View source for Medicine:Smallpox vaccine

{{Short description|Vaccine against Variola virus}}
{{Infobox drug
| type               = vaccine
| image              = File:Smallpox vaccine.jpg
| alt                = 
| caption            = The smallpox vaccine [[Chemistry:Diluent|diluent]] in a syringe alongside a vial of Dryvax dried smallpox vaccine and [[Biology:Bifurcated needle|bifurcated needle]]
| target             = [[Medicine:Smallpox|Smallpox]], [[Medicine:Mpox|Mpox]]
| vaccine_type       = Live virus

<!-- Clinical data -->
| tradename          = ACAM2000, Imvanex, Jynneos, others
| Drugs.com          = {{Drugs.com|monograph|smallpox-vaccine-live}}
| MedlinePlus        = 
| DailyMedID         = Smallpox
| pregnancy_AU       = D
| pregnancy_category = 
| routes_of_administration = [[Medicine:Subcutaneous injection|Subcutaneous]]
| ATCvet             = 
| ATC_prefix         = J07
| ATC_suffix         = BX01

<!-- Legal status -->
| legal_AU           = S4
| legal_AU_comment   = <ref>{{cite web | title=ACAM2000 smallpox vaccine (live vaccinia virus) vial with diluent | website=Therapeutic Goods Administration (TGA) | url=http://www.tga.gov.au/search/node | access-date=8 July 2022 | archive-date=18 April 2015 | archive-url=https://web.archive.org/web/20150418015930/http://www.tga.gov.au/search/node | url-status=live }}</ref>
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| legal_BR_comment   = 
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| legal_CA_comment   = /&nbsp;Schedule D<ref name="Imvamune CA PI">{{cite web | title=Imvamune Product information | website=[[Organization:Health Canada|Health Canada]] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=90121 | access-date=8 July 2022 | archive-date=22 June 2021 | archive-url=https://web.archive.org/web/20210622104300/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=90121 | url-status=live }}</ref><ref>{{cite web | title=Smallpox vaccine Product information | website=[[Organization:Health Canada|Health Canada]] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=672 | access-date=8 July 2022 | archive-date=8 July 2022 | archive-url=https://web.archive.org/web/20220708045918/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=672 | url-status=live }}</ref><ref>{{cite web | title=Smallpox vaccine Product information | website=[[Organization:Health Canada|Health Canada]] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=671 | access-date=8 July 2022 | archive-date=8 July 2022 | archive-url=https://web.archive.org/web/20220708045918/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=671 | url-status=live }}</ref>
| legal_DE           = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment   = 
| legal_NZ           = <!-- Class A, B, C -->
| legal_NZ_comment   = 
| legal_UK           = POM
| legal_UK_comment   = 
| legal_US           = Rx-only
| legal_US_comment   = with standing order<ref>{{cite web |url=https://www.cdc.gov/poxvirus/mpox/files/interim-considerations/mpox-jynneos-standing-orders-stand.pdf |title=Jynneos Smallpox and Monkeypox Vaccine |access-date=2 September 2023 |archive-date=3 September 2023 |archive-url=https://web.archive.org/web/20230903015141/https://www.cdc.gov/poxvirus/mpox/files/interim-considerations/mpox-jynneos-standing-orders-stand.pdf |url-status=live }}</ref><ref name="ACAM2000 FDA label">{{cite web | title=ACAM2000 (smallpox- vaccinia vaccine, live injection, powder, lyophilized, for solution) | website=DailyMed | date=21 March 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f8b2634b-ccd7-4a42-8db3-26ba9e9627e6 | access-date=26 May 2022 | archive-date=24 May 2022 | archive-url=https://web.archive.org/web/20220524152452/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f8b2634b-ccd7-4a42-8db3-26ba9e9627e6 | url-status=live }}</ref><ref name="Jynneos FDA label">{{cite web | title=Jynneos- vaccinia virus modified strain ankara-bavarian nordic non-replicating antigen injection, suspension | website=DailyMed | date=14 February 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=69fc3841-a461-4706-bdcb-1176c40bf486 | access-date=26 May 2022 | archive-date=27 May 2022 | archive-url=https://web.archive.org/web/20220527035655/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=69fc3841-a461-4706-bdcb-1176c40bf486 | url-status=live }}</ref>
| legal_EU           = Rx-only
| legal_EU_comment   = <ref name="Imvanex EPAR" />
| legal_UN           = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment   = 
| legal_status       = Rx-only

<!-- Identifiers -->
| CAS_number         = 
| PubChem            = 
| DrugBank           = DB15497
| UNII               = 4SV59689SK
| KEGG               = D05295
}}

The '''smallpox vaccine''' is the first [[Biology:Vaccine|vaccine]] to have been developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild [[Medicine:Cowpox|cowpox]] virus conferred immunity against the deadly [[Medicine:Smallpox|smallpox]] virus. Cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. From 1958 to 1977, the [[Organization:World Health Organization|World Health Organization]] (WHO) conducted a global vaccination campaign that [[Medicine:Smallpox#Eradication|eradicated smallpox]], making it the only human disease to be eradicated. Although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced to guard against [[Social:Bioterrorism|bioterrorism]], [[Biology:Biological warfare|biological warfare]], and [[Medicine:Mpox|mpox]].<ref>{{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 | veditors = Metzger W }}</ref><ref name="anderson">Anderson MG, Frenkel LD, Homann S, and Guffey J. (2003), "A case of severe monkeypox virus disease in an American child: emerging infections and changing professional values"; ''Pediatr Infect Dis J'';22(12): 1093–96; discussion 1096–98.</ref>

The term ''vaccine'' derives from the Latin word for cow, reflecting the origins of smallpox vaccination. Edward Jenner referred to cowpox as ''variolae vaccinae'' (smallpox of the cow). The origins of the smallpox vaccine became murky over time,<ref>{{cite book | vauthors = Baxby D |title=Jenner's Smallpox Vaccine: The Riddle of Vaccinia Virus and Its Origin |date=1981 |publisher=Heinemann Educational Books |isbn=978-0-435-54057-9 }}</ref> especially after Louis Pasteur developed laboratory techniques for creating vaccines in the 19th century. Allan Watt Downie demonstrated in 1939 that the modern smallpox vaccine was serologically distinct from cowpox,<ref name="downie1939"/> and ''[[Medicine:Vaccinia|vaccinia]]'' was subsequently recognized as a separate viral species. Whole-genome sequencing has revealed that ''vaccinia'' is most closely related to horsepox, and the cowpox strains found in Great Britain are the least closely related to ''vaccinia''.<ref name="carroll2011">{{cite journal | vauthors = Carroll DS, Emerson GL, Li Y, Sammons S, Olson V, Frace M, Nakazawa Y, Czerny CP, Tryland M, Kolodziejek J, Nowotny N, Olsen-Rasmussen M, Khristova M, Govil D, Karem K, Damon IK, Meyer H | display-authors = 6 | title = Chasing Jenner's vaccine: revisiting cowpox virus classification | journal = PLOS ONE | volume = 6 | issue = 8 | pages = e23086 | date = August 2011 | pmid = 21858000 | pmc = 3152555 | doi = 10.1371/journal.pone.0023086 | doi-access = free | title-link = doi | bibcode = 2011PLoSO...623086C }}</ref>

==Types==

As the oldest vaccine, the smallpox vaccine has gone through several generations of medical technology. From 1796 to the 1880s, the vaccine was transmitted from one person to another through arm-to-arm vaccination. Smallpox vaccine was successfully maintained in cattle starting in the 1840s, and calf lymph vaccine became the leading smallpox vaccine in the 1880s. First-generation vaccines grown on the skin of live animals were widely distributed in the 1950s–1970s to eradicate smallpox. Second-generation vaccines were grown in [[Biology:Chorioallantoic membrane|chorioallantoic membrane]] or cell cultures for greater purity, and they were used in some areas during the smallpox eradication campaign. Third-generation vaccines are based on attenuated strains of ''vaccinia'' and saw limited use prior to the eradication of smallpox.<ref name="who2017_stockpile">{{cite book |title=Operational framework for the deployment of the World Health Organization Smallpox Vaccine Emergency Stockpile in response to a smallpox event |date=2017 |publisher=[[Organization:World Health Organization|World Health Organization]] (WHO) |isbn=978-92-4-151341-8}}</ref>

All three generations of vaccine are available in stockpiles. First and second-generation vaccines contain live unattenuated ''vaccinia'' virus and can cause serious side effects in a small percentage of recipients, including death in 1–10 people per million vaccinations. Third-generation vaccines are much safer due to the milder side effects of the attenuated ''vaccinia'' strains.<ref name="who2017_stockpile"/> Second and third-generation vaccines are still being produced, with manufacturing capacity being built up in the 2000s due to fears of bioterrorism and biological warfare.

===First-generation===

The first-generation vaccines are manufactured by growing live ''vaccinia'' virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep.<ref name="who2017_stockpile"/> The development of freeze-dried vaccine in the 1950s made it possible to preserve ''vaccinia'' virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax.<ref name="belongia2003">{{cite journal | vauthors = Belongia EA, Naleway AL | title = Smallpox vaccine: the good, the bad, and the ugly | journal = Clinical Medicine & Research | volume = 1 | issue = 2 | pages = 87–92 | date = April 2003 | pmid = 15931293 | pmc = 1069029 | doi = 10.3121/cmr.1.2.87 }}</ref><ref name="Fenner_1988"/>{{rp|115}}

The vaccine is administered by multiple puncture of the skin (scarification) with a [[Biology:Bifurcated needle|bifurcated needle]] that holds vaccine solution in the fork.<ref name="who1968_instructions">{{cite web |title=Instructions for smallpox vaccination with bifurcated needle |url=https://www.who.int/publications/i/item/instructions-for-smallpox-vaccination-with-bifurcated-needle |publisher=[[Organization:World Health Organization|World Health Organization]] (WHO) |date=1968 |access-date=3 July 2022 |archive-date=16 March 2022 |archive-url=https://web.archive.org/web/20220316135121/https://www.who.int/publications/i/item/instructions-for-smallpox-vaccination-with-bifurcated-needle |url-status=live }}</ref> The skin should be cleaned with water rather than alcohol,<ref name="who1968_instructions"/> as the alcohol could inactivate the ''vaccinia'' virus.<ref name="Fenner_1988"/>{{rp|292}}<ref>{{cite web |title=Six bifurcated needles for smallpox vaccination {{!}} Science Museum Group Collection |url=https://collection.sciencemuseumgroup.org.uk/objects/co148183/six-bifurcated-needles-for-smallpox-vaccination-vaccination-needle |publisher=Science Museum (London) |quote=The skin was not disinfected before use as this killed the vaccine. |access-date=3 July 2022 |archive-date=20 May 2022 |archive-url=https://web.archive.org/web/20220520165051/https://collection.sciencemuseumgroup.org.uk/objects/co148183/six-bifurcated-needles-for-smallpox-vaccination-vaccination-needle |url-status=live }}</ref> If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered.<ref name="Fenner_1988"/>{{rp|292}} Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized ''vaccinia'' infection is known as a vaccine "take" and [[Biology:Correlates of immunity|demonstrates immunity]] to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar.<ref name="cono2003">{{cite journal |vauthors=Cono J, Casey CG, Bell DM |title=Smallpox vaccination and adverse reactions. Guidance for clinicians |journal=MMWR. Recommendations and Reports |date=February 2003 |volume=52 |issue=RR-4 |pages=1–28 |url=https://www.cdc.gov/mmwr/PDF/rr/rr5204.pdf |pmid=12617510 |access-date=11 August 2022 |archive-date=22 March 2022 |archive-url=https://web.archive.org/web/20220322232656/https://www.cdc.gov/mmwr/PDF/rr/rr5204.pdf |url-status=live }}</ref>

