200220041146/https://www.bbc.co.uk/news/uk-england-birmingham-45101091 |url-status=live }}</ref><ref>{{cite journal | vauthors = Behbehani AM | title = The smallpox story: life and death of an old disease | journal = Microbiological Reviews | volume = 47 | issue = 4 | pages = 455–509 | date = December 1983 | pmid = 6319980 | pmc = 281588 | doi = 10.1128/mmbr.47.4.455-509.1983 | url = https://europepmc.org/backend/ptpmcrender.fcgi?accid=281588&blobtype=pdf }}{{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> All known stocks of smallpox worldwide were subsequently destroyed or transferred to two WHO-designated reference laboratories with BSL-4 facilities&nbsp;– the United States' Centers for Disease Control and Prevention (CDC) and the Soviet Union's (now Russia's) State Research Center of Virology and Biotechnology VECTOR.<ref>{{cite news|last=Connor|first=Steve|title=How terrorism prevented smallpox being wiped off the face of the planet for ever|newspaper=The Independent|date=3 January 2002|url=https://www.independent.co.uk/news/science/how-terrorism-prevented-smallpox-being-wiped-off-the-face-of-the-planet-for-ever-672121.html |archive-url=https://web.archive.org/web/20111028234537/http://www.independent.co.uk/news/science/how-terrorism-prevented-smallpox-being-wiped-off-the-face-of-the-planet-for-ever-672121.html |archive-date=28 October 2011 |access-date=18 May 2016 |url-status=dead| location=London}}</ref>

WHO first recommended destruction of the virus in 1986 and later set the date of destruction to be 30 December 1993. This was postponed to 30 June 1999.<ref>{{cite news|url=https://query.nytimes.com/gst/fullpage.html?res=9800EED61639F936A15752C0A960958260&sec=&spon=|date=25 January 1996|title=Final Stock of the Smallpox Virus Now Nearer to Extinction in Labs|first=Lawrence|last= Altman|newspaper=New York Times|access-date=23 November 2007}}</ref> Due to resistance from the U.S. and Russia, in 2002 the World Health Assembly agreed to permit the temporary retention of the virus stocks for specific research purposes.<ref>{{cite magazine|url=https://www.newscientist.com/article/mg17323271.300-stay-of-execution.html|title=Stay of execution|date=26 January 2002|magazine=New Scientist|access-date=23 November 2007|first=Debora|last=MacKenzie|archive-date=24 July 2008|archive-url=https://web.archive.org/web/20080724142103/http://www.newscientist.com/article/mg17323271.300-stay-of-execution.html|url-status=live}}</ref> Destroying existing stocks would reduce the risk involved with ongoing smallpox research; the stocks are not needed to respond to a smallpox outbreak.<ref>{{cite journal | vauthors = Hammond E | title = Should the US and Russia destroy their stocks of smallpox virus? | journal = BMJ | volume = 334 | issue = 7597 | pages = 774 | date = April 2007 | pmid = 17431261 | pmc = 1851992 | doi = 10.1136/bmj.39155.695255.94 }}</ref> Some scientists have argued that the stocks may be useful in developing new vaccines, antiviral drugs, and diagnostic tests;<ref name="pmid17431262">{{cite journal | vauthors = Agwunobi JO | title = Should the US and Russia destroy their stocks of smallpox virus? | journal = BMJ | volume = 334 | issue = 7597 | pages = 775 | date = April 2007 | pmid = 17431262 | pmc = 1851995 | doi = 10.1136/bmj.39156.490799.BE }}</ref> a 2010 review by a team of public health experts appointed by WHO concluded that no essential public health purpose is served by the U.S. and Russia continuing to retain virus stocks.<ref name=AGIES>[https://archive.today/20121213045739/http://www.who.int/entity/csr/resources/publications/WHO_HSE_GAR_BDP_2010_4/en/index.html Comments on the Scientific Review of Variola Virus Research, 1999–2010.] Advisory Group of Independent Experts to review the smallpox research program (AGIES) WHO document WHO/HSE/GAR/BDP/2010.4</ref> The latter view is frequently supported in the scientific community, particularly among veterans of the WHO Smallpox Eradication Program.<ref name=eradedit>{{cite journal | vauthors = Lane JM, Poland GA | title = Why not destroy the remaining smallpox virus stocks? | journal = Vaccine | volume = 29 | issue = 16 | pages = 2823–24 | date = April 2011 | pmid = 21376120 | doi = 10.1016/j.vaccine.2011.02.081 }}</ref>

On March 31, 2003, smallpox scabs were found inside an envelope in an 1888 book on Civil War medicine in Santa Fe, New Mexico.<ref name=USA_Today_20031226>{{cite news|title=Century-old smallpox scabs in N.M. envelope|work=USA Today: Health and Behavior|url=https://www.usatoday.com/news/health/2003-12-26-smallpox-in-envelope_x.htm|access-date=23 September 2006|date=26 December 2003|archive-date=3 May 2008|archive-url=https://web.archive.org/web/20080503195140/http://www.usatoday.com/news/health/2003-12-26-smallpox-in-envelope_x.htm|url-status=live}}</ref> The envelope was labeled as containing scabs from a vaccination and gave scientists at the CDC an opportunity to study the history of smallpox vaccination in the United States.

