{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:34:29Z","timestamp":1787016869671,"version":"build-2736575974"},"reference-count":46,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["314082\/2020-4"],"award-info":[{"award-number":["314082\/2020-4"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"crossref","award":["E-26\/200.949\/2021"],"award-info":[{"award-number":["E-26\/200.949\/2021"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"crossref","award":["AUXPE 2306\/2018"],"award-info":[{"award-number":["AUXPE 2306\/2018"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"crossref","award":["INV-009850"],"award-info":[{"award-number":["INV-009850"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tonix Pharmaceuticals","award":["FECD-Tonix-001\/20"],"award-info":[{"award-number":["FECD-Tonix-001\/20"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2023,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Vaccinia virus is the active component of all modern smallpox vaccines after the mid-20th century, but it is uncertain to what extent cowpox, vaccinia, and horsepox viruses were used to produce vaccines before then. Genome sequences of six smallpox vaccines used in the United States between 1850 and 1902, namely VK01, VK02, VK05, VK08, VK12, and Mulford_1902 vaccines, revealed &gt;99.5% similarity with a 1976 strain of horsepox in the genome core. However, how these historical vaccines relate to horsepox and vaccinia viruses is still unknown. Here, we present a detailed investigation of the gene content and genomic structure of these historical smallpox vaccines. Except for VK05, all historical vaccines differ from horsepox in the genomic architecture of the flanking variable regions showing complex patterns of gene duplication\/transposition, gene fragmentation, and gene loss. The Mulford_1902 vaccine is the closest virus to contemporary vaccinia viruses and the VK02 vaccine is the most different, with several stretches of variola virus genes recombined in its genome. Our data suggest that in the late 19th and early 20th centuries, different horsepox-based vaccines and probably related unsampled progenitors of modern vaccinia virus coexisted. A better understanding of the evolutionary path of the now extinct horsepox-based vaccines will increase our knowledge of the origins of contemporary vaccinia viruses and the pathways that led to the consolidation of current smallpox vaccines. This is particularly important now that the resumption of production of smallpox vaccines for use against mpox is widely discussed, as is the improvement of available vaccines.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Modern smallpox vaccines, such as those used against mpox, are made from vaccinia viruses, but it is still unknown whether cowpox, horsepox, or vaccinia viruses were used in the early 20th century or earlier. The mystery began to be solved when the genomes of six historical smallpox vaccines used in the United States from 1850 to 1902 were determined. Our work analyzed in detail the genomes of these six historical vaccines, revealing a complex genomic structure. Historical vaccines are highly similar to horsepox in the core of their genomes, but some are closer to the structure of vaccinia virus at the ends of the genome. One of the vaccines is a recombinant virus with parts of variola virus recombined into its genome. Our data add valuable information for understanding the evolutionary path of current smallpox vaccines and the genetic makeup of the potentially extinct group of horsepox viruses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01887-23","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T15:37:50Z","timestamp":1695224270000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Gene duplication, gene loss, and recombination events with variola virus shaped the complex evolutionary path of historical American horsepox-based smallpox vaccines"],"prefix":"10.1128","volume":"14","author":[{"given":"Aline R. V.","family":"Souza","sequence":"first","affiliation":[{"name":"Instituto de Biof\u00edsica Carlos Chagas Filho , Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Brinkmann","sequence":"additional","affiliation":[{"name":"Centre for Biological Threats and Special Pathogens 1 \u2013 Highly Pathogenic Viruses &amp; German Consultant Laboratory for Poxviruses &amp; WHO Collaborating Centre for Emerging Infections and Biological Threats, Robert Koch Institute , Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Esparza","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Nitsche","sequence":"additional","affiliation":[{"name":"Centre for Biological Threats and Special Pathogens 1 \u2013 Highly Pathogenic Viruses &amp; German Consultant Laboratory for Poxviruses &amp; WHO Collaborating Centre for Emerging Infections and Biological Threats, Robert Koch Institute , Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6299-2816","authenticated-orcid":false,"given":"Clarissa R.","family":"Damaso","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica Carlos Chagas Filho , Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","volume-title":"Smallpox and its eradication","author":"Fenner F","year":"1988","unstructured":"Fenner F , Henderson DA , Arita I , Jezek Z , Ladnyi ID . 1988. Smallpox and its eradication. World Health Organization, Geneva."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007082"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1707600"},{"key":"e_1_3_4_5_2","volume-title":"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 the cow pox","author":"Jenner E","year":"1798","unstructured":"Jenner E . 1798. 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 the cow pox. Sampson Low, London."},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30445-0"},{"key":"e_1_3_4_7_2","volume-title":"History and pathology of vaccination","author":"Crookshank EM","year":"1889","unstructured":"Crookshank EM . 1889. History and pathology of vaccination. P. Blackiston, Philadelphia."},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.1646.116"},{"key":"e_1_3_4_9_2","first-page":"4","article-title":"An account of the circumstances associated with an outbreak of disease among milch cows, horses, and their attendants, believed to be of the nature of \u201ccow-pox\u201d in the county of somersetshire in the year 1909, and considerations arising thereform","volume":"15","author":"Reece RJ.","year":"1909","unstructured":"Reece RJ. 1909. An account of the circumstances associated with an outbreak of disease among milch cows, horses, and their attendants, believed to be of the nature of \u201ccow-pox\u201d in the county of somersetshire in the year 1909, and considerations arising thereform. Proc R Soc Med 15:4.","journal-title":"Proc R Soc Med"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-0813.1989.tb09788.x"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1505.090159"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0368-1742(17)80022-9"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2017.11.003"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/vr.f5587"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00945-06"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01833-15"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02202-0"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05779-11"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/136.3.453"},{"key":"e_1_3_4_20_2","volume-title":"Jenner\u2019s smallpox vaccine: the riddle of vaccinia virus and its origin","author":"Baxby D","year":"1981","unstructured":"Baxby D . 1981. Jenner\u2019s smallpox vaccine: the riddle of vaccinia virus and its origin. Heinemann Educational Books, London."},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02079-z"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mst010"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/v10110637"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.1.152-160.1999"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msy096"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01495-21"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02797-14"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02015-14"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079953"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2091933"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom13020325"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2022.101286"},{"key":"e_1_3_4_33_2","first-page":"2129","volume-title":"Fields Virology","author":"Moss B","year":"2013","unstructured":"Moss B . 2013. Poxviridae, p 2129\u20132159. In PMH DM Knipe (ed), Fields Virology. Lippincott Willimas & Wilkins."},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/v9090253"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.10.061"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-022-00519-4"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01526-22"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11080896"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/computation2040182"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.868887"},{"key":"e_1_3_4_41_2","volume-title":"Vaccination; its natural history and pathology","author":"Copeman SM","year":"1899","unstructured":"Copeman SM . 1899. Vaccination; its natural history and pathology. Macmillan and Co, London."},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.5342.1367"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15020356"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00022-14"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/v9060142"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/v14102134"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2020.05.037"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01887-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01887-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,11]],"date-time":"2024-08-11T14:31:26Z","timestamp":1723386686000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.01887-23"}},"subtitle":[],"editor":[{"given":"Rino","family":"Rappuoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,10,31]]}},"alternative-id":["10.1128\/mbio.01887-23"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01887-23","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]},"assertion":[{"value":"2023-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01887-23"}}