First generation vaccines consist of live, unattenuated ''vaccinia'' virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over {{convert|102|F|C}}. The ''vaccinia'' lesion can transmit the virus to other people.<ref name="cono2003"/> Rare side effects include postvaccinal encephalitis and myopericarditis.<ref name="cono2003"/><ref>{{cite journal | vauthors = Cassimatis DC, Atwood JE, Engler RM, Linz PE, Grabenstein JD, Vernalis MN | title = Smallpox vaccination and myopericarditis: a clinical review | journal = Journal of the American College of Cardiology | volume = 43 | issue = 9 | pages = 1503–1510 | date = May 2004 | pmid = 15120802 | doi = 10.1016/j.jacc.2003.11.053 }}</ref> Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled ''vaccinia'' infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany).<ref name="kretzschmar-2006">{{cite journal | vauthors = Kretzschmar M, Wallinga J, Teunis P, Xing S, Mikolajczyk R | title = Frequency of adverse events after vaccination with different vaccinia strains | journal = PLOS Medicine | volume = 3 | issue = 8 | pages = e272 | date = August 2006 | pmid = 16933957 | pmc = 1551910 | doi = 10.1371/journal.pmed.0030272 | doi-access = free }}</ref><ref name="kretzschmar-2006c">{{cite journal | vauthors = Kretzschmar M, Wallinga J, Teunis P, Xing S, Mikolajczyk R |title=Correction: Frequency of Adverse Events after Vaccination with Different Vaccinia Strains |journal=PLOS Medicine |date=3 October 2006 |volume=3 |issue=10 |pages=e429 |doi=10.1371/journal.pmed.0030429 |pmc=1626554 |doi-access=free }}</ref>

===Second-generation===

The second-generation vaccines consist of live ''vaccinia'' virus grown in the [[Biology:Chorioallantoic membrane|chorioallantoic membrane]] or [[Biology:Cell culture|cell culture]]. The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation ''vaccinia'' strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on.<ref name="who2017_stockpile"/>

Ernest William Goodpasture, [[Biography:Alice Miles Woodruff|Alice Miles Woodruff]], and G. John Buddingh grew ''vaccinia'' virus on the chorioallantoic membrane of chicken embryos in 1932.<ref name="goodpasture1932">{{cite journal | vauthors = Goodpasture EW, Woodruff AM, Buddingh GJ | title = Vaccinal Infection of the Chorio-Allantoic Membrane of the Chick Embryo | journal = The American Journal of Pathology | volume = 8 | issue = 3 | pages = 271–282.7 | date = May 1932 | pmid = 19970016 | pmc = 2062681 }}</ref> The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948.<ref name="Fenner_1988"/>{{rp|588}} Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959.<ref>{{cite book |author1=Council on Drugs (American Medical Association) |title=New and Nonofficial Drugs |date=1964 |publisher=Lippincott |page=739}}</ref> Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and [[Biology:Avian sarcoma leukosis virus|avian sarcoma leukosis virus]] prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens.<ref name="Fenner_1988"/>{{rp|588}}

''Vaccinia'' was first grown in cell culture in 1931 by Thomas Milton Rivers. The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RVIM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine.<ref name="Fenner_1988"/>{{rp|588–589}} Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur).<ref name="who2017_stockpile"/><ref>{{cite journal | vauthors = Wiser I, Balicer RD, Cohen D | title = An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies | journal = Vaccine | volume = 25 | issue = 6 | pages = 976–984 | date = January 2007 | pmid = 17074424 | doi = 10.1016/j.vaccine.2006.09.046 }}</ref><ref>{{cite journal | vauthors = Ferrier-Rembert A, Drillien R, Meignier B, Garin D, Crance JM | title = Safety, immunogenicity and protective efficacy in mice of a new cell-cultured Lister smallpox vaccine candidate | journal = Vaccine | volume = 25 | issue = 49 | pages = 8290–8297 | date = November 2007 | pmid = 17964011 | doi = 10.1016/j.vaccine.2007.09.050 }}</ref> Lister/Elstree-RVIM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles.<ref name="who2017_stockpile"/> However, Sanofi dropped its own vaccine after it acquired Acambis in 2008.

[[Biology:ACAM2000|ACAM2000]] is a vaccine developed by Acambis, which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of ''vaccinia'' were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in [[Biology:MRC-5|MRC-5]] cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in [[Biology:Vero cell|Vero cell]]s to develop ACAM2000, which entered mass production at [[Company:Baxter International|Baxter]]. The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine.<ref>{{cite journal | vauthors = Monath TP, Caldwell JR, Mundt W, Fusco J, Johnson CS, Buller M, Liu J, Gardner B, Downing G, Blum PS, Kemp T, Nichols R, Weltzin R | display-authors = 6 | title = ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain)--a second-generation smallpox vaccine for biological defense | journal = International Journal of Infectious Diseases | volume = 8 | issue = Suppl 2 | pages = S31–S44 | date = October 2004 | pmid = 15491873 | pmc = 7110559 | doi = 10.1016/j.ijid.2004.09.002 }}</ref><ref>{{cite journal | vauthors = Nalca A, Zumbrun EE | title = ACAM2000: the new smallpox vaccine for United States Strategic National Stockpile | journal = Drug Design, Development and Therapy | volume = 4 | pages = 71–79 | date = May 2010 | pmid = 20531961 | pmc = 2880337 | doi = 10.2147/dddt.s3687 | doi-access = free }}</ref>

===Third-generation===

The third-generation vaccines are based on attenuated ''vaccinia'' viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating.<ref name="who2017_stockpile"/>

==== MVA ====
[[Biology:Modified vaccinia Ankara|Modified vaccinia Ankara]] (MVA, {{lang-de|Modifiziertes Vakziniavirus Ankara}}) is a replication-incompetent variant of ''vaccinia'' that was developed in West Germany through [[Biology:Serial passage|serial passage]]. The original Ankara strain of ''vaccinia'' was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich. After 572 serial passages, the ''vaccinia'' virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses.<ref>{{cite journal | vauthors = Volz A, Sutter G | title = Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development | journal = Advances in Virus Research | volume = 97 | pages = 187–243 | date = 2017 | pmid = 28057259 | pmc = 7112317 | doi = 10.1016/bs.aivir.2016.07.001 | isbn = 9780128118016 }}</ref>

MVA stimulates the production of fewer antibodies than replicating vaccines.<ref name = "Mayr_1975">{{cite journal | vauthors = Mayr A, Hochstein-Mintzel V, Stickl H |title=Abstammung, Eigenschaften und Verwendung des attenuierten Vaccinia-Stammes MVA |journal=Infection |date=March 1975 |volume=3 |issue=1 |pages=6–14 |doi=10.1007/BF01641272|s2cid=46979748 }}</ref> During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine.<ref name="Fenner_1988"/>{{rp|585}} Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead.<ref name="kenner2006"/> In the 2000s, MVA was tested in animal models at much higher dosages.<ref>{{cite news | vauthors = Cohen J |title=There's a shortage of monkeypox vaccine. Could one dose instead of two suffice? |url=https://www.science.org/content/article/there-s-shortage-monkeypox-vaccine-could-one-dose-instead-two-suffice?cookieSet=1 |work=AAAS |date=1 July 2022 |quote=Because MVA does not make copies of itself, the team gave it at a higher dose—similar to what's used in the Bavarian Nordic shot today—than the Dryvax vaccine. |access-date=3 July 2022 |archive-date=8 July 2022 |archive-url=https://web.archive.org/web/20220708045919/https://www.science.org/content/article/there-s-shortage-monkeypox-vaccine-could-one-dose-instead-two-suffice?cookieSet=1 |url-status=live }}</ref> When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects.<ref>{{cite journal | vauthors = Earl PL, Americo JL, Wyatt LS, Espenshade O, Bassler J, Gong K, Lin S, Peters E, Rhodes L, Spano YE, Silvera PM, Moss B | display-authors = 6 | title = Rapid protection in a monkeypox model by a single injection of a replication-deficient vaccinia virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 31 | pages = 10889–10894 | date = August 2008 | pmid = 18678911 | pmc = 2495015 | doi = 10.1073/pnas.0804985105 | doi-access = free | bibcode = 2008PNAS..10510889E }}</ref>

==== MVA-BN ====
{{anchor|Imvamune}}{{anchor|Imvanex}}{{anchor|Jynneos}}
MVA-BN (also known as: '''Imvanex''' in the European Union; '''Imvamune''' in Canada; and '''Jynneos'''<ref name="NIAID Supply">{{cite web | title=Smallpox Vaccine Supply & Strength | website=[[Organization:National Institute of Allergy and Infectious Diseases|National Institute of Allergy and Infectious Diseases]] (NIAID) | date=26 September 2019 | url=https://www.niaid.nih.gov/diseases-conditions/smallpox-vaccine | archive-url=https://web.archive.org/web/20191017060706/https://www.niaid.nih.gov/diseases-conditions/smallpox-vaccine | archive-date=17 October 2019 | url-status=live | access-date=16 October 2019}}</ref><ref>{{cite journal | vauthors = Greenberg RN, Hay CM, Stapleton JT, Marbury TC, Wagner E, Kreitmeir E, Röesch S, von Krempelhuber A, Young P, Nichols R, Meyer TP, Schmidt D, Weigl J, Virgin G, Arndtz-Wiedemann N, Chaplin P | display-authors = 6 | title = A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0157335 | date = 2016 | pmid = 27327616 | pmc = 4915701 | doi = 10.1371/journal.pone.0157335 | doi-access = free | title-link = doi | bibcode = 2016PLoSO..1157335G }}</ref>) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take."<ref>{{cite web |title=Summary Basis for Regulatory Action Template |url=https://www.fda.gov/media/131802/download |website=FDA |publisher=U.S. Food & Drug Administration |access-date=8 October 2021 |archive-date=8 October 2021 |archive-url=https://web.archive.org/web/20211008212419/https://www.fda.gov/media/131802/download |url-status=live }}</ref>  A "take" or "major cutaneous reaction" is a pustular lesion or an area of definite induration or congestion surrounding a central lesion, which can be a scab or an ulcer.<ref>{{cite web |title=Vaccine "Take" Evaluation |url=https://www.cdc.gov/smallpox/clinicians/vaccination-take-evaluation4.html |website=CDC |publisher=U.S. Centers for Disease Control and Prevention |access-date=9 January 2022 |archive-date=26 January 2022 |archive-url=https://web.archive.org/web/20220126003741/https://www.cdc.gov/smallpox/clinicians/vaccination-take-evaluation4.html |url-status=live }}</ref>

