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Characterization of a live-attenuated HCMV-based vaccine platform
Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. Vaccine efficacy is associated with the ability of CMV to elicit and indefinitely maintain high frequencies of circulating effector memory T cells (T(EM)) providing continuous, life-long...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917771/ https://www.ncbi.nlm.nih.gov/pubmed/31848362 http://dx.doi.org/10.1038/s41598-019-55508-w |
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author | Caposio, Patrizia van den Worm, Sjoerd Crawford, Lindsey Perez, Wilma Kreklywich, Craig Gilbride, Roxanne M. Hughes, Colette M. Ventura, Abigail B. Ratts, Robert Marshall, Emily E. Malouli, Daniel Axthelm, Michael K. Streblow, Daniel Nelson, Jay A. Picker, Louis J. Hansen, Scott G. Früh, Klaus |
author_facet | Caposio, Patrizia van den Worm, Sjoerd Crawford, Lindsey Perez, Wilma Kreklywich, Craig Gilbride, Roxanne M. Hughes, Colette M. Ventura, Abigail B. Ratts, Robert Marshall, Emily E. Malouli, Daniel Axthelm, Michael K. Streblow, Daniel Nelson, Jay A. Picker, Louis J. Hansen, Scott G. Früh, Klaus |
author_sort | Caposio, Patrizia |
collection | PubMed |
description | Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. Vaccine efficacy is associated with the ability of CMV to elicit and indefinitely maintain high frequencies of circulating effector memory T cells (T(EM)) providing continuous, life-long anti-pathogen immune activity. To allow for the clinical testing of human CMV (HCMV)-based vaccines we constructed and characterized as a vector backbone the recombinant molecular clone TR3 representing a wildtype genome. We demonstrate that TR3 can be stably propagated in vitro and that, despite species incompatibility, recombinant TR3 vectors elicit high frequencies of T(EM) to inserted antigens in rhesus macaques (RM). Live-attenuated versions of TR3 were generated by deleting viral genes required to counteract intrinsic and innate immune responses. In addition, we eliminated subunits of a viral pentameric glycoprotein complex thus limiting cell tropism. We show in a humanized mouse model that such modified vectors were able to establish persistent infection but lost their ability to reactivate from latency. Nevertheless, attenuated TR3 vectors preserved the ability to elicit and maintain T(EM) to inserted antigens in RM. We further demonstrate that attenuated TR3 can be grown in approved cell lines upon elimination of an anti-viral host factor using small interfering RNA, thus obviating the need for a complementing cell line. In sum, we have established a versatile platform for the clinical development of live attenuated HCMV-vectored vaccines and immunotherapies. |
format | Online Article Text |
id | pubmed-6917771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69177712019-12-19 Characterization of a live-attenuated HCMV-based vaccine platform Caposio, Patrizia van den Worm, Sjoerd Crawford, Lindsey Perez, Wilma Kreklywich, Craig Gilbride, Roxanne M. Hughes, Colette M. Ventura, Abigail B. Ratts, Robert Marshall, Emily E. Malouli, Daniel Axthelm, Michael K. Streblow, Daniel Nelson, Jay A. Picker, Louis J. Hansen, Scott G. Früh, Klaus Sci Rep Article Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. Vaccine efficacy is associated with the ability of CMV to elicit and indefinitely maintain high frequencies of circulating effector memory T cells (T(EM)) providing continuous, life-long anti-pathogen immune activity. To allow for the clinical testing of human CMV (HCMV)-based vaccines we constructed and characterized as a vector backbone the recombinant molecular clone TR3 representing a wildtype genome. We demonstrate that TR3 can be stably propagated in vitro and that, despite species incompatibility, recombinant TR3 vectors elicit high frequencies of T(EM) to inserted antigens in rhesus macaques (RM). Live-attenuated versions of TR3 were generated by deleting viral genes required to counteract intrinsic and innate immune responses. In addition, we eliminated subunits of a viral pentameric glycoprotein complex thus limiting cell tropism. We show in a humanized mouse model that such modified vectors were able to establish persistent infection but lost their ability to reactivate from latency. Nevertheless, attenuated TR3 vectors preserved the ability to elicit and maintain T(EM) to inserted antigens in RM. We further demonstrate that attenuated TR3 can be grown in approved cell lines upon elimination of an anti-viral host factor using small interfering RNA, thus obviating the need for a complementing cell line. In sum, we have established a versatile platform for the clinical development of live attenuated HCMV-vectored vaccines and immunotherapies. Nature Publishing Group UK 2019-12-17 /pmc/articles/PMC6917771/ /pubmed/31848362 http://dx.doi.org/10.1038/s41598-019-55508-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Caposio, Patrizia van den Worm, Sjoerd Crawford, Lindsey Perez, Wilma Kreklywich, Craig Gilbride, Roxanne M. Hughes, Colette M. Ventura, Abigail B. Ratts, Robert Marshall, Emily E. Malouli, Daniel Axthelm, Michael K. Streblow, Daniel Nelson, Jay A. Picker, Louis J. Hansen, Scott G. Früh, Klaus Characterization of a live-attenuated HCMV-based vaccine platform |
title | Characterization of a live-attenuated HCMV-based vaccine platform |
title_full | Characterization of a live-attenuated HCMV-based vaccine platform |
title_fullStr | Characterization of a live-attenuated HCMV-based vaccine platform |
title_full_unstemmed | Characterization of a live-attenuated HCMV-based vaccine platform |
title_short | Characterization of a live-attenuated HCMV-based vaccine platform |
title_sort | characterization of a live-attenuated hcmv-based vaccine platform |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917771/ https://www.ncbi.nlm.nih.gov/pubmed/31848362 http://dx.doi.org/10.1038/s41598-019-55508-w |
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