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Human cytomegalovirus containing foreign antigen

A technology of human cytomegalovirus and heterologous antigen, applied in the field of vaccine platform, can solve the problem that primary cells are difficult to achieve

Active Publication Date: 2021-07-06
OREGON HEALTH & SCI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this often requires the generation of complementing cell lines, which is difficult to achieve with the primary cells used to grow CMV

Method used

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  • Human cytomegalovirus containing foreign antigen
  • Human cytomegalovirus containing foreign antigen
  • Human cytomegalovirus containing foreign antigen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Embodiment 1.HCMV-TR3 carrier platform

[0082] Clinical use of effector memory T cell-inducing CMV vectors requires vectors that are genetically stable and maintain persistent infection, but lack the ability to confer on immunocompromised subjects in which HCMV is pathogenic. Previous attenuation strategies for HCMV variants entering clinical trials relied on serial passage of the virus in fibroblasts (Plotkin SA et al., J Infect Dis 134, 470-475 (1976); incorporated herein by reference), attenuated versus non-attenuated Recombination of HCMV strains (Heineman J et al. 2006, supra) or generation of replication-deficient recombinant vectors (WO2013 / 036465; incorporated herein by reference). However, the resulting virus retains pathogenicity or loses beneficial characteristics, such as the ability to establish latent infection or secondary infection in a subject previously naturally infected with CMV.

[0083] An HCMV vector platform, HCMV-TR3, that overcomes these limi...

Embodiment 2

[0088] Example 2. HCMV-TR is superior to other HCMV strains in establishing latent infection

[0089] A humanized mouse model that allows for the study of HCMV latency and reactivation is described in Smith MS et al., Cell Host Microbe 8, 284-291 (2010) (incorporated herein by reference). This model was used to demonstrate that HCMV-TR is superior to other HCMV strains (AD169, Toledo) in establishing persistent infection. Persistent infection is important for the induction of effector memory T cells. The ability to generate persistent infection is independent of the UL128-150 region, which is mutated in many HCMV strains, including all strains previously used in clinical trials of HCMV vaccines (AD169, Towne and Toledo). Restoration of UL131A in the AD169 strain did not restore the ability to establish latency, but HCMV-TRΔ4 strains lacking UL128-150 maintained the ability to establish latency ( Figure 1B ). Note that these previous clinical trials did not involve HCMV con...

Embodiment 3

[0090] Example 3. HCMV-TR3 is sensitive to ganciclovir and contains the US2-7 region, whereas native HCMV-TR is not

[0091] HCMV TR was cloned by BAC recombination engineering from a virus isolate resistant to the antiviral drug ganciclovir (Smith IL et al., J Infect Dis 176, 69-77 (1997); incorporated herein by reference). Ganciclovir resistance is not a desirable trait in HCMV vectors since treatment with ganciclovir is important in the context of CMV-associated disease caused by HCMV-based vectors. Confirmation of ganciclovir resistance is shown in image 3 middle.

[0092] Insert the complete UL97 gene into HCMVTR ( figure 2 ) to produce a ganciclovir-sensitive carrier. Molecular cloning of further modified HCMV-TR. Insertion of the BAC cassette during the original cloning of the HCMV TR resulted in a deletion of the US2-7 region (Murphy et al., 2003, supra). US2-7 was subsequently identified as a region essential for reinfection of CMV-positive individuals (Hansen ...

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Abstract

Human cytomegalovirus vectors comprising heterologous antigens are disclosed. The vector derived from the TR strain is ganciclovir-sensitive, contains active US2, US3, US6, US7, and UL131A genes, and has a deleterious or inactivating mutation in the UL82 gene that prevents expression of pp71.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 025,348, filed July 16, 2014, entitled HUMAN CYTOMEGALOVIRUS COMPRIZING EXOGENOUS ANTIGENS, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] In general, the field relates to vaccine platforms. More specifically, the field relates to recombinant human cytomegalovirus vectors expressing foreign antigens. Background technique [0004] Animal experiments have demonstrated that cytomegalovirus (CMV)-loaded vaccines are unique in that they: a) induce and sustain a high frequency of extralymphoid T cell responses (so-called effector memory T cells) ; b) superinfect CMV-positive hosts; and c) remain immunogenic even when host-to-host spreads the defect. Furthermore, experiments in animal models have shown that vaccine vectors derived from animal CMV induce protective immune responses against infectious...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N7/01C12N15/869C12N5/10C12N15/38A61K39/21A61P31/18
CPCA61K39/12C12N7/00C12N15/86A61K2039/5256A61K2039/5254C12N2740/16234C12N2710/16143C12N2710/16151C12N2710/16121A61K2039/572A61P31/18Y02A50/30A61K35/33A61K39/0011A61K39/21A61K39/39A61P31/00A61P31/22A61P35/00A61P37/04C07K14/045C07K14/161C12N15/85C12N2740/15034C07K14/005
Inventor 克劳斯·弗吕斯克特·G·汉森杰伊·纳尔逊路易斯·皮克帕特里齐亚·卡波西奥
Owner OREGON HEALTH & SCI UNIV
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