MVA-BN can also be administered [[Medicine:Intradermal injection|intradermally]] to increase the number of available doses.<ref>{{cite web |last=CDC |date=13 October 2022 |title=Monkeypox in the U.S. |url=https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/jynneos-vaccine.html |access-date=19 October 2022 |website=Centers for Disease Control and Prevention |language=en-us |archive-date=19 October 2022 |archive-url=https://web.archive.org/web/20221019033901/https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/jynneos-vaccine.html |url-status=live }}</ref> It is safer for immunocompromised patients and those who are at risk from a ''vaccinia''{{Definition needed|date=July 2023}} infection.{{cn|date=July 2023}} MVA-BN has been approved in the European Union,<ref name="Imvanex EPAR">{{cite web |url=https://www.ema.europa.eu/en/medicines/human/EPAR/imvanex |title=Imvanex EPAR |access-date=2 October 2014 |publisher=[[Organization:European Medicines Agency|European Medicines Agency]] (EMA) |archive-date=27 April 2022 |archive-url=https://web.archive.org/web/20220427235228/https://www.ema.europa.eu/en/medicines/human/EPAR/imvanex |url-status=live }}</ref> Canada,<ref>{{cite web | title=Smallpox and monkeypox vaccine: Canadian Immunization Guide | website=Public Health Agency of Canada | date=16 June 2022 | url=https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html | access-date=8 July 2022 | archive-date=20 July 2020 | archive-url=https://web.archive.org/web/20200720171112/https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-21-smallpox-vaccine.html | url-status=live }}</ref><ref>{{cite web | title=Register of Innovative Drugs | website=[[Organization:Health Canada|Health Canada]] | date=June 2020 | url=https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/drug-products/applications-submissions/register-innovative-drugs/reg-innov-dr-eng.pdf | access-date=24 June 2020 | archive-date=26 June 2020 | archive-url=https://web.archive.org/web/20200626124518/https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/drug-products/applications-submissions/register-innovative-drugs/reg-innov-dr-eng.pdf | url-status=live }}</ref><ref name="Health Canada">{{cite web|url=http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/regist/reg_innov_dr-eng.php |title=Products for Human Use. Submission #144762 |work=Register of Innovative Drugs |access-date=30 October 2014 |publisher=[[Organization:Health Canada|Health Canada]] |url-status=dead |archive-url=https://web.archive.org/web/20140617224429/http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/regist/reg_innov_dr-eng.php |archive-date=17 June 2014 }}</ref> and the United States.<ref>{{cite web | title=Jynneos | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=24 September 2019 | url=https://www.fda.gov/vaccines-blood-biologics/jynneos | archive-url=https://web.archive.org/web/20191017060019/https://www.fda.gov/vaccines-blood-biologics/jynneos | archive-date=17 October 2019 | url-status=live | access-date=16 October 2019 | id=STN 125678}} {{PD-notice}}</ref><ref>{{cite press release | title=FDA approves first live, non-replicating vaccine to prevent smallpox and monkeypox | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=24 September 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-live-non-replicating-vaccine-prevent-smallpox-and-monkeypox | archive-url=https://web.archive.org/web/20191017055501/https://www.fda.gov/news-events/press-announcements/fda-approves-first-live-non-replicating-vaccine-prevent-smallpox-and-monkeypox | archive-date=17 October 2019 | url-status=live | access-date=17 October 2019}} {{PD-notice}}</ref> Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000.<ref>{{cite web |url=http://id.bavarian-nordic.com/pipeline/clinical-trials.aspx |title=Infectious Diseases: Clinical Trials |access-date=30 October 2014 |publisher=Bavarian Nordic |archive-url=https://web.archive.org/web/20160426132236/http://id.bavarian-nordic.com/pipeline/clinical-trials.aspx |archive-date=26 April 2016 |url-status=dead }}</ref><ref name="Clinicaltrials.gov-NIAID">{{cite web |url=http://www.clinicaltrials.gov/ct2/show/study/NCT01827371 |title=Phase II Trial to Assess Safety and Immunogenicity of Imvamune |access-date=30 October 2014 |publisher=U.S. National Institutes of Health |work=ClinicalTrials.gov |archive-date=13 March 2022 |archive-url=https://web.archive.org/web/20220313044946/https://clinicaltrials.gov/ct2/show/study/NCT01827371 |url-status=live }}</ref><ref>{{cite journal | vauthors = Pittman PR, Hahn M, Lee HS, Koca C, Samy N, Schmidt D, Hornung J, Weidenthaler H, Heery CR, Meyer TP, Silbernagl G, Maclennan J, Chaplin P | display-authors = 6 | title = Phase 3 Efficacy Trial of Modified Vaccinia Ankara as a Vaccine against Smallpox | journal = The New England Journal of Medicine | volume = 381 | issue = 20 | pages = 1897–1908 | date = November 2019 | pmid = 31722150 | doi = 10.1056/NEJMoa1817307 | doi-access = free | title-link = doi }}</ref> This vaccine has also been approved for use against [[Medicine:Mpox|mpox]].<ref>{{cite web |date=19 May 2023 |title=Jynneos Vaccine Effectiveness |url=https://www.cdc.gov/poxvirus/mpox/cases-data/JYNNEOS-vaccine-effectiveness.html |access-date=24 May 2023 |website=Centers for Disease Control and Prevention |archive-date=24 May 2023 |archive-url=https://web.archive.org/web/20230524073420/https://www.cdc.gov/poxvirus/mpox/cases-data/JYNNEOS-vaccine-effectiveness.html |url-status=live }}</ref><ref>{{cite web |date=19 August 2022 |title=Considerations on posology for the use of the vaccine Jynneos/ Imvanex (MVA-BN) against monkeypox |url=https://www.ema.europa.eu/en/documents/other/considerations-posology-use-vaccine-jynneos/imvanex-mva-bn-against-monkeypox_en.pdf |access-date=28 May 2023 |website=European Medicines Agency |archive-date=28 May 2023 |archive-url=https://web.archive.org/web/20230528112802/https://www.ema.europa.eu/en/documents/other/considerations-posology-use-vaccine-jynneos/imvanex-mva-bn-against-monkeypox_en.pdf |url-status=live }}</ref><ref>{{cite web |title=Protecting you from mpox (monkeypox): information on the smallpox vaccination |url=https://www.gov.uk/government/publications/monkeypox-vaccination-resources/protecting-you-from-monkeypox-information-on-the-smallpox-vaccination |access-date=28 May 2023 |website=GOV.UK |language=en |archive-date=28 May 2023 |archive-url=https://web.archive.org/web/20230528112802/https://www.gov.uk/government/publicationsMentioned/monkeypox-vaccination-resources/protecting-you-from-monkeypox-information-on-the-smallpox-vaccination |url-status=live }}</ref>

==== LC16m8 ====
LC16m8 is a replicating attenuated strain of ''vaccinia'' that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on [[Biology:Chorioallantoic membrane|chorioallantoic membrane]] and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral ''vaccinia''. However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take", but safety is similar to MVA.<ref name="kenner2006">{{cite journal | vauthors = Kenner J, Cameron F, Empig C, Jobes DV, Gurwith M | title = LC16m8: an attenuated smallpox vaccine | journal = Vaccine | volume = 24 | issue = 47–48 | pages = 7009–7022 | date = November 2006 | pmid = 17052815 | pmc = 7115618 | doi = 10.1016/j.vaccine.2006.03.087 }}</ref>

== Safety ==
Vaccinia is infectious, which improves its effectiveness, but causes serious complications for people with impaired [[Biology:Immune system|immune system]]s (for example [[Medicine:Chemotherapy|chemotherapy]] and AIDS patients) or history of eczema, and is not considered safe for pregnant women.<ref>{{cite journal | vauthors = Rotz LD, Dotson DA, Damon IK, Becher JA | title = Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001 | journal = MMWR. Recommendations and Reports | volume = 50 | issue = RR-10 | pages = 1–25; quiz CE1–7 | date = June 2001 | pmid = 15580803 | url = https://www.cdc.gov/mmwr/PDF/rr/rr5010.pdf | access-date = 13 June 2022 | archive-date = 13 October 2021 | archive-url = https://web.archive.org/web/20211013105825/https://www.cdc.gov/mmwr/pdf/rr/rr5010.pdf | url-status = live }}</ref> A woman planning on conceiving should not receive smallpox immunization. Vaccines that only contain attenuated vaccinia viruses (an attenuated virus is one in which the pathogenicity has been decreased through [[Biology:Serial passage|serial passage]]) have been proposed, but some researchers{{who|date=March 2019}} have questioned the possible effectiveness of such a vaccine. According to the US Centers for Disease Control and Prevention (CDC), "within 3 days of being exposed to the virus, the vaccine might protect you from getting the disease. If you still get the disease, you might get much less sick than an unvaccinated person would. Within 4 to 7 days of being exposed to the virus, the vaccine likely gives you some protection from the disease. If you still get the disease, you might not get as sick as an unvaccinated person would."<ref>{{cite web | title=Prevention and Treatment | website=U.S. Centers for Disease Control and Prevention (CDC) | date=18 October 2021 | url=https://www.cdc.gov/smallpox/prevention-treatment/index.html | access-date=11 August 2022 | 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 }} {{PD-notice}}</ref>

In May 2007, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) voted unanimously that a new live virus vaccine produced by Acambis, [[Biology:ACAM2000|ACAM2000]], is both safe and effective for use in persons at high risk of exposure to smallpox virus. However, due to the high rate of serious adverse effects, the vaccine will only be made available to the CDC for the [[Social:Strategic National Stockpile|Strategic National Stockpile]].<ref>{{cite web | publisher = U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | title = Vaccines and Related Biological Products Advisory Committee Meeting | date = 17 May 2007 | access-date = 2 May 2013 | url = https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4292B2-00-index.htm | archive-date = 20 October 2017 | archive-url = https://web.archive.org/web/20171020103830/https://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4292B2-00-index.htm | url-status = live }} {{PD-notice}}</ref>

== Stockpiles ==

Since smallpox has been eradicated, the public is not routinely vaccinated against the disease. The World Health Organization maintained a stockpile of 200{{nbsp}}million doses in 1980, to guard against reemergence of the disease, but 99% of the stockpile was destroyed in the late 1980s when smallpox failed to return.<ref name="who2017_stockpile"/> After the [[Religion:September 11 attacks|September 11 attacks]] in 2001, many governments began building up vaccine stockpiles again for fear of bioterrorism. Several companies sold off their stockpiles of vaccines manufactured in the 1970s, and production of smallpox vaccines resumed.<ref name="spiegel20030126"/> Aventis Pasteur discovered a stockpile from the 1950s and donated it to the U.S. government.<ref>{{cite news | vauthors = Lueck S |title=Aventis to Donate Smallpox Vaccine To the U.S. Government's Stockpile |url=https://www.wsj.com/articles/SB1017428453582730240 |work={{wipe|The Wall Street Journal}} |date=1 April 2002 |access-date=4 July 2022 |archive-date=12 January 2018 |archive-url=https://web.archive.org/web/20180112192526/https://www.wsj.com/articles/SB1017428453582730240 |url-status=live | name-list-style=vanc }}</ref>