On July 1, 2014, six sealed glass vials of smallpox dated 1954, along with sample vials of other pathogens, were discovered in a cold storage room in an FDA laboratory at the [[Organization:National Institutes of Health|National Institutes of Health]] location in Bethesda, Maryland. The smallpox vials were subsequently transferred to the custody of the CDC in Atlanta, where virus taken from at least two vials proved viable in culture.<ref>{{cite news|url=https://www.theguardian.com/science/2014/jul/08/smallpox-vials-found-cardboard-box-maryland-laboratory|title=Forgotten smallpox vials found in cardboard box at Maryland laboratory|newspaper=The Guardian|date=8 July 2014|access-date=16 July 2015|archive-date=6 August 2016|archive-url=https://web.archive.org/web/20160806173856/https://www.theguardian.com/science/2014/jul/08/smallpox-vials-found-cardboard-box-maryland-laboratory|url-status=live}}</ref><ref>{{cite news|url=https://www.washingtonpost.com/national/health-science/fda-found-more-than-smallpox-vials-in-storage-room/2014/07/16/850d4b12-0d22-11e4-8341-b8072b1e7348_story.html|title=FDA found more than smallpox vials in storage room|newspaper=The Washington Post|date=16 July 2014|access-date=24 February 2017|archive-date=21 May 2017|archive-url=https://web.archive.org/web/20170521235018/https://www.washingtonpost.com/national/health-science/fda-found-more-than-smallpox-vials-in-storage-room/2014/07/16/850d4b12-0d22-11e4-8341-b8072b1e7348_story.html|url-status=live}}</ref> After studies were conducted, the CDC destroyed the virus under WHO observation on February 24, 2015.<ref>{{cite web | url=https://osp.od.nih.gov/wp-content/uploads/Final_Report_of_the_Variola_BRP.pdf | title=Report of the Blue Ribbon Panel to Review the 2014 Smallpox (variola) Virus Incident on the NIH Campus | publisher=National Institutes of Health | access-date=24 February 2018 | archive-date=3 December 2018 | archive-url=https://web.archive.org/web/20181203230205/https://osp.od.nih.gov/wp-content/uploads/Final_Report_of_the_Variola_BRP.pdf | url-status=live }}</ref>

In 2017, scientists at the University of Alberta recreated an extinct horse pox virus to demonstrate that the variola virus can be recreated in a small lab at a cost of about $100,000, by a team of scientists without specialist knowledge.<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 = January 19, 2018 | pmid = 29351298 | pmc = 5774680 | doi = 10.1371/journal.pone.0188453 | bibcode = 2018PLoSO..1388453N | doi-access = free }}</ref> This makes the retention controversy irrelevant since the virus can be easily recreated even if all samples are destroyed. Although the scientists performed the research to help development of new vaccines as well as trace smallpox's history, the possibility of the techniques being used for nefarious purposes was immediately recognized, raising questions on [[Engineering:Dual-use technology#Biological|dual use research]] and regulations.<ref>{{cite web|url=http://www.sciencemag.org/news/2017/07/how-canadian-researchers-built-poxvirus-100000-using-mail-order-dna|url-status=dead|archive-url=https://web.archive.org/web/20170709074157/http://www.sciencemag.org/news/2017/07/how-canadian-researchers-built-poxvirus-100000-using-mail-order-dna |first=Kai |last=Kupferschmidt|title=How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA|work=Science Magazine|date=6 July 2017|archive-date=9 July 2017|access-date=11 August 2023}}</ref><ref>{{cite journal | vauthors = Noyce RS, Evans DH | title = Synthetic horsepox viruses and the continuing debate about dual use research | journal = PLOS Pathogens | volume = 14 | issue = 10 | pages = e1007025 | date = October 2018 | pmid = 30286190 | pmc = 6171955 | doi = 10.1371/journal.ppat.1007025 | doi-access = free }}</ref>

In September 2019, the Russian lab housing smallpox samples experienced a gas explosion that injured one worker. It did not occur near the virus storage area, and no samples were compromised, but the incident prompted a review of risks to containment.<ref>{{cite news|url=https://www.npr.org/sections/goatsandsoda/2019/09/19/762013515/russian-lab-explosion-raises-question-should-smallpox-virus-be-kept-or-destroyed|title=Russian Lab Explosion Raises Question: Should Smallpox Virus Be Kept Or Destroyed?|publisher=NPR|date=19 September 2019|last1=Kritz|first1=Fran|access-date=11 August 2023|archive-date=23 July 2020|archive-url=https://web.archive.org/web/20200723010532/https://www.npr.org/sections/goatsandsoda/2019/09/19/762013515/russian-lab-explosion-raises-question-should-smallpox-virus-be-kept-or-destroyed|url-status=live}}</ref>

