Special Issue "Cytomegalovirus Infection and Vaccine Development"

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editor

Guest Editor
Prof. Dr. Don J. Diamond Website E-Mail
Department of Hematology/HCT, Beckman Research Institute of the City of Hope, Duarte, California, USA
Phone: 626-218-3450
Interests: Cytomegalovirus; vaccines; immune response; T cells; neutralizing antibodies; viral vectors; peptides; antigen receptors

Special Issue Information

Dear Colleagues,

The Type 5 herpes virus cytomegalovirus (CMV) has been extensively studied since its discovery in 1956. The immunology of infection has been of high interest, since it was discovered that transplant recipients, either stem cell or solid organ, develop T cell responses to viral antigens. The first successful adoptive immunotherapy was applied to stem cell transplant recipients as a therapy to protect against CMV viremia. Throughout the last four decades, various subunit and whole virus vaccine strategies have been developed and tested in transplant recipients with mixed results. Simultaneously, vaccine strategies to protect the developing fetus from maternal CMV infection have been pursued. The best results, and they are imperfect, have been with protein-based gB vaccine formulations. In this monograph, we will consider a selection of CMV vaccine strategies as solutions to the dual problem of prophylaxis of women of child-bearing years and the therapy of the immunosuppressed transplant recipient. While CMV viruses are exquisitely species-specific, homologous viruses and animal models have contributed to a better understanding of the correlates of protective immunity. While there is no licensed CMV vaccine for any population, there is considerable will to overcome the obstacles that hinder the successful development of either a prophylactic or a therapeutic vaccine.

Prof. Dr. Don J. Diamond
Guest Editor

Manuscript Submission Information

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Keywords

  • Cytomegalovirus
  • Immune response
  • T cells
  • Neutralizing antibodies
  • Viral vectors
  • RNA vaccines
  • Pentamer
  • Glycoproteins
  • Congenital infection
  • Viremia
  • Transplantation

Published Papers (4 papers)

