Characterization of a live-attenuated HCMV-based vaccine platform

Patrizia Caposio, Sjoerd van den Worm, Lindsey Crawford, Wilma Perez, Craig Kreklywich, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Robert Ratts, Emily E. Marshall, Daniel Malouli, Michael K. Axthelm, Daniel Streblow, Jay A. Nelson, Louis J. Picker, Scott G. Hansen, Klaus Früh

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 (TEM) 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 TEM 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 TEM 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.

Original languageEnglish (US)
Article number19236
JournalScientific Reports
Issue number1
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • General


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