== Society and culture ==
=== Biological warfare ===

In 1763, Pontiac's War broke out as a Native American confederacy led by Pontiac attempted to counter British control over the Great Lakes region.<ref name = "Jennings_1988" /><ref>{{cite book | vauthors = Peckham HH | title = Pontiac and the Indian Uprising | year=1947 | page = 226 | publisher = Princeton University Press | edition = 1st }}</ref><ref>{{cite book | first = John | last = Grenier | title = The First Way of War: American War Making on the Frontier, 1607–1814 | edition = 1st | publisher = Cambridge University Press | date = 2008 | isbn = 978-0-521-73263-5 | page = 144 }}</ref> A group of Native American warriors [[Social:Siege of Fort Pitt|laid siege]] to British-held Fort Pitt on June 22.<ref>{{cite book | first = William R. | last = Nester | title = Haughty Conquerors: Amherst and the Great Indian Uprising of 1763 | pages = 114–15 | publisher = Greenwood Publishing Group | date = 2000 }}</ref> In response, Henry Bouquet, the commander of the fort, ordered his subordinate Simeon Ecuyer to give smallpox-infested blankets from the infirmary to a Delaware delegation outside the fort. Bouquet had discussed this with his superior, [[Biography:Jeffery Amherst, 1st Baron Amherst|Sir Jeffrey Amherst]], who wrote to Bouquet stating: "Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet agreed with the proposal, writing back that "I will try to inocculate {{sic}} the Indians by means of Blankets that may fall in their hands".<ref name="Dixon">{{cite book | last = Dixon | first = David | url = https://books.google.com/books?id=UeaN0-Ra64oC | title = Never Come to Peace Again: Pontiac's Uprising and the Fate of the British Empire in North America | pages = 152–55 | publisher = University of Oklahoma Press | date = 2005 | isbn = 0-8061-3656-1 }}</ref> On 24 June 1763, William Trent, a local trader and commander of the Fort Pitt militia, wrote, "Out of our regard for them, we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect."<ref>{{cite journal | vauthors = Gill Jr HB | title = Colonial germ warfare | journal = Journal of Colonial Williamsburg | date = April 2004 | url = http://www.history.org/Foundation/journal/Spring04/warfare.cfm | access-date = 15 April 2010 | archive-date = 1 August 2015 | archive-url = https://web.archive.org/web/20150801092104/http://www.history.org/Foundation/journal/Spring04/warfare.cfm | url-status = live }}</ref><ref name = "Jennings_1988">{{cite book | first = Francis | last = Jennings | chapter = Crucible of War | title = Empire of fortune : crowns, colonies, and tribes in the Seven Years War in America | pages = 541–42 | date = 1988 | publisher = Replica Books | isbn = 978-0-7351-0021-3 }}</ref> The effectiveness of this effort to broadcast the disease is unknown. There are also accounts that smallpox was used as a weapon during the American Revolutionary War (1775–1783).<ref name="BBC pox_weapon_01">{{cite journal |first=Colette |last=Flight |url=https://www.bbc.co.uk/history/worldwars/coldwar/pox_weapon_01.shtml |title=Silent Weapon: Smallpox and Biological Warfare |date=17 February 2011 |access-date=28 July 2015 |journal=BBC History |archive-date=11 August 2015 |archive-url=https://web.archive.org/web/20150811000507/http://www.bbc.co.uk/history/worldwars/coldwar/pox_weapon_01.shtml |url-status=live }}</ref><ref>{{cite journal | vauthors = Fenn EA | title = Biological warfare in eighteenth-century North America: beyond Jeffery Amherst. | journal = The Journal of American History | date = March 2000 | volume = 86 | issue = 4 | pages = 1552–80 | doi = 10.2307/2567577 | jstor = 2567577 | pmid = 18271127 }}</ref>

According to a theory put forward in ''Journal of Australian Studies'' (''JAS'') by independent researcher Christopher Warren, Royal Marines used smallpox in 1789 against indigenous tribes in New South Wales.<ref>{{cite journal |last=Warren |first= Christopher |title=Smallpox at Sydney Cove – who, when, why? |journal = Journal of Australian Studies |volume=38 |year=2013 |pages=68–86 |doi= 10.1080/14443058.2013.849750|s2cid= 143644513 }}</ref> This theory was also considered earlier in ''Bulletin of the History of Medicine''<ref name="Bennett_2009">{{cite journal | vauthors = Bennett MJ | title = Smallpox and cowpox under the Southern Cross: the smallpox epidemic of 1789 and the advent of vaccination in colonial Australia | journal = Bulletin of the History of Medicine | volume = 83 | issue = 1 | pages = 37–62 | date = 2009 | pmid = 19329841 | doi = 10.1353/bhm.0.0167 | s2cid = 24057488 }}</ref> and by David Day.<ref>{{cite book | first = David | last = Day | title = Claiming a Continent: A New History of Australia | location = Sydney | publisher = Harper Collins Publishers PTY Limited | year=2001 | page = 42 | isbn = 978-0-7322-6976-0 }}</ref> However it is disputed by some medical academics, including Professor Jack Carmody, who in 2010 claimed that the rapid spread of the outbreak in question was more likely indicative of [[Medicine:Chickenpox|chickenpox]]—a more infectious disease which, at the time, was often confused, even by surgeons, with smallpox, and may have been comparably deadly to Aborigines and other peoples without natural immunity to it.<ref>{{cite web|url=http://www.abc.net.au/radionational/programs/ockhamsrazor/chicken-pox-or-smallpox-in-the-colony-at-sydney/2972652#transcript|title=Chicken pox or smallpox in the colony at Sydney Cove in April, 1789|work=Radio National|date=2010-09-17|access-date=7 July 2014|archive-date=25 September 2015|archive-url=https://web.archive.org/web/20150925213836/http://www.abc.net.au/radionational/programs/ockhamsrazor/chicken-pox-or-smallpox-in-the-colony-at-sydney/2972652#transcript|url-status=live}}].</ref> Carmody noted that in the 8-month voyage of the First Fleet and the following 14 months there were no reports of smallpox amongst the colonists and that, since smallpox has an incubation period of 10–12 days, it is unlikely it was present in the First Fleet; however, Warren argued in the ''JAS'' article that the likely source was bottles of variola virus possessed by First Fleet surgeons. Ian and Jennifer Glynn, in ''The life and death of smallpox'', confirm that bottles of "variolous matter" were carried to Australia for use as a vaccine, but think it unlikely the virus could have survived till 1789.<ref name = "Glynn_2004" /> In 2007, Christopher Warren offered evidence that the British smallpox may have been still viable.<ref>{{cite journal | vauthors = Warren C | title = Could First Fleet smallpox infect Aborigines? – A note | url = https://www.scribd.com/doc/49665744/Warren-AbHist31-2007 | journal = Aboriginal History | volume = 31 | pages = 152–64 | access-date = 31 March 2019 | archive-date = 5 March 2016 | archive-url = https://web.archive.org/web/20160305174741/https://www.scribd.com/doc/49665744/Warren-AbHist31-2007 | url-status = dead }}</ref> However, the only non-Aborigine reported to have died in this outbreak was a seaman called Joseph Jeffries, who was recorded as being of "American Indian" origin.<ref>{{cite web |title=Joseph Jeffries [Crew "Supply" 1788] |url=https://www.geni.com/people/Joseph-Jeffries-Crew-Supply-1788/6000000073111673102 |website=www.geni.com |year=1767 |access-date=29 March 2019 |archive-date=7 August 2020 |archive-url=https://web.archive.org/web/20200807055930/https://www.geni.com/people/Joseph-Jeffries-Crew-Supply-1788/6000000073111673102 |url-status=live }}
{{cite web |title=Friends of the First Government House Site Inc – Smallpox Epidemic |url=http://www.ffghs.org.au/page8.php |website=www.ffghs.org.au |access-date=29 March 2019 |archive-date=7 August 2020 |archive-url=https://web.archive.org/web/20200807054007/http://www.ffghs.org.au/page8.php |url-status=dead }}</ref>