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Open AccessFeature PaperReview
Human Cytomegalovirus Cell Tropism and Host Cell Receptors
Vaccines 2019, 7(3), 70; https://doi.org/10.3390/vaccines7030070 - 22 Jul 2019
Abstract
In the 1970s–1980s, a striking increase in the number of disseminated human cytomegalovirus (HCMV) infections occurred in immunosuppressed patient populations. Autopsy findings documented the in vivo disseminated infection (besides fibroblasts) of epithelial cells, endothelial cells, and polymorphonuclear leukocytes. As a result, multiple diagnostic [...] Read more.
In the 1970s–1980s, a striking increase in the number of disseminated human cytomegalovirus (HCMV) infections occurred in immunosuppressed patient populations. Autopsy findings documented the in vivo disseminated infection (besides fibroblasts) of epithelial cells, endothelial cells, and polymorphonuclear leukocytes. As a result, multiple diagnostic assays, such as quantification of HCMV antigenemia (pp65), viremia (infectious virus), and DNAemia (HCMV DNA) in patient blood, were developed. In vitro experiments showed that only low passage or endothelial cell-passaged clinical isolates, and not laboratory-adapted strains, could reproduce both HCMV leuko- and endothelial cell-tropism, which were found through genetic analysis to require the three viral genes UL128, UL130, and UL131 of the HCMV UL128 locus (UL128L). Products of this locus, together with gH/gL, were shown to form the gH/gL/pUL128L pentamer complex (PC) required for infection of epithelial cells/endothelial cells, whereas gH/gL and gO form the gH/gL/gO trimer complex (TC) required for infection of all cell types. In 2016, following previous work, a receptor for the TC that mediates entry into fibroblasts was identified as PDGFRα, while in 2018, a receptor for the PC that mediates entry into endothelial/epithelial cells was identified as neuropilin2 (Nrp2). Furthermore, the olfactory receptor family member OR14I1 was recently identified as a possible additional receptor for the PC in epithelial cells. Thus, current data support two models of viral entry: (i) in fibroblasts, following interaction of PDGFRα with TC, the latter activates gB to fuse the virus envelope with the cell membrane, whereas (ii) in epithelial cells/endothelial cells, interaction of Nrp2 (and OR14I1) with PC promotes endocytosis of virus particles, followed by gB activation by gH/gL/gO (or gH/gL) and final low-pH entry into the cell. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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Open AccessReview
The Humoral Immune Response Against the gB Vaccine: Lessons Learnt from Protection in Solid Organ Transplantation
Vaccines 2019, 7(3), 67; https://doi.org/10.3390/vaccines7030067 - 17 Jul 2019
Abstract
Human cytomegalovirus (hCMV) is considered to be the highest priority for vaccine development. This view is underscored by the significant morbidity associated with congenital hCMV infection and viraemia in transplant patients. Although a number of vaccines have been trialed, none have been licensed. [...] Read more.
Human cytomegalovirus (hCMV) is considered to be the highest priority for vaccine development. This view is underscored by the significant morbidity associated with congenital hCMV infection and viraemia in transplant patients. Although a number of vaccines have been trialed, none have been licensed. The hCMV vaccine candidate that has performed best in clinical trials to date is the recombinant glycoprotein B (gB) vaccine that has demonstrated protection, ranging from a 43% to 50% efficacy in three independent phase II trials. In this review, we focus on data from the phase II trial performed in solid organ transplant patients and the outcomes of follow-up studies attempting to identify immunological and mechanistic correlates of protection associated with this vaccine strategy. We relate this to other vaccine studies of gB as well as other vaccine strategies to determine areas of commonality and divergence. Finally, through the review, we discuss the unique challenges and opportunities presented with vaccine studies in transplant populations with recommendations that could empower subsequent trials. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
Open AccessReview
From Vaccine Vector to Oncomodulation: Understanding the Complex Interplay between CMV and Cancer
Vaccines 2019, 7(3), 62; https://doi.org/10.3390/vaccines7030062 - 09 Jul 2019
Abstract
Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent, but generally asymptomatic, infection in most people in the world. However, CMV drives and sustains extremely large numbers of antigen-specific T cells and is, therefore, emerging as an exciting platform for vaccines against infectious [...] Read more.
Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent, but generally asymptomatic, infection in most people in the world. However, CMV drives and sustains extremely large numbers of antigen-specific T cells and is, therefore, emerging as an exciting platform for vaccines against infectious diseases and cancer. Indeed, pre-clinical data strongly suggest that CMV-based vaccines can sustain protective CD8+ T cell and antibody responses. In the context of vaccines for infectious diseases, substantial pre-clinical studies have elucidated the efficacy and protective mechanisms of CMV-based vaccines, including in non-human primate models of various infections. In the context of cancer vaccines, however, much less is known and only very early studies in mice have been conducted. To develop CMV-based cancer vaccines further, it will be critical to better understand the complex interaction of CMV and cancer. An array of evidence suggests that naturally-acquired human (H)CMV can be detected in cancers, and it has been proposed that HCMV may promote tumor growth. This would obviously be a concern for any therapeutic cancer vaccines. In experimental models, CMV has been shown to play both positive and negative roles in tumor progression, depending on the model studied. However, the mechanisms are still largely unknown. Thus, more studies assessing the interaction of CMV with the tumor microenvironment are needed. This review will summarize the existing literature and major open questions about CMV-based vaccines for cancer, and discuss our hypothesis that the balance between pro-tumor and anti-tumor effects driven by CMV depends on the location and the activity of the virus in the lesion. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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Open AccessConcept Paper
Production Strategies for Pentamer-Positive Subviral Dense Bodies as a Safe Human Cytomegalovirus Vaccine
Vaccines 2019, 7(3), 104; https://doi.org/10.3390/vaccines7030104 - 01 Sep 2019
Abstract
Infections with the human cytomegalovirus (HCMV) are associated with severe clinical manifestations in children following prenatal transmission and after viral reactivation in immunosuppressed individuals. The development of an HCMV vaccine has long been requested but there is still no licensed product available. Subviral [...] Read more.
Infections with the human cytomegalovirus (HCMV) are associated with severe clinical manifestations in children following prenatal transmission and after viral reactivation in immunosuppressed individuals. The development of an HCMV vaccine has long been requested but there is still no licensed product available. Subviral dense bodies (DB) are immunogenic in pre-clinical models and are thus a promising HCMV vaccine candidate. Recently, we established a virus based on the laboratory strain Towne that synthesizes large numbers of DB containing the pentameric protein complex gH/gL/UL128-131 (Towne-UL130repΔGFP). The work presented here focuses on providing strategies for the production of a safe vaccine based on that strain. A GMP-compliant protocol for DB production was established. Furthermore, the DB producer strain Towne-UL130rep was attenuated by deleting the UL25 open reading frame. Additional genetic modifications aim to abrogate its capacity to replicate in vivo by conditionally expressing pUL51 using the Shield-1/FKBP destabilization system. We further show that the terminase inhibitor letermovir can be used to reduce infectious virus contamination of a DB vaccine by more than two orders of magnitude. Taken together, strategies are provided here that allow for the production of a safe and immunogenic DB vaccine for clinical testing. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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