Editing Smallpox vaccine (section)

===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>