W. S. Carus, an expert in biological weapons, has written that there is circumstantial evidence that smallpox was deliberately introduced to the Aboriginal population.<ref>{{cite journal | vauthors = Carus WS | title = The History of Biological Weapons Use: What We Know and What We Don't | journal = Health Security | volume = 13 | issue = 4 | pages = 219–55 | date = 2015 | pmid = 26221997 | doi = 10.1089/hs.2014.0092 }}</ref> However Carmody and the Australian National University's Boyd Hunter continue to support the chickenpox hypothesis.<ref>See a fuller discussion of their views and those of Dr. G. E. Ford in [[History:History wars#Controversy over smallpox in Australia|"The History Wars: Smallpox Debates"]].</ref> In a 2013 lecture at the Australian National University,<ref>{{cite web |url=https://caepr.cass.anu.edu.au/events/myth-smallpox-sydney-cove-april-1789 |title=''The 'myth' of smallpox at Sydney Cove in April 1789'' |date=3 August 2013 |access-date=28 June 2020 |archive-date=29 June 2020 |archive-url=https://web.archive.org/web/20200629052308/https://caepr.cass.anu.edu.au/events/myth-smallpox-sydney-cove-april-1789 |url-status=live }}</ref> Carmody pointed out that chickenpox, unlike smallpox, was known to be present in the Sydney Cove colony. He also suggested that all {{circa|18th century}} (and earlier) identifications of smallpox outbreaks were dubious because: "surgeons … would have been unaware of the distinction between smallpox and chickenpox – the latter having traditionally been considered a milder form of smallpox."<ref>See also [https://www.watoday.com.au/national/act/chickenpox-blamed-for-aboriginal-deaths-20130807-2rh3m.html Chickenpox blamed for Aboriginal deaths] {{Webarchive|url=https://web.archive.org/web/20200630081058/https://www.watoday.com.au/national/act/chickenpox-blamed-for-aboriginal-deaths-20130807-2rh3m.html |date=30 June 2020 }}, by Tom McIlroy, ''WA Today'', 8 August 2013.</ref>

During [[Social:World War II|World War II]], scientists from the United Kingdom, United States, and Japan (Unit 731 of the Imperial Japanese Army) were involved in research into producing a biological weapon from smallpox.<ref>{{cite web |url=http://www.dhhr.wv.gov/oeps/disease/documents/usamriid_bluebook.pdf |title=USAMRIID's Medical Management of Biological Casualties Handbook |access-date=18 July 2015 |archive-date=12 August 2015 |archive-url=https://web.archive.org/web/20150812210729/http://www.dhhr.wv.gov/oeps/disease/Documents/USAMRIID_BlueBook.pdf |url-status=dead }}</ref> Plans of large scale production were never carried through as they considered that the weapon would not be very effective due to the wide-scale availability of a [[Biology:Vaccine|vaccine]].<ref name="BBC pox_weapon_01" />

In 1947, the [[Place:Soviet Union|Soviet Union]] established a smallpox weapons factory in the city of Zagorsk, 75&nbsp;km to the northeast of Moscow.<ref name="Alibek">{{cite book |title=Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World&nbsp;– Told from Inside by the Man Who Ran It |publisher=Delta |location=New York |year=1999 |isbn=978-0-385-33496-9 | vauthors = Alibek K, Handelman S |url=https://archive.org/details/biohazardchillin00alib_0 }}</ref> An [[Social:Aral smallpox incident|outbreak of weaponized smallpox]] occurred during testing at a facility on an island in the Aral Sea in 1971. General Prof. Peter Burgasov, former Chief Sanitary Physician of the Soviet Army and a senior researcher within the Soviet program of biological weapons, described the incident:

{{blockquote|On Vozrozhdeniya Island in the Aral Sea, the strongest recipes of smallpox were tested. Suddenly I was informed that there were mysterious cases of mortalities in Aralsk. A research ship of the Aral fleet came to within 15&nbsp;km of the island (it was forbidden to come any closer than 40&nbsp;km). The lab technician of this ship took samples of plankton twice a day from the top deck. The smallpox formulation&nbsp;– 400 gr. of which was exploded on the island&nbsp;– "got her" and she became infected. After returning home to Aralsk, she infected several people including children. All of them died. I suspected the reason for this and called the Chief of General Staff of the Ministry of Defense and requested to forbid the stop of the Alma-Ata–Moscow train in Aralsk. As a result, the epidemic around the country was prevented. I called Andropov, who at that time was Chief of KGB, and informed him of the exclusive recipe of smallpox obtained on Vozrazhdenie Island.<ref name="Shoham">{{cite journal | vauthors = Shoham D, Wolfson Z | title = The Russian biological weapons program: vanished or disappeared? | journal = Critical Reviews in Microbiology | volume = 30 | issue = 4 | pages = 241–61 | year = 2004 | pmid = 15646399 | doi = 10.1080/10408410490468812 | s2cid = 30487628 }}</ref><ref>{{cite web|title=Smallpox – not a bad weapon |work=Interview with General Burgasov |publisher=Moscow News |language=ru |url=http://mn.ru/issue.php?2001-46-48 |access-date=18 June 2007 |url-status=dead |archive-url=https://web.archive.org/web/20071014200222/http://mn.ru/issue.php?2001-46-48 |archive-date=14 October 2007 }}</ref>}}

Others contend that the first patient may have contracted the disease while visiting Uyaly or Komsomolsk-on-Ustyurt, two cities where the boat docked.<ref>{{cite journal | vauthors = Enserink M | title = Biowarfare. Did bioweapons test cause a deadly smallpox outbreak? | journal = Science | volume = 296 | issue = 5576 | pages = 2116–17 | date = June 2002 | pmid = 12077372 | doi = 10.1126/science.296.5576.2116 | s2cid = 27029430 }}</ref><ref>{{cite book|last1=Bellomo|first1=Michael|last2=Zelicoff|first2=Alan P.|title=Microbe: are we ready for the next plague?|year=2005|publisher=American Management Association|location=New York|isbn=978-0-8144-0865-0|page=[https://archive.org/details/microbeareweread00alan/page/101 101]|url=https://archive.org/details/microbeareweread00alan/page/101}}</ref>

Responding to international pressures, in 1991 the Soviet government allowed a joint U.S.–British inspection team to tour four of its main weapons facilities at [[Social:Biopreparat|Biopreparat]]. The inspectors were met with evasion and denials from the Soviet scientists and were eventually ordered out of the facility.<ref name= Preston /> In 1992, Soviet defector Ken Alibek alleged that the Soviet bioweapons program at Zagorsk had produced a large stockpile&nbsp;– as much as twenty tons&nbsp;– of weaponized smallpox (possibly engineered to resist vaccines, Alibek further alleged), along with refrigerated [[Engineering:Warhead|warhead]]s to deliver it. Alibek's stories about the former Soviet program's smallpox activities have never been independently verified.

In 1997, the Russian government announced that all of its remaining smallpox samples would be moved to the Vector Institute in Koltsovo.<ref name= Preston>{{cite book | last1 = Preston | first1 = Richard | title = The Demon in the Freezer | publisher = Fawcett | isbn = 978-0-345-46663-1 | pages = 105–15 | year = 2003 }}</ref> With the breakup of the Soviet Union and unemployment of many of the weapons program's scientists, U.S. government officials have expressed concern that smallpox and the expertise to weaponize it may have become available to other governments or terrorist groups who might wish to use virus as means of biological warfare.<ref name=CDCcourse>{{cite web | series = Smallpox: Disease, Prevention, and Intervention | quote = Slide 16–17 | publisher = CDC and the [[Organization:World Health Organization|World Health Organization]] | url = http://www.bt.cdc.gov/agent/smallpox/training/overview/pdf/eradicationhistory.pdf | title = History and Epidemiology of Global Smallpox Eradication | archive-url = https://web.archive.org/web/20070715234749/http://www.bt.cdc.gov/agent/smallpox/training/overview/pdf/eradicationhistory.pdf | archive-date=15 July 2007 }}</ref> Specific allegations made against Iraq in this respect proved to be false.<ref name= USfalseallegation>{{cite web | last = Burkeman | first = Oliver | date = 19 September 2003 | url = https://www.theguardian.com/world/2003/sep/20/iraq.oliverburkeman | title = No evidence of smallpox | work = {{wipe|The Guardian}} | access-date = 10 May 2012 | archive-date = 27 August 2013 | archive-url = https://web.archive.org/web/20130827133911/http://www.theguardian.com/world/2003/sep/20/iraq.oliverburkeman | url-status = live }}</ref>

=== Notable cases ===
[[File:Martini bologna mozart 1777.jpg|thumb|In 1767, the 11-year-old composer Wolfgang Amadeus Mozart survived a smallpox outbreak in Austria that killed Holy Roman Empress Maria Josepha, who became the second consecutive wife of Holy Roman Emperor Joseph II to die of the disease, as well as Archduchess Maria Josepha. (See Mozart and smallpox.)]]