Stockpiles of newer vaccines must be repurchased periodically since they carry expiration dates. The United States had received 269 million doses of ACAM2000 and 28 million doses of MVA-BN by 2019,<ref>{{cite press release |title=Emergent BioSolutions Awarded 10-Year HHS Contract to Deliver ACAM2000®, (Smallpox (Vaccinia) Vaccine, Live) Into the Strategic |url=https://www.bloomberg.com/press-releases/2019-09-03/emergent-biosolutions-awarded-10-year-hhs-contract-to-deliver-acam2000-smallpox-vaccinia-vaccine-live-into-the-strategic |author1=Emergent BioSolutions |date=3 September 2019 |access-date=4 July 2022 }}</ref><ref>{{cite press release |author1=Bavarian Nordic |title=Bavarian Nordic Announces U.S. FDA Approval of Jynneos (Smallpox and Monkeypox Vaccine, Live, Non-Replicating) for Prevention of Smallpox and Monkeypox Disease in Adults |url=https://www.bavarian-nordic.com/investor/news/news.aspx?news=5758 |access-date=4 July 2022 |archive-date=28 June 2022 |archive-url=https://web.archive.org/web/20220628171758/https://www.bavarian-nordic.com/investor/news/news.aspx?news=5758 |url-status=live }}</ref> but only 100 million doses of ACAM2000 and 65,000 doses of MVA-BN were still available from the stockpile at the start of the [[Medicine:2022 monkeypox outbreak|2022 monkeypox outbreak]].<ref name="hhs20220701">{{cite press release |author1=U.S. Department of Health and Human Services |title=HHS Orders 2.5 Million More Doses of JYNNEOS Vaccine For Monkeypox Preparedness |url=https://www.hhs.gov/about/news/2022/07/01/hhs-orders-2-point-5-million-more-doses-jynneos-vaccine-for-monkeypox-preparedness.html |date=1 July 2022 |access-date=4 July 2022 |archive-date=4 July 2022 |archive-url=https://web.archive.org/web/20220704005859/https://www.hhs.gov/about/news/2022/07/01/hhs-orders-2-point-5-million-more-doses-jynneos-vaccine-for-monkeypox-preparedness.html |url-status=live }}</ref> First-generation vaccines have no specified expiration date and remain viable indefinitely in deep freeze. The U.S. stockpile of WetVax was manufactured in 1956–1957 and maintained since then at {{convert|-4|°F}},<ref>{{cite journal | vauthors = Petersen BW, Damon IK, Pertowski CA, Meaney-Delman D, Guarnizo JT, Beigi RH, Edwards KM, Fisher MC, Frey SE, Lynfield R, Willoughby RE | display-authors = 6 | title = Clinical guidance for smallpox vaccine use in a postevent vaccination program | journal = MMWR. Recommendations and Reports | date = February 2015 | volume = 64 | issue = RR-2 | pages = 1–26 | url = https://www.cdc.gov/mmwr/pdf/rr/rr6402.pdf | pmid = 25695372 | access-date = 11 August 2022 | archive-date = 19 January 2022 | archive-url = https://web.archive.org/web/20220119040039/http://www.cdc.gov/mmwr/pdf/rr/rr6402.pdf | url-status = live }}</ref> and it was still effective when tested in 2004.<ref name="talbot2004">{{cite journal | vauthors = Talbot TR, Stapleton JT, Brady RC, Winokur PL, Bernstein DI, Germanson T, Yoder SM, Rock MT, Crowe JE, Edwards KM | display-authors = 6 |title=Vaccination success rate and reaction profile with diluted and undiluted smallpox vaccine: a randomized controlled trial |journal=JAMA |date=September 2004 |volume=292 |issue=10 |pages=1205–12 |doi=10.1001/jama.292.10.1205 |pmid=15353533 }}</ref> Replicating vaccines also remain effective even at 1:10 dilution, so a limited number of doses can be stretched to cover a much larger population.<ref name="talbot2004"/>

{| class="wikitable"
|+ Smallpox vaccine stockpiles
|-
! Country, region, or organization !! Year !! Doses (millions) !! Composition (generation)
|-
| {{flag|World Health Organization}} (Geneva) || 2013 || 2.7 ||
* 300,000 ACAM2000 (2nd)
* 2.4 million various (1st)
|-
| {{flag|World Health Organization}}<br/>(pledged) || 2018 || 27 || Various (1st, 2nd, 3rd)<ref>{{cite web | vauthors = Costa A |title= Smallpox vaccine stockpile |url= http://terrance.who.int/mediacentre/data/sage/SAGE_Docs_Ppt_Nov2013/8_session_smallpox/Nov2013_session8_Presentation1_smallpox_vaccine_emergency_stockpile.pdf |publisher=[[Organization:World Health Organization|World Health Organization]] (WHO) |date=5-7 November 2013 |access-date=4 July 2022 |archive-date=4 July 2022 |archive-url=https://web.archive.org/web/20220704202756/http://terrance.who.int/mediacentre/data/sage/SAGE_Docs_Ppt_Nov2013/8_session_smallpox/Nov2013_session8_Presentation1_smallpox_vaccine_emergency_stockpile.pdf |url-status=live }}</ref><ref>{{cite web |title=Smallpox eradication: destruction of variola virus stocks |url=https://apps.who.int/gb/ebwha/pdf_files/WHA72/A72_28-en.pdf |date=4 April 2019 |access-date=4 July 2022 |archive-date=16 May 2022 |archive-url=https://web.archive.org/web/20220516015609/https://apps.who.int/gb/ebwha/pdf_files/WHA72/A72_28-en.pdf |url-status=live }}</ref>
|-
| {{flag|France}} || 2006 || 55 || 55 million Pourquier (1st)<ref>{{cite web |title=Plan national de réponse à une menace de variole |url=https://solidarites-sante.gouv.fr/IMG/pdf/plan_variole_2006-2.pdf |publisher=Ministère de la Santé et des Solidarités (France) |date=August 2006 |access-date=4 July 2022 |archive-date=19 May 2022 |archive-url=https://web.archive.org/web/20220519223556/https://solidarites-sante.gouv.fr/IMG/pdf/plan_variole_2006-2.pdf |url-status=live }}</ref>
|-
| {{flag|Germany}} || 2022 || 100 ||
* MVA-BN (3rd)<ref name="spiegel20030126"/>
* 30+ million Lister/Elstree-BN (2nd)<ref name="spiegel20030126"/>
* 24 million various (1st)<ref name="spiegel20030126">{{cite news | vauthors = Kneip A |title=Pocken-Fieber |url=https://www.spiegel.de/panorama/pocken-fieber-a-91bca2ca-0002-0001-0000-000026218476 |work=Der Spiegel |date=26 January 2003 |language=de |access-date=4 July 2022 |archive-date=4 July 2022 |archive-url=https://web.archive.org/web/20220704005900/https://www.spiegel.de/panorama/pocken-fieber-a-91bca2ca-0002-0001-0000-000026218476 |url-status=live }}</ref>
|-
|{{Flag|Italy}}
|2022
|5<ref>{{cite web|url=https://www.adnkronos.com/vaiolo-delle-scimmie-abbiamo-5-milioni-dosi-di-vaccino-pronti-se-servira_3Xf2lbmIZJ1H4LXAfvoX6T|title=Vaiolo delle scimmie, 'abbiamo 5 milioni dosi di vaccino: pronti se servirà'|publisher=adnkronos|date=27 May 2022|access-date=14 July 2022|language=Italian|archive-date=14 July 2022|archive-url=https://web.archive.org/web/20220714041652/https://www.adnkronos.com/vaiolo-delle-scimmie-abbiamo-5-milioni-dosi-di-vaccino-pronti-se-servira_3Xf2lbmIZJ1H4LXAfvoX6T|url-status=live}}</ref>
|
|-
| {{flag|Japan}} || 2006 || 56 || LC16m8 (3rd)<ref name="kenner2006"/>
|-
| {{flag|Netherlands}} || 2017 || ?|| Lister/Elstree-RVIM (2nd)<ref name="Fenner_1988"/>{{rp|588–589}}
|-
| {{flag|South Korea}} || 2022 || 35|| Lancy-Vaxina (1st)<ref>{{cite web |url=https://n.news.naver.com/mnews/article/003/0011202227?sid=102 |title=15개국 퍼진 원숭이 두창, 불안 확산…백신·치료제는? |author=Jihyun Kim |date=23 May 2022 |access-date=23 May 2022 |newspaper=Newsis |location=Seoul |archive-date=23 May 2022 |archive-url=https://web.archive.org/web/20220523034625/https://n.news.naver.com/mnews/article/003/0011202227?sid=102 |url-status=live }}</ref><ref>{{cite journal | vauthors = Oh MD, Lee JK | title = Milestones in history of adult vaccination in Korea | journal = Clinical and Experimental Vaccine Research | volume = 1 | issue = 1 | pages = 9–17 | date = July 2012 | pmid = 23596574 | pmc = 3623517 | doi = 10.7774/cevr.2012.1.1.9 }}</ref>
|-
| {{flag|United States}} || 2022 || 185 ||
* 65,000 MVA-BN (3rd)<ref name="hhs20220701"/>
* 100 million ACAM2000 (2nd)<ref name="hhs20220701"/>
* 85 million WetVax (1st)<ref name="talbot2004"/>
|}

==History==
===Variolation===
{{Main|Biology:Variolation}}
The mortality of the severe form of smallpox – ''variola major'' – was very high without vaccination, up to 35% in some outbreaks.<ref name=Sherris>{{cite book | veditors = Ryan KJ, Ray CG | title = Sherris Medical Microbiology | url = https://archive.org/details/sherrismedicalmi00ryan | url-access = limited | edition = 4th | pages = [https://archive.org/details/sherrismedicalmi00ryan/page/n542 525]–28 | publisher = McGraw Hill | year = 2004 |isbn = 978-0-8385-8529-0 }}</ref> A method of inducing immunity known as inoculation, insufflation or "[[Biology:Variolation|variolation]]" was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe.<ref name="riedel2005">{{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> It may also have occurred in India, but this is disputed; other investigators contend the ancient [[Social:Sanskrit|Sanskrit]] medical texts of India do not describe these techniques.<ref name="riedel2005"/><ref>{{cite book | vauthors = Van Alphen J, Aris A | year=1995 | chapter=Medicine in India | title=Oriental Medicine: An Illustrated Guide to the Asian Arts of Healing | pages= 19–38 | location=London | publisher=Serindia Publications | isbn=978-0-906026-36-6}}</ref> The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his ''Douzhen xinfa'' (痘疹心法) 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> Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty.<ref>{{cite book | vauthors = Temple R | year=1986 | title=The Genius of China: 3,000 Years of Science, Discovery, and Invention | location=New York | publisher= Simon and Schuster | isbn=978-0-671-62028-8| page=137}}</ref> In China, powdered smallpox scabs were blown up the noses of the healthy. The patients 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|vauthors=Silverstein AM|page=293|publisher=Academic Press|year=2009|edition=2nd|url=https://books.google.com/books?id=2xNYjigte14C|isbn=9780080919461|access-date=6 July 2017|archive-date=3 August 2020|archive-url=https://web.archive.org/web/20200803070343/https://books.google.com/books?id=2xNYjigte14C|url-status=live}}.</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>{{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>

