Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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
_version_ 1783480469151547392
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
work_keys_str_mv AT caposiopatrizia characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT vandenwormsjoerd characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT crawfordlindsey characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT perezwilma characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT kreklywichcraig characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT gilbrideroxannem characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT hughescolettem characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT venturaabigailb characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT rattsrobert characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT marshallemilye characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT maloulidaniel characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT axthelmmichaelk characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT streblowdaniel characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT nelsonjaya characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT pickerlouisj characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT hansenscottg characterizationofaliveattenuatedhcmvbasedvaccineplatform
AT fruhklaus characterizationofaliveattenuatedhcmvbasedvaccineplatform