Famous historical figures who contracted smallpox include Lakota Chief Sitting Bull, Ramses V,<ref name="Koplow 2003">{{cite book|last=Koplow|first=David|title=Smallpox: The Fight to Eradicate a Global Scourge|publisher=University of California Press|year=2003|location=Berkeley and Los Angeles|isbn=978-0-520-23732-2|url=https://archive.org/details/smallpoxfighttoe00kopl}}</ref> the Kangxi Emperor (survived), Shunzhi Emperor and Tongzhi Emperor of China, Emperor Komei of Japan (died of smallpox in 1867), and Date Masamune of Japan (who lost an eye to the disease). Cuitláhuac, the 10th tlatoani (ruler) of the Aztec city of Tenochtitlan, died of smallpox in 1520, shortly after its introduction to the [[Earth:Americas|Americas]], and the Incan emperor Huayna Capac died of it in 1527 (causing a civil war of succession in the Inca empire and the eventual conquest by the Spaniards). More recent public figures include [[Biography:Guru Har Krishan|Guru Har Krishan]], 8th Guru of the Sikhs, in 1664, Louis I of Spain in 1724 (died), Peter II of Russia in 1730 (died),<ref name="doctorzebra.com">{{cite web|title=President Abraham Lincoln: Health & Medical History|url=http://www.doctorzebra.com/prez/g16.htm#25|date=24 March 2007|access-date=18 June 2007|archive-date=10 July 2015|archive-url=https://web.archive.org/web/20150710025155/http://www.doctorzebra.com/prez/g16.htm#25|url-status=live}}</ref> George Washington (survived), Louis XV of France in 1774 (died) and Maximilian III Joseph of Bavaria in 1777 (died).

Prominent families throughout the world often had several people infected by and/or perish from the disease. For example, several relatives of [[Biography:Henry VIII of England|Henry VIII of England]] survived the disease but were scarred by it. These include his sister Margaret, his wife Anne of Cleves, and his two daughters: Mary I in 1527 and Elizabeth I in 1562. Elizabeth tried to disguise the pockmarks with heavy makeup. Mary, Queen of Scots, contracted the disease as a child but had no visible scarring.

In Europe, deaths from smallpox often changed dynastic succession. Louis XV of France succeeded his great-grandfather Louis XIV through a series of deaths of smallpox or measles among those higher in the succession line. He himself died of the disease in 1774. Peter II of Russia died of the disease at 14 years of age. Also, before becoming emperor, Peter III of Russia caught the virus and suffered greatly from it.{{citation needed|date=July 2022}} He was left scarred and disfigured. His wife, Catherine the Great, was spared but fear of the virus clearly had its effects on her. She feared for the safety of her son, Paul, so much that she made sure that large crowds were kept at bay and sought to isolate him. Eventually, she decided to have herself inoculated by a British doctor, Thomas Dimsdale. While this was considered a controversial method at the time, she succeeded. Paul was later inoculated as well. Catherine then sought to have inoculations throughout her empire stating: "My objective was, through my example, to save from death the multitude of my subjects who, not knowing the value of this technique, and frightened of it, were left in danger." By 1800, approximately two&nbsp;million inoculations had been administered in the Russian Empire.<ref>{{cite book | last = Massie | first = Robert K. | date = 2011 | title = Catherine the Great: Portrait of as Woman | pages = 387–88 | publisher = Random House | location = New York | isbn = 978-0-679-45672-8}}</ref>

In China, the Qing dynasty had extensive protocols to protect Manchus from Peking's endemic smallpox.

U.S. Presidents George Washington, Andrew Jackson, and Abraham Lincoln all contracted and recovered from the disease. Washington became infected with smallpox on a visit to Barbados in 1751.<ref name="Michael B. A. Oldstone">{{cite book|title=Viruses, Plagues, and History|last=Oldstone|first=Michael|year=2010|pages=65–71|publisher=Oxford University Press| isbn=978-0-19-532731-1}}</ref> Jackson developed the illness after being taken prisoner by the British during the American Revolution, and though he recovered, his brother Robert did not.<ref name="Michael B. A. Oldstone" /> Lincoln contracted the disease during his presidency, possibly from his son Tad, and was quarantined shortly after giving the Gettysburg address in 1863.<ref name="Michael B. A. Oldstone" />

The famous theologian [[Biography:Jonathan Edwards (theologian)|Jonathan Edwards]] died of smallpox in 1758 following an inoculation.<ref name="Edwards bio">{{cite web|url=http://edwards.yale.edu/research/about-edwards/biography|title=Biography at the Edwards Center at Yale University|publisher=Yale University|access-date=13 September 2009|archive-date=12 October 2008|archive-url=https://web.archive.org/web/20081012130037/http://edwards.yale.edu/research/about-edwards/biography|url-status=live}}</ref>

[[Place:Soviet Union|Soviet]] leader {{wipe|Joseph Stalin}} fell ill with smallpox at the age of seven. His face was badly scarred by the disease. He later had photographs retouched to make his pockmarks less apparent.<ref>{{cite book | title = Young Stalin | year=2008 | first = Simon Sebag | last = Montefiore | page = 61 | publisher = Phoenix | isbn = 978-1-4072-2145-8 }}</ref>

Hungarian poet Ferenc Kölcsey, who wrote the Hungarian national anthem, lost his right eye to smallpox.<ref>{{cite book | last = Szinnyei | first = József | url = http://mek.niif.hu/03600/03630/html/k/k12495.htm | title = Magyar írók élete és munkái | publisher = Arcanum | location = Budapest | date = 2000 | isbn = 963-86029-9-6 | access-date = 19 January 2010 | archive-date = 6 September 2014 | archive-url = https://web.archive.org/web/20140906191638/http://mek.niif.hu/03600/03630/html/k/k12495.htm | url-status = live }}</ref>

=== Tradition and religion ===
[[File:Kalighat Shitala.jpg|thumb|The Hindu goddess Shitala was worshipped to prevent or cure smallpox.]]