Variolation was also practiced throughout the latter half of the 17th century by physicians in [[Place:Turkey|Turkey]], Persia, and Africa. In 1714 and 1716, two reports of the [[Place:Ottoman Empire|Ottoman Empire]] Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople,<ref name=Behbehani_1983>{{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 }}</ref> and Giacomo Pylarini. Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation."<ref>{{cite journal | title = Smallpox inoculation and the Ottoman contribution: A Brief Historiography | vauthors = Aboul-Enein BH, Ross MW, Aboul-Enein FH | year = 2012 | journal = Texas Public Health Journal | volume = 64 | issue = 1 | page = 12 | url = https://cdn.ymaws.com/www.texaspha.org/resource/resmgr/docs/Journal_Files/TPHJ_Volume_64_Issue_1.pdf | access-date = 23 December 2018 | archive-date = 11 October 2021 | archive-url = https://web.archive.org/web/20211011061111/https://cdn.ymaws.com/www.texaspha.org/resource/resmgr/docs/Journal_Files/TPHJ_Volume_64_Issue_1.pdf | url-status = live }}</ref> In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland, during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison. This was successful and in 1722 Caroline of Ansbach, the Princess of Wales, allowed Maitland to vaccinate her children.<ref>Livingstone, N. 2015. ''The Mistresses of Cliveden. Three centuries of scandal, power and intrigue'' (p. 229)</ref> The success of these variolations assured the British people that the procedure was safe.<ref name=Behbehani_1983 />

{{quote box|align=right|width=40em|salign=right|...scarred the wrists, legs, and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for eight or ten days, after this time the patient was credibly informed. The patient would then develop a mild case [of smallpox], recover, and thereafter be immune.<ref>{{cite book | vauthors = Kennedy P | title = An Essay on External Remedies Wherein it is Considered, Whether all the curable Distempers incident to Human Bodies, may not be cured by Outward Means | year = 1715 | publisher = A. Bell | location = London }}</ref>|—Dr. Peter Kennedy}}

Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher [[Biography:Cotton Mather|Cotton Mather]] learned it from Onesimus, a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped.<ref name=Willoughby_2004>{{cite web | title= Black History Month II: Why Wasn't I Taught That? | vauthors = Willoughby B | work=Tolerance in the News | url=http://www.tolerance.org/news/article_tol.jsp?id=942 | date=12 February 2004| access-date=4 December 2008|archive-url=https://web.archive.org/web/20090114071421/http://www.tolerance.org/news/article_tol.jsp?id=942|archive-date=14 January 2009}}</ref> This practice was widely criticized at first.<ref>{{cite web | title = Open Collections Program: Contagion, The Boston Smallpox Epidemic, 1721 | access-date = 27 August 2008 | url = http://ocp.hul.harvard.edu/contagion/smallpox.html | archive-date = 26 July 2018 | archive-url = https://web.archive.org/web/20180726145425/http://ocp.hul.harvard.edu/contagion/smallpox.html | url-status = live }}</ref> However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies.<ref name = "Fenner_1988">{{cite book |vauthors=Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID |title=Smallpox and Its Eradication |series=History of International Public Health |issue=6 |publisher=[[Organization:World Health Organization|World Health Organization]] (WHO) |location=Geneva |year=1988 |isbn=978-92-4-156110-5 |url=https://apps.who.int/iris/bitstream/handle/10665/39485/9241561106.pdf |access-date=5 November 2013 |archive-date=25 May 2021 |archive-url=https://web.archive.org/web/20210525012647/http://apps.who.int/iris/bitstream/handle/10665/39485/9241561106.pdf |url-status=live }}</ref><!-- By 1777, George Washington, who initially hesitated to have his Revolutionary War troops inoculated during a smallpox outbreak, wrote, "should We inoculate generally, the Enemy, knowing it, will certainly take Advantage of our Situation;", and eventually ordered mandatory inoculation of all troops and recruits who had not had the disease.<ref>{{cite book |vauthors=Grizzard FE, Washington G, Chase PD, Twohig D |title= George Washington to Major General Horatio Gates, 5–6 February 1777. In: The papers of George Washington |publisher=University Press of Virginia |location=Charlottesville |year=1985 |volume=8 |isbn=0-8139-1787-5}}</ref>{{Clarify|date=July 2012}} INFO COMMENTED OUT : SEE TALK -->

The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedy's description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassador's wife [[Biography:Lady Mary Wortley Montagu|Lady Mary Wortley Montagu]], who four years later introduced the practice to England.<ref>{{cite book | vauthors = Robertson P | title = The book of firsts | publisher = C. N. Potter : distributed by Crown Publishers | location = New York | year = 1974 | isbn = 978-0-517-51577-8 | url-access = registration | url = https://archive.org/details/bookoffirsts00robe }}</ref>

An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment:
{{blockquote|The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them.<ref>{{cite web |url=http://www.ic.arizona.edu/ic/mcbride/ws200/montltrs.htm |title=Montagu, Turkish Embassy Letters |access-date=4 December 2008 |archive-date=15 April 2013 |archive-url=https://web.archive.org/web/20130415065402/http://www.ic.arizona.edu/ic/mcbride/ws200/montltrs.htm |url-status=live }}</ref>}}

===Early vaccination===
[[File:Jenner phipps 01.jpg|thumbnail|Dr Edward Jenner performing his first vaccination on James Phipps, a boy of age 8. 14 May 1796. Painting by Ernest Board (early 20th century).]]

In the early empirical days of vaccination, before Louis Pasteur's work on establishing the germ theory and Joseph Lister's on antisepsis and asepsis, there was considerable cross-infection. William Woodville, one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the [[Medicine:Cowpox|cowpox]] matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle.<ref>{{cite web|url=http://lachlan.bluehaze.com.au/london2001/august2001/18aug2001c/|title=Statue of Dr Edward Jenner near the Italian Fountains, Kensington Gardens|website=lachlan.bluehaze.com.au|access-date=16 October 2019|archive-date=28 March 2006|archive-url=https://web.archive.org/web/20060328062647/http://lachlan.bluehaze.com.au/london2001/august2001/18aug2001c/|url-status=live}}</ref>

During the earlier days of empirical experimentation in 1758, American Calvinist [[Biography:Jonathan Edwards (theologian)|Jonathan Edwards]] died from a smallpox inoculation. Some of the earliest [[Statistics|statistical]] and [[Social:Epidemiology|epidemiological]] studies were performed by James Jurin in 1727 and [[Biography:Daniel Bernoulli|Daniel Bernoulli]] in 1766.<ref name="pmid15334536">{{cite journal | vauthors = Blower S, Bernoulli D | title = An attempt at a new analysis of the mortality caused by smallpox and of the advantages of inoculation to prevent it. 1766 | journal = Reviews in Medical Virology | volume = 14 | issue = 5 | pages = 275–288 | year = 2004 | pmid = 15334536 | doi = 10.1002/rmv.443 | url = http://www.semel.ucla.edu/biomedicalmodeling/pdf/Bernoulli&Blower.pdf | url-status = dead | s2cid = 8169180 | archive-url = https://web.archive.org/web/20070927032605/http://www.semel.ucla.edu/biomedicalmodeling/pdf/Bernoulli%26Blower.pdf | archive-date = 27 September 2007 }}</ref> In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox.<ref>{{cite book | veditors = Pearson G | title = An inquiry concerning the history of the cowpox, principally with a view to supersede and extinguish the smallpox | location = London, England | publisher = J. Johnson | date = 1798 | url = https://books.google.com/books?id=osdEAAAAcAAJ&pg=PA102 | pages = 102–104 | access-date = 31 December 2015 | archive-date = 25 January 2022 | archive-url = https://web.archive.org/web/20220125171737/https://books.google.com/books?id=osdEAAAAcAAJ&pg=PA102 | url-status = live }}</ref><ref>{{cite journal | vauthors = Thurston L, Williams G | title = An examination of John Fewster's role in the discovery of smallpox vaccination | journal = The Journal of the Royal College of Physicians of Edinburgh | volume = 45 | issue = 2 | pages = 173–179 | date = 2015 | pmid = 26181536 | doi = 10.4997/JRCPE.2015.217 | doi-access = free | title-link = doi }}</ref>
[[Image:The cow pock.jpg|thumb|right|An 1802 caricature by James Gillray depicting the early controversy surrounding Jenner's vaccination theory]]
Edward Jenner was born in Berkeley, England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered.<ref>Michael J. Bennett, War against Smallpox: Edward Jenner and the Global Spread of Vaccination (Cambridge, United Kingdom: Cambridge University Press, 2020), 32.</ref> At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury. He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St Georges Hospital and as the private pupil of John Hunter, then returned to set up practice in Berkeley.<ref name=Bailey1996/>

Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid" seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans.<ref>{{cite journal | vauthors = Hammarsten JF, Tattersall W, Hammarsten JE | title = Who discovered smallpox vaccination? Edward Jenner or Benjamin Jesty? | journal = Transactions of the American Clinical and Climatological Association | volume = 90 | pages = 44–55 | date = 1979 | pmid = 390826 | pmc = 2279376 }}</ref>

[[File:Smallpox vaccine.svg|thumb|Diagram A: Exposure to the cowpox virus builds immunity to the smallpox virus. 1a.&nbsp;Cowpox virus is injected into the bloodstream. 2a.&nbsp;The virus enters the cells and a mild fever develops. 3a.&nbsp;T-cells recognize the antigen as a threat. 4a.&nbsp;Activated T-cells replicate, and their offspring become memory T-cells. 5a.&nbsp;Antibodies are produced and destroy the virus. Diagram B: When exposed to the smallpox virus, the immune system is resistant. 1b.&nbsp;Smallpox virus is injected into the bloodstream. 2b.&nbsp;Memory T cells recognize the virus. 3b.&nbsp;Antibodies are produced and destroy the virus.]]

[[File:Edward Jenner- Smallpox.svg|thumb|upright=1.35|left| The process above shows the steps taken by Edward Jenner to create vaccination. Jenner did this by inoculating James Phipps with cowpox, a similar virus to smallpox, to create immunity, unlike variolation, which used smallpox to create an immunity to itself.]]

Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Society's records. Jenner had sent the paper informally to Sir Joseph Banks, the Society's president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations.<ref>{{cite journal | vauthors = Baxby D | title = Edward Jenner's unpublished cowpox inquiry and the Royal Society: Everard Home's report to Sir Joseph Banks | journal = Medical History | volume = 43 | issue = 1 | pages = 108–110 | date = January 1999 | pmid = 10885136 | pmc = 1044113 | doi = 10.1017/S0025727300064747 }}</ref> Additional vaccinations were performed and in 1798 Jenner published his work entitled ''An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox.''<ref name="riedel2005"/><ref>{{cite journal | vauthors = Winkelstein W | title = Not just a country doctor: Edward Jenner, scientist | journal = Epidemiologic Reviews | volume = 14 | pages = 1–15 | year = 1992 | pmid = 1289108 | doi = 10.1093/oxfordjournals.epirev.a036081 }}/</ref><ref>{{cite journal | vauthors = Willis NJ | title = Edward Jenner and the eradication of smallpox | journal = Scottish Medical Journal | volume = 42 | issue = 4 | pages = 118–121 | date = August 1997 | pmid = 9507590 | doi = 10.1177/003693309704200407 | s2cid = 43179073 }}</ref> It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included 'several children and adults'. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect.<ref name=Baxby1999/> Jenner also tried to distinguish between 'True' cowpox which produced the desired result and 'Spurious' cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would now{{when|date=October 2019}} be recognised as non-infectious vaccine, a different virus (e.g. [[Biology:Paravaccinia virus|paravaccinia]]/milker's nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development.<ref name=Baxby2001>{{cite book|title=Smallpox Vaccine, Ahead of Its Time – How the Late Development of Laboratory Methods and Other Vaccines Affected the Acceptance of Smallpox Vaccine | vauthors = Baxby D |year=2001|publisher=Jenner Museum|location=Berkeley, UK|isbn=978-0-9528695-1-1|pages=12–16}}</ref> A further source of confusion was Jenner's belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as ''grease''. This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus, the virus in present-day vaccine.<ref name=baxby1981>{{cite book| vauthors = Baxby D |title=Jenner's smallpox vaccine; the riddle of vaccinia virus and its origin|year=1981|publisher=Heinemann Educational Books|location=London|isbn=0-435-54057-2}}</ref>{{rp|165–78}}

The introduction of the vaccine to the New World took place in Trinity, Newfoundland, in 1798 by Dr. John Clinch, boyhood friend and medical colleague of Jenner.<ref>{{cite web|url=http://ngb.chebucto.org/Articles/clinch1a.shtml|title=Plaque in Memory of Rev. John Clinch|vauthors=Piercey T|date=August 2002|access-date=28 May 2014|archive-url=https://web.archive.org/web/20180320171350/http://ngb.chebucto.org/Articles/clinch1a.shtml|archive-date=20 March 2018|url-status=live}}</ref><ref>{{cite book |vauthors=Handcock G |year=1996 |title=The Story of Trinity |location=Trinity |publisher=The Trinity Historical Society |page=1 |isbn=978-098100170-8}}</ref> The first smallpox vaccine in the United States was administered in 1799. The physician [[Biography:Valentine Seaman|Valentine Seaman]] gave his children a smallpox vaccination using a serum acquired from Jenner.<ref>{{cite web |url=http://libweb5.princeton.edu/visual_materials/maps/websites/thematic-maps/quantitative/medicine/medicine.html |title=First X, Then Y, Now Z : Landmark Thematic Maps – Medicine |website=Princeton University Library|date=2012|access-date=22 May 2018|archive-url=https://web.archive.org/web/20180913015235/http://libweb5.princeton.edu/visual_materials/maps/websites/thematic-maps/quantitative/medicine/medicine.html|archive-date=13 September 2018|url-status=dead}}</ref><ref>{{cite book|title=Encyclopedia of the New American Nation| vauthors=Morman ET |publisher=Charles Scribner's Sons|year=2006| veditors=Finkelman P |pages=207–08|chapter=Smallpox}}</ref> By 1800, Jenner's work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest.<ref name = "Hopkins_2002">{{cite book | vauthors = Hopkins DR |title=The greatest killer : smallpox in history, with a new introduction |date=2002 |publisher=University of Chicago Press |location=Chicago |isbn=978-0-226-35168-1}}</ref>{{rp|262–67}} Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States.<ref name="Bazin_2000">{{cite book|vauthors=Bazin H|title=The Eradication of Smallpox|year=2000|publisher=Academic Press|location=London |isbn=978-0-12-083475-4|pages=94–102}}</ref><ref>{{cite journal |vauthors=Rusnock A |title=Catching cowpox: the early spread of smallpox vaccination, 1798-1810 |journal=Bulletin of the History of Medicine |volume=83 |issue=1 |pages=17–36 |year=2009 |pmid=19329840 |doi=10.1353/bhm.0.0160 |s2cid=24344691}}</ref>

[[File:Real Expedición Filantrópica de la Vacuna 01.svg|thumb|upright=1.35|right|The Balmis Expedition took the vaccine to Spanish America in 1804.]]
In 1804 the Balmis Expedition, an official Spanish mission commanded by Francisco Javier de Balmis, sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to [[Place:Manila|Manila]] in the Philippines and on to Canton and [[Place:Macau|Macao]] on the Chinese coast. He returned to Spain in 1806.<ref>{{cite journal| vauthors = Smith MM |title=The 'Real Expedición Marítima de la Vacuna' in New Spain and Guatemala|journal=Trans. Am. Philos. Soc. |series=New Series|year=1970|volume=64|issue=4|pages=1–74|doi=10.2307/1006158|jstor=1006158 }}</ref> The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were 'carriers' of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations".<ref name="lancet">{{cite journal |vauthors=Ranscombe P |date=July 2022 |title=Vaccine Voyages: where science meets slavery |url=https://doi.org/10.1016/S1473-3099(22)00270-5 |journal=The Lancet Infectious Diseases |volume=22 |issue=7 |pages=956 |doi=10.1016/s1473-3099(22)00270-5 |issn=1473-3099 |pmc=9023002 |access-date=26 June 2022 |archive-date=8 July 2022 |archive-url=https://web.archive.org/web/20220708045921/https://www.thelancet.com/retrieve/pii/S1473309922002705 |url-status=live }}</ref>

Napoleon was an early proponent of smallpox vaccination and ordered that army recruits be given the vaccine. Additionally a vaccination program was created for the French Army and his Imperial Guard. In 1811 he had his son, Napoleon II, vaccinated after his birth. By 1815 about half of French children were vaccinated and by the end of the Napoleonic Empire smallpox deaths accounted for 1.8% of deaths, as opposed to the 4.8% of deaths it accounted for at the time of the {{wipe|French Revolution}}.<ref>{{cite book |last1=Tizard |first1=Ian R. |title=A History of Vaccines and Their Opponents |date=2023 |publisher=[[Company:Elsevier|Elsevier]] |page=99}}</ref>

The first state to introduce compulsory vaccinations was the Principality of Lucca and Piombino on 25 September 1806.<ref>{{cite journal | vauthors = | title = Nova et Vetera | journal = British Medical Journal | volume = 1 | issue = 2370 | pages = 1297–1298 | date = June 1906 | pmid = 20762710 | pmc = 2381502 | doi = 10.1136/bmj.1.2370.1297 }}</ref> On 26 August 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act.<ref name="MeyerReiter">{{cite journal | vauthors = Meyer C, Reiter S | title = [Vaccine opponents and sceptics. History, background, arguments, interaction] | language = German | journal = Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | volume = 47 | issue = 12 | pages = 1182–1188 | date = December 2004 | pmid = 15583889 | doi = 10.1007/s00103-004-0953-x | s2cid = 23282373 }}</ref><ref name=":3">{{cite journal | vauthors = Klein S, Schöneberg I, Krause G | journal = Bundesgesundheitsblatt|title=Vom Zwang zur Pockenschutzimpfung zum Nationalen Impfplan|volume=55|at=pp.&nbsp;1512–1523|date=October 2012|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>{{cite book | vauthors = Jarlert A | title = Sveriges Kyrkohistoria. | volume = 6 | location = Stockholm | date = 2001 | pages = 33–54 }}</ref> The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.<ref>{{cite book | vauthors = Rheinberger R | chapter = Zum 200. Geburtstag von Landesphysikus Gebhard Schaedler. Ein Liechtensteinischer Artzt als Pionier der Pockenschutzimpfung. | title = Jahrbuch des Historischen Vereins fur das Furstentum Liechtenstein. Historischer Verein fur das Furstentum Liechtenstein | date = 1976 | volume = 76 | pages = 337–343 | chapter-url = http://www.eliechtensteinensia.li/viewer/image/000000453_76/333/ | access-date = 27 October 2021 | archive-date = 27 October 2021 | archive-url = https://web.archive.org/web/20211027101204/https://www.eliechtensteinensia.li/viewer/image/000000453_76/333/ | url-status = live }}</ref>

The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty, Peter Plett and John Fewster. In 1774 Jesty, a farmer of Yetminster in Dorset, observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenner's prominence at a time when he was applying to Parliament for financial reward.<ref>{{cite journal | vauthors = Pead PJ | title = Benjamin Jesty: new light in the dawn of vaccination | journal = Lancet | volume = 362 | issue = 9401 | pages = 2104–2109 | date = December 2003 | pmid = 14697816 | doi = 10.1016/S0140-6736(03)15111-2 | s2cid = 4254402 }}</ref> During 1790–92 Peter Plett, a teacher from Holstein, reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel. However, the Faculty favoured variolation and took no action.<ref>{{cite journal | vauthors = Plett PC | title = [Peter Plett and other discoverers of cowpox vaccination before Edward Jenner] | language = de | journal = Sudhoffs Archiv | volume = 90 | issue = 2 | pages = 219–232 | year = 2006 | pmid = 17338405 | jstor = 20778029 }}</ref> John Fewster, a surgeon friend of Jenner's from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenner's reputation.<ref name = "Williams_2010">{{cite book| vauthors = Williams G |title=Angel of Death; the story of smallpox|url=https://archive.org/details/angeldeathstorys00will|url-access=limited|year=2010|publisher=Palgrave Macmillan|location=Basingstoke|isbn=978-0-230-27471-6|pages=[https://archive.org/details/angeldeathstorys00will/page/n182 162]–73}}</ref> It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official [[Organization:World Health Organization|World Health Organization]] (WHO) account ''Smallpox and its Eradication'' assessing Jenner's role wrote:<ref name = "Fenner_1988" />{{rp|264}}

{{blockquote|Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit.}}

As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances.<ref name = "Williams_2010" />{{rp|236–40}}<ref name = "Williamson_2007">{{cite book| vauthors = Williamson S |title=The Vaccination Controversy; the rise, reign and decline of compulsory vaccination|year=2007|publisher=Liverpool University Press|location=Liverpool|isbn=9781846310867}}</ref> Compulsory infant vaccination was introduced in England by the 1853 [[Biology:Vaccination Act|Vaccination Act]]. By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment.<ref name = "Williamson_2007" />{{rp|202–13}} This intensified opposition, and the 1898 Vaccination Act introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further Act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the 1907 Act effectively marked the end of compulsory infant vaccination in England.<ref name = "Williamson_2007" />{{rp|233–38}}

[[File:PO Notice 1919 re Small Pox Vaccination.jpg|thumb|upright|1919 Notice issued by the British General Post Office encouraging postal staff to apply for the free vaccination]]
In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory.<ref name = "Hopkins_2002" />{{rp|292–93}} Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated.<ref>{{cite journal | vauthors = George NA | title = Compulsory smallpox vaccination; the University City, Missouri, case | journal = Public Health Reports | volume = 67 | issue = 11 | pages = 1135–1138 | date = November 1952 | pmid = 12993980 | pmc = 2030845 | doi = 10.2307/4588305 | jstor = 4588305 }}</ref> Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in ''[[Biology:Jacobson v. Massachusetts|Jacobson v. Massachusetts]]'' in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good.<ref>{{cite journal |date=May 2008 |title=Toward a Twenty-First-Century ''Jacobson v. Massachusetts'' |url=http://cdn.harvardlawreview.org/wp-content/uploads/pdfs/a_twenty-first-century_jacobson_v_massachusetts.pdf |journal=Harvard Law Review |publisher=The Harvard Law Review Association |volume=121 |issue=7 |pages=1823–1824 |access-date=13 March 2014 |archive-date=26 October 2014 |archive-url=https://web.archive.org/web/20141026203112/http://cdn.harvardlawreview.org/wp-content/uploads/pdfs/a_twenty-first-century_jacobson_v_massachusetts.pdf |url-status=live }}</ref>

