Editing Smallpox vaccine (section)

==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 [[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=[[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===
[[File:Dried smallpox vaccine.jpg|left|thumb|274x274px|Ovine smallpox vaccine, manufactured by growing live ''vaccinia'' in sheep, 1980s<ref>{{Cite web |title=1613.002 {{!}} Collections Online |url=https://collections.thackraymuseum.co.uk/object-1613-002 |access-date=29 May 2024 |website=collections.thackraymuseum.co.uk}}</ref>]]
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 [[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=[[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 [[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=<!-- Official 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 | title-link = doi }}</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 | title-link = doi }}</ref>

===Second-generation===

The second-generation vaccines consist of live ''vaccinia'' virus grown in the [[chorioallantoic membrane]] or [[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]], [[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 [[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]] (RIVM) 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-RIVM 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{{cn|date=April 2025}}.

[[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 [[MRC-5]] cells to make the ACAM1000 vaccine. After a successful phase I trial of ACAM1000, the virus was passaged three times in [[Vero cell]]s to develop ACAM2000, which entered mass production at [[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 | 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 | title-link = doi }}</ref>

ACAM2000 was approved for mpox prevention in the United States in August 2024.<ref name="FDA ACAM2000">{{cite web | title=ACAM2000 | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 August 2024 | url=https://www.fda.gov/vaccines-blood-biologics/vaccines/acam2000 | access-date=1 September 2024 | archive-date=17 October 2019 | archive-url=https://web.archive.org/web/20191017062633/https://www.fda.gov/vaccines-blood-biologics/vaccines/acam2000 | url-status=dead }}</ref><ref name="FDA PR 20240830">{{cite press release | title=FDA Roundup: August 30, 2024 | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 August 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-roundup-august-30-2024 | access-date=1 September 2024 | archive-date=1 September 2024 | archive-url=https://web.archive.org/web/20240901025048/https://www.fda.gov/news-events/press-announcements/fda-roundup-august-30-2024 | url-status=dead }}</ref><ref>{{cite press release | title=Emergent Biosolutions' ACAM2000, (Smallpox and Mpox (Vaccinia) Vaccine, Live) Receives U.S. FDA Approval for Mpox Indication; Public Health Mpox Outbreak Continues Across Africa & Other Regions | publisher=Emergent Biosolutions | via=GlobeNewswire | date=29 August 2024 | url=https://www.globenewswire.com/en/news-release/2024/08/29/2938196/33240/en/Emergent-BioSolutions-ACAM2000-Smallpox-and-Mpox-Vaccinia-Vaccine-Live-Receives-U-S-FDA-Approval-for-Mpox-Indication-Public-Health-Mpox-Outbreak-Continues-Across-Africa-Other-Regio.html | access-date=1 September 2024 | archive-date=1 September 2024 | archive-url=https://web.archive.org/web/20240901025044/https://www.globenewswire.com/en/news-release/2024/08/29/2938196/33240/en/Emergent-BioSolutions-ACAM2000-Smallpox-and-Mpox-Vaccinia-Vaccine-Live-Receives-U-S-FDA-Approval-for-Mpox-Indication-Public-Health-Mpox-Outbreak-Continues-Across-Africa-Other-Regio.html | url-status=live }}</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 ====
[[Modified vaccinia Ankara]] (MVA, {{langx|de|Modifiziertes Vakziniavirus Ankara}}) is a replication-incompetent variant of ''vaccinia'' that was developed in West Germany through [[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 [[Ludwig Maximilian University of Munich|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 | 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 | title-link = doi | 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=[[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 | 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 |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=dead }}</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 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |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 [[Intradermal injection|intradermally]] to increase the number of available doses.<ref>{{cite web |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=U.S. [[Centers for Disease Control and Prevention]] (CDC) |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'' 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 |date=16 August 2013 |access-date=2 October 2014 |publisher=[[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=[[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=[[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. [[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=dead | 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. [[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=dead | 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 | 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 [[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=U.S. [[Centers for Disease Control and Prevention]] (CDC) |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 |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 [[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>