In the face of the devastation of smallpox, various smallpox gods and goddesses have been worshipped throughout parts of the [[Earth:Old World|Old World]], for example in China and India. In China, the smallpox goddess was referred to as T'ou-Shen Niang-Niang ({{zh|c=痘疹娘娘}}).<ref name="HopkinsDonald">{{cite book | last = Hopkins | first = Donald R. | title = Princes and Peasants: Smallpox in History | location = Chicago, IL| publisher = University of Chicago Press | date = 1983 }}</ref> Chinese believers actively worked to appease the goddess and pray for her mercy, by such measures as referring to smallpox pustules as "beautiful flowers" as a [[Social:Euphemism|euphemism]] intended to avert offending the goddess, for example (the Chinese word for smallpox is {{linktext|lang=zh|天花}}, literally "heaven flower").<ref name="GiblinJames">{{cite book | last = Giblin | first = James C. | title = When Plague Strikes: The Black Death, Smallpox, AIDS| location = United States | publisher = HarperCollins Publishers | date = 1995 }}</ref> In a related New Year's Eve custom it was prescribed that the children of the house wear ugly masks while sleeping, so as to conceal any beauty and thereby avoid attracting the goddess, who would be passing through sometime that night.<ref name="GiblinJames" /> If a case of smallpox did occur, shrines would be set up in the homes of the victims, to be worshipped and offered to as the disease ran its course. If the victim recovered, the shrines were removed and carried away in a special paper chair or boat for burning. If the patient did not recover, the shrine was destroyed and cursed, to expel the goddess from the house.<ref name="HopkinsDonald" />

In the [[Social:Yoruba language|Yoruba language]] smallpox is known as ṣọpọná, but it was also written as shakpanna, shopona, ṣhapana, and ṣọpọnọ. The word is a combination of 3 words, the verb ṣán, meaning to cover or plaster (referring to the pustules characteristic of smallpox), kpa or pa, meaning to kill, and enia, meaning human. Roughly translated, it means One who kills a person by covering them with pustules.<ref>{{cite book | last = Keane | first = Augustus H. | title = Man, past and present| location = Cambridge | publisher = University Press | date = 1920}}</ref> Among the Yorùbá people of West Africa, and also in Dahomean religion, Trinidad, and in Brazil, The deity Sopona, also known as Obaluaye, is the deity of smallpox and other deadly diseases (like leprosy, HIV/AIDS, and fevers). One of the most feared deities of the [[Religion:Orisha|orisha]] pantheon, smallpox was seen as a form of punishment from Shopona.<ref name="cdc.gov">{{cite web|url=https://www.cdc.gov/museum/history/shapona.html|title=Shapona, the Yoruba god of smallpox &#124; David J. Sencer CDC Museum|date=30 April 2021|access-date=11 July 2020|archive-date=21 July 2020|archive-url=https://web.archive.org/web/20200721183322/https://www.cdc.gov/museum/history/shapona.html|url-status=live}}</ref> Worship of Shopona was highly controlled by his priests, and it was believed that priests could also spread smallpox when angered.<ref name="cdc.gov"/> However, Shopona was also seen as a healer who could cure the diseases he inflicted, and he was often called upon by his victims to heal them.<ref name="africanart.nl">{{cite web|url=http://www.africanart.nl/en/pokken-in-afrika-amerika-en-terug-in-afrika/|title=Smallpox controlfrom Africa to America and back again &#124; African Art|date=3 July 2017|access-date=11 July 2020|archive-date=7 August 2020|archive-url=https://web.archive.org/web/20200807080630/http://www.africanart.nl/en/pokken-in-afrika-amerika-en-terug-in-afrika/|url-status=live}}</ref> The British government banned the worship of the god because it was believed his priests were purposely spreading smallpox to their opponents.<ref name="africanart.nl"/><ref name="cdc.gov"/>

India's first records of smallpox can be found in a medical book that dates back to 400 CE. This book describes a disease that sounds exceptionally like smallpox.<ref name="GiblinJames" /> India, like China and the Yorùbá, created a goddess in response to its exposure to smallpox. The Hindu goddess [[Religion:Shitala|Shitala]] was both worshipped and feared during her reign. It was believed that this goddess was both evil and kind and had the ability to inflict victims when angered, as well as calm the fevers of the already affected.<ref>{{cite book | vauthors = Wiley AS, Allen JS | title = Medical Anthropology: A Biocultural Approach | location = New York | publisher = Oxford University Press | date = 2009 }}</ref><ref name="Hopkins2002">{{cite book|url=https://archive.org/details/greatestkillersm0000hopk|url-access=registration|title=The Greatest Killer: Smallpox in History| first = Donald R. | last = Hopkins |date=2002|publisher=University of Chicago Press|isbn=978-0-226-35168-1|page=[https://archive.org/details/greatestkillersm0000hopk/page/159 159]}}</ref> Portraits of the goddess show her holding a broom in her right hand to continue to move the disease and a pot of cool water in the other hand in an attempt to soothe patients.<ref name="GiblinJames" /> Shrines were created where many Indian natives, both healthy and not, went to worship and attempt to protect themselves from this disease. Some Indian women, in an attempt to ward off Shitala, placed plates of cooling foods and pots of water on the roofs of their homes.<ref>{{cite book | last = Tucker | first = Jonathan B. | title = Scourge: The Once and Future Threat of Smallpox | location = New York | publisher = Atlantic Monthly Press | date = 2001 }}</ref>