Louis T. Wright,<ref name=North_by_South>{{cite web|title=A Brief Biography of Dr. Louis T. Wright|work=North by South: from Charleston to Harlem, the great migration|url=http://northbysouth.kenyon.edu/1998/health/wright.htm|access-date=23 September 2006|archive-date=20 October 2017|archive-url=https://web.archive.org/web/20171020103829/http://northbysouth.kenyon.edu/1998/health/wright.htm|url-status=live}}</ref> an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during [[Social:World War I|World War I]], intradermal, smallpox vaccination for the soldiers.<ref name=MITRE_CDAC>{{cite web|title=Spotlight on Black Inventors, Scientists, and Engineers |work=Department of Computer Science of Georgetown University |url=http://www.cs.georgetown.edu/~blakeb/mm/BHM/Spotlight%20on%20Black%20Inventors,%20Scientists,%20and%20Engineers.htm |access-date=23 September 2006 |url-status=dead |archive-url=https://web.archive.org/web/20060907060826/http://www.cs.georgetown.edu/~blakeb/mm/BHM/Spotlight%20on%20Black%20Inventors,%20Scientists,%20and%20Engineers.htm |archive-date=7 September 2006 }}</ref>

===Developments in production===

Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer;<ref name=Copeman1898>{{cite journal | vauthors = Copeman SM | title = The Milroy Lectures on the Natural History of Vaccina: Delivered at the Royal College of Physicians | journal = British Medical Journal | volume = 1 | issue = 1951 | pages = 1312–1318 | date = May 1898 | pmid = 20757828 | pmc = 2411485 | doi = 10.1136/bmj.1.1951.1312 }}</ref> initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century.<ref name=Dudgeon1963>{{cite journal | vauthors = Didgeon JA | title = Development of Smallpox Vaccine in England in the Eighteenth and Nineteenth Centuries | journal = British Medical Journal | volume = 1 | issue = 5342 | pages = 1367–1372 | date = May 1963 | pmid = 20789814 | pmc = 2124036 | doi = 10.1136/bmj.1.5342.1367 }}</ref> During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis.<ref name=Baxby2001/> In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations,<ref name = "Bazin_2000" />{{rp|122}} some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis.<ref>{{cite book| vauthors = Creighton C |title=The Natural History of Cowpox and Vaccinal Syphilis|year=1887|publisher=Cassell|location=London}}</ref> Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of [[Medicine:Vaccine controversies|vaccine controversies]] that spread to other vaccines and into the 21st century.{{citation needed|date=July 2020}}

Sydney Arthur Monckton Copeman, an English Government bacteriologist interested in smallpox vaccine investigated the effects on the bacteria in it of various treatments, including [[Chemistry:Glycerol|glycerine]]. Glycerine was sometimes used simply as a [[Chemistry:Diluent|diluent]] by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations.<ref>{{cite book|title=Transactions of the Seventh International Congress of Hygiene and Demography|year=1892|publisher=Eyre and Spottiswoode|pages=319–26| vauthors = Copeman SM |chapter=The Bacteriology of Vaccine Lymph| veditors = Shelley CE |chapter-url=https://archive.org/details/transactionssev09shelgoog|access-date=14 January 2014}}</ref> He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent.<ref name=Copeman1898/> In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII.<ref>{{cite journal | vauthors = Copeman PW | title = Extinction of the speckled monster celebrated in 1996 | journal = Journal of Medical Biography | volume = 6 | issue = 1 | pages = 39–42 | date = February 1998 | pmid = 11619875 | doi = 10.1177/096777209800600108 | s2cid = 8918951 }}</ref>

Vaccine produced by Copeman's method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 [[Biology:Vaccination Act|Vaccination Act]] banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers.<ref>{{cite book| vauthors = Dixon CW |title=Smallpox|year=1962|publisher=J. & A. Churchill|location=London|pages=280–81}}</ref> Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram.<ref>{{cite journal| author = Special Commission|title=Report of the Lancet Special Commission on Glycerinated Calf Lymph Vaccines|journal=Lancet|year=1900|volume=155|issue=4000|pages=1227–36|doi=10.1016/s0140-6736(01)96895-3}}</ref> The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections.<ref name=Baxby2001/> Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where a satisfactory [[Physics:Cold chain|cold chain]] was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens' eggs.<ref name = "Fenner_1988" />{{rp|543–45}} English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used.<ref name=Dudgeon1963/>

In the late 1940s and early 1950s, Leslie Collier, an English microbiologist working at the [[Organization:Lister Institute of Preventive Medicine|Lister Institute of Preventive Medicine]], developed a method for producing a heat-stable freeze-dried vaccine in powdered form.<ref>{{cite journal | vauthors = Collier LH | title = The development of a stable smallpox vaccine | journal = The Journal of Hygiene | volume = 53 | issue = 1 | pages = 76–101 | date = March 1955 | pmid = 14367805 | pmc = 2217800 | doi = 10.1017/S002217240000053X }}</ref><ref>{{cite news|title=Professor Leslie Collier|work=The Telegraph|access-date=2 May 2013|date=22 March 2011|url=https://www.telegraph.co.uk/news/obituaries/8399116/Professor-Leslie-Collier.html |archive-url=https://ghostarchive.org/archive/20220112/https://www.telegraph.co.uk/news/obituaries/8399116/Professor-Leslie-Collier.html |archive-date=12 January 2022 |url-access=subscription |url-status=live}}{{cbignore}}</ref> Collier added 0.5% [[Chemistry:Phenol|phenol]] to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at {{convert|37|°C}} allowing it to be transported to, and stored in, remote tropical areas. Collier's method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain.<ref name = "Fenner_1988" />{{rp|545, 550}}

In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby, Donald Henderson, chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit".<ref>{{cite journal | vauthors = Baxby D | title = Development of a stable smallpox vaccine: Collier L. J Hyg 1955; 53: 76–101 | journal = Epidemiology and Infection | volume = 133 | issue = Suppl. 1 | pages = S25–S27 | date = October 2005 | pmid = 24965243 | doi = 10.1017/S0950268805004280 | doi-access = free | title-link = doi }}</ref>

Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose.<ref>{{cite book| vauthors = Kirkup JR |title=The Evolution of Surgical Instruments|year=2006|publisher=Norman Publishing|location=Novato, California|isbn=978-0-930405-86-1|pages=419–37}}</ref>

A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin, an American microbiologist working for [[Company:Wyeth|Wyeth]] Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the [[Biology:Bifurcated needle|bifurcated needle]]. This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity.<ref name=Rubin1980>{{cite journal | vauthors = Rubin BA | title = A note on the development of the bifurcated needle for smallpox vaccination | journal = WHO Chronicle | volume = 34 | issue = 5 | pages = 180–181 | date = May 1980 | pmid = 7376638 }}</ref> Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968.<ref name = "Fenner_1988" />{{rp|472–73, 568–72}} Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign.<ref name=Rubin1980/> Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign.<ref>{{cite book| vauthors = Henderson DA |title=Smallpox; the death of a disease|year=2009|publisher=Prometheus Books|location=Amherst, New York|isbn=978-1-59102-722-5|pages=26–27}}</ref>

=== Eradication of smallpox ===
[[Image:Poster for vaccination against smallpox.jpg|right|thumb|upright|Smallpox eradication promotional poster]]


Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a [[Organization:World Health Organization|World Health Organization]] (WHO) unit, set up and headed by Donald Henderson. The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977.<ref name = "Fenner_1988" />{{rp|526–37}} A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980.<ref name = "Fenner_1988" />{{rp|1261–62}} However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal (Janet Parker), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School, the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Mary's Hospital, London were transferred to more secure facilities at Porton Down and then to the U.S. at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia.<ref name = "Fenner_1988" />{{rp|1273–76}} These states report that their repositories are for possible anti-[[Biology:Biological warfare|bioweaponry]] research and insurance if some obscure reservoir of natural smallpox is discovered in the future.{{citation needed|date=July 2020}}<ref>{{cite web |title=Smallpox > Bioterrorism |url=https://www.cdc.gov/smallpox/bioterrorism/public/threat.html |website=U.S. Centers for Disease Control and Prevention (CDC) |access-date=21 May 2022 |date=19 December 2016 |archive-date=19 May 2022 |archive-url=https://web.archive.org/web/20220519202433/https://www.cdc.gov/smallpox/bioterrorism/public/threat.html |url-status=live }} {{PD-notice}}</ref>

=== Anti-terrorism preparation ===

Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable [[Medicine:Myopericarditis|myopericarditis]] were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived.<ref>{{cite journal |display-authors=6 |vauthors=Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA, Gray GC, Ostroff S, Eckart RE, Hospenthal DR, Gibson RL, Grabenstein JD, Arness MK, Tornberg DN |date=June 2003 |title=Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel |journal=JAMA |volume=289 |issue=24 |pages=3283–3289 |doi=10.1001/jama.289.24.3283 |pmid=12824210}}</ref>

In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic.<ref>{{cite book |vauthors=Strom B, Stratton K, Anason AP, Baciu A |url=https://www.nap.edu/read/11240/chapter/6 |title=The Smallpox Vaccination Program: Public Health in an Age of Terrorism |publisher=National Academies Press |year=2005 |isbn=0-309-54877-2 |location=Washington, DC |pages=82–97 |chapter=4. Lessons Learned from the Smallpox Vaccination Program |doi=10.17226/11240 |access-date=21 August 2022 |archive-date=14 March 2022 |archive-url=https://web.archive.org/web/20220314005423/https://www.nap.edu/read/11240/chapter/6 |url-status=live }}</ref> Fewer than 40,000 actually received the vaccine.<ref name="ns2003">{{cite news |date=22 August 2003 |title=US smallpox vaccination plan grinds to a halt |work=New Scientist |url=https://www.newscientist.com/article/dn4074-us-smallpox-vaccination-plan-grinds-to-a-halt/ |url-status=live |access-date=1 September 2019 |archive-url=https://web.archive.org/web/20220207023525/https://www.newscientist.com/article/dn4074-us-smallpox-vaccination-plan-grinds-to-a-halt/ |archive-date=7 February 2022 |vauthors=Mackenzie D}}</ref>

On 21 April 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus.<ref>{{cite web |last=Public Services and Procurement Canada |date=21 April 2022 |title=Third Generation Smallpox Vaccine (6D024-215700/A) |url=https://buyandsell.gc.ca/procurement-data/tender-notice/PW-PH-893-81160 |url-status=live |archive-url=https://web.archive.org/web/20220620184646/https://buyandsell.gc.ca/procurement-data/tender-notice/PW-PH-893-81160 |archive-date=20 June 2022 |access-date=20 June 2022 |website=Government of Canada}}</ref> On 6 May, the contract was awarded to Bavarian Nordic for their Imvamune vaccine.<ref>{{cite web |vauthors=Osman L |date=20 May 2022 |title=Canada considering smallpox vaccine for monkeypox cases, says Dr. Theresa Tam |url=https://www.ctvnews.ca/health/canada-considering-smallpox-vaccine-for-monkeypox-cases-says-dr-theresa-tam-1.5913357 |url-status=live |access-date=20 June 2022 |website=CTV News |archive-date=20 June 2022 |archive-url=https://web.archive.org/web/20220620202548/https://www.ctvnews.ca/health/canada-considering-smallpox-vaccine-for-monkeypox-cases-says-dr-theresa-tam-1.5913357 }}</ref> These were deployed by the [[Organization:Public Health Agency of Canada|Public Health Agency of Canada]] for targeted vaccination in response to the [[Medicine:2022 monkeypox outbreak|2022 monkeypox outbreak]].<ref>{{cite web |last=[[Organization:Public Health Agency of Canada|Public Health Agency of Canada]] |date=24 May 2022 |title=Statement from the Minister of Health on Canada's Response to Monkeypox |url=https://www.canada.ca/en/public-health/news/2022/05/statement-from-the-minister-of-health-on-canadas-response-to-monkeypox.html |access-date=26 May 2022 |website=Government of Canada |archive-date=11 June 2022 |archive-url=https://web.archive.org/web/20220611020614/https://www.canada.ca/en/public-health/news/2022/05/statement-from-the-minister-of-health-on-canadas-response-to-monkeypox.html |url-status=live }}</ref>

