Krauter, Steffi and Buescher, Nicole and Braeuchle, Eric and Ortega Iannazzo, Samira and Penner, Inessa and Kraemer, Nadine and Gogesch, Patricia and Thomas, Simone and Kreutz, Marina and Dejung, Mario and Freiwald, Anja and Butter, Falk and Waibler, Zoe and Plachter, Bodo (2022) An Attenuated Strain of Human Cytomegalovirus for the Establishment of a Subviral Particle Vaccine. VACCINES, 10 (8): 1326. ISSN , 2076-393X
Full text not available from this repository. (Request a copy)Abstract
Human cytomegalovirus (HCMV) infection is associated with severe disease conditions either following congenital transmission of the virus or viral reactivation in immunosuppressed individuals. Consequently, the establishment of a protective vaccine is of high medical need. Several candidates have been tested in preclinical and clinical studies, yet no vaccine has been licensed. Subviral dense bodies (DB) are a promising vaccine candidate. We have recently provided a GMP-compliant protocol for the production of DB, based on a genetically modified version of the HCMV laboratory strain Towne, expressing the pentameric complex of envelope protein gH-gL-pUL128-131 (Towne-UL130rep). In this work, we genetically attenuated Towne-UL130rep by abrogating the expression of the tegument protein pUL25 and by fusing the destabilizing domain ddFKBP to the N-terminus of the IE1- and IE2-proteins of HCMV. The resulting strain, termed TR-VAC, produced high amounts of DB under TE1/IE2 repressive conditions and concomitant supplementation of the viral terminase inhibitor letermovir to the producer cell culture. TR-VAC DB retained the capacity to induce neutralizing antibodies. A complex pattern of host protein induction was observed by mass spectrometry following exposure of primary human monocytes with TR-VAC DB. Human monocyte-derived dendritic cells (DC) moderately increased the expression of activation markers and MHC molecules upon stimulation with TR-VAC DB. In a co-culture with autologous T cells, the TR-VAC DB-stimulated DC induced a robust HCMV-specific T cell-activation and -proliferation. Exposure of donor-derived monocytic cells to DB led to the activation of a rapid innate immune response. This comprehensive data set thus shows that TR-VAC is an optimal attenuated seed virus strain for the production of a DB vaccine to be tested in clinical studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; CELLULAR IMMUNE-RESPONSES; DENSE BODIES; NEUTRALIZING ANTIBODIES; INFECTED CELLS; CMV VACCINE; PROTEIN; EXPRESSION; REPLICATION; ACTIVATION; human cytomegalovirus; vaccine; subviral particles; dense bodies; conditional expression; ddFKBP; IE1/IE2; UL25 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Feb 2024 07:15 |
| Last Modified: | 27 Feb 2024 07:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57843 |
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