In cultures that did not recognize a smallpox deity, there was often nonetheless a belief in smallpox demons, who were accordingly blamed for the disease. Such beliefs were prominent in Japan, Europe, Africa, and other parts of the world. Nearly all cultures who believed in the demon also believed that it was afraid of the color red. This led to the invention of the so-called red treatment, where patients and their rooms would be decorated in red. The practice spread to Europe in the 12th century and was practiced by (among others) Charles V of France and Elizabeth I of England.<ref name="Fenner_1988" /> Afforded scientific credibility through the studies by [[Biography:Niels Ryberg Finsen|Niels Ryberg Finsen]] showing that red light reduced scarring,<ref name="Fenner_1988" /> this belief persisted even until the 1930s.

== See also ==
* [[Medicine:List of epidemics|List of epidemics]]
* {{slink|List of epidemics and pandemics#Chronology}}
* {{slink|Population history of indigenous peoples of the Americas#Depopulation by Old World diseases}}
* [[Social:1971 Aral smallpox incident|1971 Aral smallpox incident]]
* ''[[Biology:Jacobson v. Massachusetts|Jacobson v. Massachusetts]]''

== References ==
{{Reflist}}

== Further reading ==
{{Refbegin|60em}}
* {{cite book |last=Fenner |first=Frank |title=Smallpox and Its Eradication (History of International Public Health, No. 6) |url=http://whqlibdoc.who.int/smallpox/9241561106.pdf |publisher=World Health Organization |location=Geneva |year=1988 |isbn=978-92-4-156110-5 |access-date=7 September 2007 |archive-date=19 February 2015 |archive-url=https://web.archive.org/web/20150219005302/http://whqlibdoc.who.int/smallpox/9241561106.pdf |url-status=live }}
* Henderson, Donald Ainslie. ''Smallpox: the death of a disease: the inside story of eradicating a worldwide killer''. Prometheus Books, 2009.
* {{cite book|last1=Pallen|first1=Mark|title=The Last Days of Smallpox: Tragedy in Birmingham|date=2018|publisher=Amazon KDP|location=UK|isbn=978-1-9804-5522-6}}
* {{cite book | last = Reinhardt | first = Bob H. | title = The End of a Global Pox: America and the Eradication of Smallpox in the Cold War Era | publisher = University of North Carolina Press | date = 2015 | pages = xviii, 268 }}
* {{cite book |last=Tucker |first=Jonathan B. |title=Scourge: The Once and Future Threat of Smallpox |publisher=Grove Press |location=New York |year=2001 |isbn=978-0-8021-3939-9 |url=https://archive.org/details/scourgeoncefutur00tuck |url-access=registration }}
* {{cite book|editor-first1 = Lord | editor-last1 = Wharncliffe | editor-first2 = W. Moy | editor-last2 = Thomas |title=The Letters and Works of Lady Mary Wortley Montagu | volume = 1 |location=London |publisher=Henry G. Bohn |date=1861}}
{{Refend}}

== External links ==
* [http://www.smallpoxbiosafety.org/ Smallpox Biosafety: A Website About Destruction of Smallpox Virus Stocks]
* [http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/biofacts/index.html Detailed CIDRAP Smallpox overview] {{Webarchive|url=https://web.archive.org/web/20130506170240/http://www.cidrap.umn.edu/cidrap/content/bt/smallpox/biofacts/index.html |date=6 May 2013 }}
* [https://web.archive.org/web/20100628224033/http://www.upmc-biosecurity.org/website/focus/agents_diseases/fact_sheets/smallpox.html Agent Fact Sheet: Smallpox], Center for Biosecurity
* [http://www.logicalimages.com/resourcesBTAgentsSmallpox.htm Smallpox Images and Diagnosis Synopsis] {{Webarchive|url=https://web.archive.org/web/20080729020333/http://www.logicalimages.com/resourcesBTAgentsSmallpox.htm |date=29 July 2008 }}
* [http://www.viprbrc.org/brc/home.do?decorator=pox Virus Pathogen Database and Analysis Resource (ViPR): Poxviridae]{{Dead link|date=November 2021 |bot=InternetArchiveBot |fix-attempted=yes }}
* [https://www.pbs.org/video/vaccines-huvzkv/ Episode 1 (of 4): Vaccines] of the BBC Four and PBS show: [https://www.pbs.org/show/extra-life-short-history-living-longer/ Extra Life: A Short History of Living Longer] (2021)

{{Viral cutaneous conditions}}
{{Medical resources
| ICD10           = {{ICD10|B|03| |b|00}}
| ICD9            = {{ICD9|050}}
| DiseasesDB      = 12219
| MedlinePlus     = 001356
| eMedicineSubj   = emerg
| eMedicineTopic  = 885
| MeshName        = Smallpox
| MeshNumber      = D012899
| Scholia         = Q12214
}}
{{Taxonbar|from=Q11877169}}

[[Category:Chordopoxvirinae]]
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Smallpox}}