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

In 1939, Allan Watt Downie showed that the vaccinia virus was [[Biology:Serology|serologically]] distinct from the "spontaneous" cowpox virus.<ref name="downie1939">{{cite journal | vauthors = Downie AW |title=The Immunological Relationship of the Virus of Spontaneous Cowpox to Vaccinia Virus |journal=British Journal of Experimental Pathology |date=April 1939 |volume=20 |issue=2 |pages=158–76 |pmc=2065307 |issn=0007-1021}}</ref> This work established [[Medicine:Vaccinia|vaccinia]] and cowpox as two separate viral species. The term ''[[Medicine:Vaccinia|vaccinia]]'' now refers only to the smallpox vaccine,<ref>{{cite encyclopedia | vauthors = Smith GL, Vanderplasschen A |title=Extracellular Enveloped Vaccinia virus: Entry, Egress, and Evasion | veditors = Enjuanes L, Siddel SG, Spaan W |encyclopedia=Coronaviruses and Arteriviruses |date=1998 |volume=440 |publisher=Springer Science & Business Media |isbn=978-0-306-45910-8 |page=396|pmid=9782308 }}</ref> while cowpox no longer has a Latin name.<ref>{{cite encyclopedia |title=ICTV Taxonomy history: Cowpox virus |url=https://ictv.global/taxonomy/taxondetails?taxnode_id=201904769 |date=14 April 2021 |quote=Varidnaviria > Bamfordvirae > Nucleocytoviricota > Pokkesviricetes > Chitovirales > Poxviridae > Chordopoxvirinae > Orthopoxvirus > Cowpox virus |access-date=15 April 2021 |archive-date=15 April 2021 |archive-url=https://web.archive.org/web/20210415161543/https://talk.ictvonline.org/taxonomy/p/taxonomy-history?taxnode_id=201904769 |url-status=live }}</ref> The development of [[Biology:Whole genome sequencing|whole genome sequencing]] in the 1990s made it possible to compare [[Biology:Orthopoxvirus|orthopoxvirus]] genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to ''vaccinia''.<ref>{{cite journal | vauthors = Tulman ER, Delhon G, Afonso CL, Lu Z, Zsak L, Sandybaev NT, Kerembekova UZ, Zaitsev VL, Kutish GF, Rock DL | display-authors = 6 | title = Genome of horsepox virus | journal = Journal of Virology | volume = 80 | issue = 18 | pages = 9244–9258 | date = September 2006 | pmid = 16940536 | doi = 10.1128/JVI.00945-06 | pmc = 1563943 }}</ref> In a [[Biology:Phylogenetic tree|phylogenetic tree]] of the [[Biology:Orthopoxvirus|orthopoxvirus]]es, horsepox forms a [[Biology:Clade|clade]] with ''vaccinia'' strains, and cowpox strains form a different clade.<ref name="carroll2011"/>

Horsepox is extinct in the wild, and the only known sample was collected in 1976.<ref>{{cite journal | vauthors = Esparza J | title = Has horsepox become extinct? | journal = The Veterinary Record | volume = 173 | issue = 11 | pages = 272–273 | date = September 2013 | pmid = 24057497 | doi = 10.1136/vr.f5587 | s2cid = 36975171 | doi-access = free }}</ref> Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of ''vaccinia'' that had escaped into the wild.<ref name="duggan2020"/> However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern ''vaccinia'' strains. A smallpox vaccine manufactured by [[Company:H. K. Mulford Company|Mulford]] in 1902 is 99.7% similar to horsepox, closer than any previously known strain of ''vaccinia''.<ref>{{cite journal | vauthors = Schrick L, Tausch SH, Dabrowski PW, Damaso CR, Esparza J, Nitsche A | title = An Early American Smallpox Vaccine Based on Horsepox | journal = The New England Journal of Medicine | volume = 377 | issue = 15 | pages = 1491–1492 | date = October 2017 | pmid = 29020595 | doi = 10.1056/NEJMc1707600 | doi-access = free }}</ref> Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of ''vaccinia''.<ref name="damaso2017">{{cite journal |vauthors=Damaso CR |title=Revisiting Jenner's mysteries, the role of the Beaugency lymph in the evolutionary path of ancient smallpox vaccines |journal=The Lancet Infectious Diseases |date=February 2018 |volume=18 |issue=2 |pages=e55–e63 |doi=10.1016/S1473-3099(17)30445-0 |pmid=28827144 |url=https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30445-0/fulltext |access-date=13 June 2022 |archive-date=21 May 2020 |archive-url=https://web.archive.org/web/20200521124915/https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30445-0/fulltext |url-status=live }}</ref> Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox,<ref name="duggan2020">{{cite journal | vauthors = Duggan AT, Klunk J, Porter AF, Dhody AN, Hicks R, Smith GL, Humphreys M, McCollum AM, Davidson WB, Wilkins K, Li Y, Burke A, Polasky H, Flanders L, Poinar D, Raphenya AR, Lau TT, Alcock B, McArthur AG, Golding GB, Holmes EC, Poinar HN | display-authors = 6 | title = The origins and genomic diversity of American Civil War Era smallpox vaccine strains | journal = Genome Biology | volume = 21 | issue = 1 | pages = 175 | date = July 2020 | pmid = 32684155 | doi = 10.1186/s13059-020-02079-z | pmc = 7370420 | doi-access = free }}</ref> as well as the 1902 Mulford vaccine.<ref name="brinkmann2020"/> One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in ''vaccinia''.<ref name="brinkmann2020">{{cite journal | vauthors = Brinkmann A, Souza AR, Esparza J, Nitsche A, Damaso CR | title = Re-assembly of nineteenth-century smallpox vaccine genomes reveals the contemporaneous use of horsepox and horsepox-related viruses in the USA | journal = Genome Biology | volume = 21 | issue = 1 | pages = 286 | date = December 2020 | pmid = 33272280 | doi = 10.1186/s13059-020-02202-0 | pmc = 7716468 | doi-access = free }}</ref>

==Terminology==
The word "vaccine" is derived from ''Variolae vaccinae'' (i.e. smallpox of the cow), the term devised by Jenner to denote cowpox and used in the long title of his ''An enquiry into the causes and effects of Variolae vaccinae, known by the name of cow pox''.<ref name=Baxby1999>{{cite journal | vauthors = Baxby D | title = Edward Jenner's Inquiry; a bicentenary analysis | journal = Vaccine | volume = 17 | issue = 4 | pages = 301–307 | date = January 1999 | pmid = 9987167 | doi = 10.1016/S0264-410X(98)00207-2 }}</ref> [[Biology:Vaccination|Vaccination]], the term which soon replaced ''cowpox inoculation'' and ''vaccine inoculation'', was first used in print by Jenner's friend, Richard Dunning in 1800.<ref name=Bailey1996>{{cite journal | vauthors = Bailey I | title = Edward Jenner (1749–1823): naturalist, scientist, country doctor, benefactor to mankind | journal = Journal of Medical Biography | volume = 4 | issue = 2 | pages = 63–70 | date = May 1996 | pmid = 11616266 | doi = 10.1177/096777209600400201 | s2cid = 30318738 }}</ref> Initially, the terms ''vaccine''/''vaccination'' referred only to smallpox, but in 1881 Louis Pasteur proposed at the ''7th International Congress of Medicine''<ref>{{cite book | url=https://catalog.hathitrust.org/Record/001579591 | title=Transactions of the International medical congress, seventh session, held in London, August 2d to 9th, 1881. | year=1881 | publisher=J. W. Kolckmann | access-date=23 May 2022 | archive-date=23 May 2022 | archive-url=https://web.archive.org/web/20220523202648/https://catalog.hathitrust.org/Record/001579591 | url-status=live }}</ref> that to honour Jenner the terms be widened to cover the new protective inoculations being introduced.<ref>{{cite journal | vauthors = Esparza J, Lederman S, Nitsche A, Damaso CR | title = Early smallpox vaccine manufacturing in the United States: Introduction of the "animal vaccine" in 1870, establishment of "vaccine farms", and the beginnings of the vaccine industry | journal = Vaccine | volume = 38 | issue = 30 | pages = 4773–4779 | date = June 2020 | pmid = 32473878 | pmc = 7294234 | doi = 10.1016/j.vaccine.2020.05.037 | quote = To honor Jenner, in 1881 Louis Pasteur proposed at the 7th International Congress of Medicine held in London, to generalize the term "vaccination" to refer to all protective immunization procedures against any infectious diseases [19] and since then we talk about vaccines against different diseases. }}</ref> According to some sources the term was first introduced by Jenner's friend ''Richard Dunning'' in 1800.<ref>{{cite journal | vauthors = Baxby D | title = Edward Jenner's inquiry after 200 years | journal = BMJ | volume = 318 | issue = 7180 | pages = 390 | date = February 1999 | pmid = 9933209 | pmc = 1114848 | doi = 10.1136/bmj.318.7180.390 | quote = Unjustified credit is sometimes given to Jenner for introducing the terms virus (already long used to indicate a transmissible poison) and vaccination (introduced by his friend Richard Dunning in 1800. }}</ref>

== References ==
{{Reflist}}

== External links ==
* [https://www.cdc.gov/smallpox/ Smallpox] US Centers for Disease Control and Prevention
* [https://www.cidrap.umn.edu/infectious-disease-topics/smallpox Smallpox] Center for Infectious Disease Research and Policy
* {{cite web | title=Smallpox/Monkeypox Vaccine Information Statement | website=U.S. Centers for Disease Control and Prevention (CDC) | date=November 2022 | url=https://www.cdc.gov/vaccines/hcp/vis/vis-statements/smallpox-monkeypox.html }}
* {{cite web | title=Interim Clinical Considerations for Use of JYNNEOS and ACAM2000 Vaccines during the 2022 U.S. Mpox Outbreak | website=U.S. Centers for Disease Control and Prevention (CDC) | date=2 August 2023 | url=https://www.cdc.gov/poxvirus/mpox/clinicians/vaccines/vaccine-considerations.html | access-date=3 September 2023}}</ref>
* {{cite web | title=Medication Guide Smallpox (Vaccinia) Vaccine, Live ACAM2000 | publisher=Emergent Biosolutions | url=https://www.fda.gov/media/75800/download | format=PDF }}

{{Vaccines}}

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[[Category:Smallpox vaccines| ]]

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