Design of a highly effective therapeutic HPV16 E6/E7-specific DNA vaccine: optimization by different ways of sequence rearrangements (shuffling)
Persistent infection with the high-risk Human Papillomavirus type 16 (HPV 16) is the causative event for the development of cervical cancer and other malignant tumors of the anogenital tract and of the head and neck. Despite many attempts to develop therapeutic vaccines no candidate has entered late...
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| Veröffentlicht in: | PloS one 2014-11, Vol.9 (11), p.e113461-e113461 |
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| creator | Almajhdi, Fahad N Senger, Tilo Amer, Haitham M Gissmann, Lutz Öhlschläger, Peter |
| description | Persistent infection with the high-risk Human Papillomavirus type 16 (HPV 16) is the causative event for the development of cervical cancer and other malignant tumors of the anogenital tract and of the head and neck. Despite many attempts to develop therapeutic vaccines no candidate has entered late clinical trials. An interesting approach is a DNA based vaccine encompassing the nucleotide sequence of the E6 and E7 viral oncoproteins. Because both proteins are consistently expressed in HPV infected cells they represent excellent targets for immune therapy. Here we report the development of 8 DNA vaccine candidates consisting of differently rearranged HPV-16 E6 and E7 sequences within one molecule providing all naturally occurring epitopes but supposedly lacking transforming activity. The HPV sequences were fused to the J-domain and the SV40 enhancer in order to increase immune responses. We demonstrate that one out of the 8 vaccine candidates induces very strong cellular E6- and E7- specific cellular immune responses in mice and, as shown in regression experiments, efficiently controls growth of HPV 16 positive syngeneic tumors. This data demonstrates the potential of this vaccine candidate to control persistent HPV 16 infection that may lead to malignant disease. It also suggests that different sequence rearrangements influence the immunogenecity by an as yet unknown mechanism. |
| doi_str_mv | 10.1371/journal.pone.0113461 |
| format | Article |
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Despite many attempts to develop therapeutic vaccines no candidate has entered late clinical trials. An interesting approach is a DNA based vaccine encompassing the nucleotide sequence of the E6 and E7 viral oncoproteins. Because both proteins are consistently expressed in HPV infected cells they represent excellent targets for immune therapy. Here we report the development of 8 DNA vaccine candidates consisting of differently rearranged HPV-16 E6 and E7 sequences within one molecule providing all naturally occurring epitopes but supposedly lacking transforming activity. The HPV sequences were fused to the J-domain and the SV40 enhancer in order to increase immune responses. We demonstrate that one out of the 8 vaccine candidates induces very strong cellular E6- and E7- specific cellular immune responses in mice and, as shown in regression experiments, efficiently controls growth of HPV 16 positive syngeneic tumors. This data demonstrates the potential of this vaccine candidate to control persistent HPV 16 infection that may lead to malignant disease. It also suggests that different sequence rearrangements influence the immunogenecity by an as yet unknown mechanism.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0113461</identifier><identifier>PMID: 25422946</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alphapapillomavirus - immunology ; Animals ; Anogenital ; Antibodies, Viral - biosynthesis ; Antigenic determinants ; Antigens ; Biology and Life Sciences ; Cell Line, Tumor ; Cervical cancer ; Clinical trials ; Deoxyribonucleic acid ; Development and progression ; Disease control ; DNA ; DNA vaccines ; Epitopes ; Female ; Gene expression ; Gene sequencing ; Head ; Head and neck ; Health aspects ; Health risks ; Human papillomavirus ; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 ; Humans ; Immune response ; Immune response (cell-mediated) ; Infection ; Infections ; Medical research ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Neoplasms, Experimental - pathology ; Nucleotide sequence ; Oncogene Proteins, Viral - immunology ; Optimization ; Papillomavirus E7 Proteins - immunology ; Papillomavirus infections ; Papillomavirus Vaccines - genetics ; Peptides ; Persistent infection ; Proteins ; Repressor Proteins - immunology ; Research and Analysis Methods ; Tumors ; Vaccines ; Vaccines, DNA - genetics ; Virology ; Viruses ; Womens health</subject><ispartof>PloS one, 2014-11, Vol.9 (11), p.e113461-e113461</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Almajhdi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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It also suggests that different sequence rearrangements influence the immunogenecity by an as yet unknown mechanism.