A Phase 1 Study of 4 Live, Recombinant Human Cytomegalovirus Towne/Toledo Chimeric Vaccines

Heineman, Thomas C.; Schleiss, Mark R.; Bernstein, David I.; Spaete, Richard R.; Yan, Lihan; Duke, Gregory; Prichard, Mark N.; Wang, Zhaoti; Yan, Qiaoyuan; Sharp, Margaret; Klein, Nicola P.; Arvin, Ann M.; Kemble, George

doi:10.1086/503365

Cited by 91 publications

(70 citation statements)

References 40 publications

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“…In studies with a total of nearly 1,000 human subjects, the Towne vaccine has been evaluated for safety and efficacy in renal transplant recipients (11,12) and HCMV-seronegative mothers of young children who were actively shedding virus (13). Because of inadequate efficacy in clinical trials, efforts to improve the immunogenicity of the Towne vaccine have included the generation of chimeric viruses containing both Towne sequences and sequences from the less attenuated Toledo strain (14), the evaluation of prime-boost strategies (15), and the coadministration of Towne vaccine with recombinant interleukin-12 (16). The molecular basis of attenuation of the Towne vaccine is uncertain, although a mutation in the Towne UL130 gene coding sequence that abrogates the synthesis of a functional UL130 protein (17), a component of the pentameric complex (PC) of HCMV proteins that have recently received considerable attention as potential HCMV subunit vaccine candidates, has been described (18).…”

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confidence: 99%

Vaccination with a Live Attenuated Cytomegalovirus Devoid of a Protein Kinase R Inhibitory Gene Results in Reduced Maternal Viremia and Improved Pregnancy Outcome in a Guinea Pig Congenital Infection Model

Schleiss

Bierle

Swanson

et al. 2015

J Virol

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Development of a vaccine to prevent congenital cytomegalovirus infection is a major public health priority. Live vaccines attenuated through mutations targeting viral mechanisms responsible for evasion of host defense may be both safe and efficacious. Safety and vaccine efficacy were evaluated using a guinea pig cytomegalovirus (GPCMV) model. Recombinant GPCMV with a targeted deletion of gp145 (designated ⌬145), a viral protein kinase R (PKR) inhibitor, was generated. Attenuation was evaluated following inoculation of 10 7 PFU of ⌬145 or parental virus into guinea pigs immunosuppressed with cyclophosphamide. Efficacy was evaluated by immunizing GPCMV-naive guinea pigs twice with either 10 5 or 10 6 PFU of ⌬145, establishing pregnancy, and challenging the guinea pigs with salivary gland-adapted GPCMV. The immune response, maternal viral load, pup mortality, and congenital infection rates in the vaccine and control groups were compared. ⌬145 was substantially attenuated for replication in immunocompromised guinea pigs. Vaccination with ⌬145 induced enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody levels comparable to those achieved in natural infection. In the higher-and lower-dose vaccine groups, pup mortality was reduced to 1/24 (4%) and 4/29 (14%) pups, respectively, whereas it was 26/31 (81%) in unvaccinated control pups (P < 0.0001 for both groups versus the control group). Congenital infection occurred in 20/31 (65%) control pups but only 8/24 (33%) pups in the group vaccinated with 10 6 PFU (P < 0.05). Significant reductions in the magnitude of maternal DNAemia and pup viral load were noted in the vaccine groups compared to those in the controls. Deletion of a GPCMV genome-encoded PKR inhibitor results in a highly attenuated virus that is immunogenic and protective as a vaccine against transplacental infection. Infection with human cytomegalovirus (HCMV) causes considerable morbidity and occasional mortality in immunocompromised solid organ transplant and hematopoietic stem cell transplant patients, HIV-infected individuals, and newborns that acquire infection in utero (1, 2). Due to the lifelong morbidity associated with congenital CMV infection, a preconception vaccine capable of preventing virus transmission to the fetus would provide a highly cost-effective public health advance (3). Unfortunately, the lack of clear immunological correlates of protective immunity has hampered development of an HCMV vaccine. In spite of this uncertainty, there is evidence that virus-neutralizing antibody responses targeting viral envelope glycoproteins, as well as cellular immune responses (CD4 ϩ and CD8 ϩ ) targeting multiple structural and regulatory proteins, play important roles in protection against acquisition and reactivation of infection (4-7).

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confidence: 99%

Vaccination with a Live Attenuated Cytomegalovirus Devoid of a Protein Kinase R Inhibitory Gene Results in Reduced Maternal Viremia and Improved Pregnancy Outcome in a Guinea Pig Congenital Infection Model

Schleiss

Bierle

Swanson

et al. 2015

J Virol

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“…Specific antigenic differences between the attenuated virus and natural isolates and differences in the levels of antigen presented by the attenuated virus and potentially other factors may all have contributed to these differences. With the goal of improving the Towne vaccine, chimeric viruses were developed to transfer genes from the low-passagenumber strain Toledo into the Towne vaccine strain, and these viruses were well tolerated in a small phase I trial (41,42). Other live virus HCMV vaccine candidates may emerge from the efforts to restore the gH/gL/UL128/UL130/UL131A complex to an attenuated strain (17).…”

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confidence: 99%

Cytomegalovirus Vaccine Strain Towne-Derived Dense Bodies Induce Broad Cellular Immune Responses and Neutralizing Antibodies That Prevent Infection of Fibroblasts and Epithelial Cells

Cayatte

Schneider-Ohrum

Wang

et al. 2013

J Virol

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“…The characterized strain Toledo UL/bЈ sequence has at some stage undergone a sequence inversion that inactivates UL128, a gene required for endothelial tropism. Repairing the deletion in the Towne strain with the strain Toledo UL/bЈ sequence was not sufficient to restore virulence (24), yet it did confer a much enhanced capacity to resist natural killer cell (NK) recognition (54). The UL/bЈ sequence has been predicted to encode 23 additional open reading frames, including genes implicated in regulating viral tropism (UL128 to UL131A) (15,23) and immune modulation, including two chemokine homologues (UL146, UL147) (42,49) and a tumor necrosis factor receptor homologue (UL144) (2), and confers remarkable protection against NK attack (10,58) associated with the NK evasion functions UL141 and UL142 (12,54,57,62).…”

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confidence: 99%

Cytomegalovirus Destruction of Focal Adhesions Revealed in a High-Throughput Western Blot Analysis of Cellular Protein Expression

Stanton¹,

McSharry²,

Rickards³

et al. 2007

J Virol

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Human cytomegalovirus (HCMV) is a clinically important herpesvirus associated with severe disease following congenital infection and in immunocompromised individuals. As a herpesvirus, primary infection is accompanied by lifelong persistence during which the infection must be controlled by continuous host immune surveillance. HCMV has the largest genome of any characterized human virus (ϳ236 kb) and is predicted to encode on the order of 165 potential open reading frames (15). Systematic deletion of individual open reading frames from the Towne strain revealed that only 45 are essential for virus replication in vitro; thus, accessory genes account for most of the HCMV coding capacity (16). While the functions of most of these genes have not been determined, a significant number have been implicated in the targeting of both the innate and adaptive host immune responses (40). HCMV has also recently been shown to express microRNAs during productive infection that also have the potential to modulate host cell gene expression (17,21,43). A high-throughput proteomic approach was used in this study with a view to providing further insight into how the virus may modulate its host cell.HCMV replicates slowly in permissive human fibroblasts, with gene expression conventionally being divided into three phases: immediate-early (IE), early, and late (reviewed in reference 40). Early-phase transcription precedes viral DNA replication (initiates at 16 to 24 h postinfection [hpi]), with significant virus production detected from 72 hpi and peaking at approximately 144 hpi. Productive HCMV infection is associated with an overall stimulation of both cellular transcription and translation (50). Virion binding (13, 59), release of virion tegument proteins following virion fusion (6, 36), and de novo expression of powerful transcriptional regulators (most notably, IE2 and IE1) during infection all modulate cellular gene expression. Following infection, while cellular proteins associated with DNA metabolism are induced, host cell cyclins are dysregulated and licensing of host cell DNA replication is inhibited, resulting in a "pseudo-G 1 " environment compatible with efficient virus DNA replication (3,5,25). Microarray experiments have proved highly informative in revealing the dynamic regulation of steady-state levels of cellular transcripts, both positively and negatively, during the course of infection (7,26,48,65,66). HCMV is known not only to regulate transcriptional initiation but also to control RNA processing (1,9,14,20,35,63), translation, and posttranslational modification and protein trafficking (31,34,44,54,61). The result of many of these processes is liable to be an alteration of host cell protein levels.

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A Phase 1 Study of 4 Live, Recombinant Human Cytomegalovirus Towne/Toledo Chimeric Vaccines

Abstract: The Towne/Toledo chimeric vaccine candidates were well tolerated and did not cause systemic infection. Additional human trials are warranted to further evaluate the potential of these vaccine candidates as live virus vaccines.

Cited by 91 publications

References 40 publications

Vaccination with a Live Attenuated Cytomegalovirus Devoid of a Protein Kinase R Inhibitory Gene Results in Reduced Maternal Viremia and Improved Pregnancy Outcome in a Guinea Pig Congenital Infection Model

Vaccination with a Live Attenuated Cytomegalovirus Devoid of a Protein Kinase R Inhibitory Gene Results in Reduced Maternal Viremia and Improved Pregnancy Outcome in a Guinea Pig Congenital Infection Model

Cytomegalovirus Vaccine Strain Towne-Derived Dense Bodies Induce Broad Cellular Immune Responses and Neutralizing Antibodies That Prevent Infection of Fibroblasts and Epithelial Cells

Cytomegalovirus Destruction of Focal Adhesions Revealed in a High-Throughput Western Blot Analysis of Cellular Protein Expression

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