</description><subject>Alphapapillomavirus - immunology</subject><subject>Animals</subject><subject>Anogenital</subject><subject>Antibodies, Viral - biosynthesis</subject><subject>Antigenic determinants</subject><subject>Antigens</subject><subject>Biology and Life Sciences</subject><subject>Cell Line, Tumor</subject><subject>Cervical cancer</subject><subject>Clinical trials</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>Disease control</subject><subject>DNA</subject><subject>DNA vaccines</subject><subject>Epitopes</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Head</subject><subject>Head and neck</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>Human papillomavirus</subject><subject>Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune response (cell-mediated)</subject><subject>Infection</subject><subject>Infections</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Neoplasms, Experimental - 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Despite many attempts to develop therapeutic vaccines no candidate has entered late clinical trials. An interesting approach is a DNA based vaccine encompassing the nucleotide sequence of the E6 and E7 viral oncoproteins. Because both proteins are consistently expressed in HPV infected cells they represent excellent targets for immune therapy. Here we report the development of 8 DNA vaccine candidates consisting of differently rearranged HPV-16 E6 and E7 sequences within one molecule providing all naturally occurring epitopes but supposedly lacking transforming activity. The HPV sequences were fused to the J-domain and the SV40 enhancer in order to increase immune responses. We demonstrate that one out of the 8 vaccine candidates induces very strong cellular E6- and E7- specific cellular immune responses in mice and, as shown in regression experiments, efficiently controls growth of HPV 16 positive syngeneic tumors. This data demonstrates the potential of this vaccine candidate to control persistent HPV 16 infection that may lead to malignant disease. It also suggests that different sequence rearrangements influence the immunogenecity by an as yet unknown mechanism.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25422946</pmid><doi>10.1371/journal.pone.0113461</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alphapapillomavirus - immunology Animals Anogenital Antibodies, Viral - biosynthesis Antigenic determinants Antigens Biology and Life Sciences Cell Line, Tumor Cervical cancer Clinical trials Deoxyribonucleic acid Development and progression Disease control DNA DNA vaccines Epitopes Female Gene expression Gene sequencing Head Head and neck Health aspects Health risks Human papillomavirus Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 Humans Immune response Immune response (cell-mediated) Infection Infections Medical research Medicine and Health Sciences Mice Mice, Inbred C57BL Neoplasms, Experimental - pathology Nucleotide sequence Oncogene Proteins, Viral - immunology Optimization Papillomavirus E7 Proteins - immunology Papillomavirus infections Papillomavirus Vaccines - genetics Peptides Persistent infection Proteins Repressor Proteins - immunology Research and Analysis Methods Tumors Vaccines Vaccines, DNA - genetics Virology Viruses Womens health |
| title | Design of a highly effective therapeutic HPV16 E6/E7-specific DNA vaccine: optimization by different ways of sequence rearrangements (shuffling) |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-11T09%3A49%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Design%20of%20a%20highly%20effective%20therapeutic%20HPV16%20E6/E7-specific%20DNA%20vaccine:%20optimization%20by%20different%20ways%20of%20sequence%20rearrangements%20(shuffling)&rft.jtitle=PloS%20one&rft.au=Almajhdi,%20Fahad%20N&rft.date=2014-11-25&rft.volume=9&rft.issue=11&rft.spage=e113461&rft.epage=e113461&rft.pages=e113461-e113461&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0113461&rft_dat=%3Cgale_plos_%3EA417793725%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1627987238&rft_id=info:pmid/25422946&rft_galeid=A417793725&rft_doaj_id=oai_doaj_org_article_69341370faab41b49cde57428b39b47d&rfr_iscdi=true |