Cytomegalovirus Infection and Vaccine Development

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

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 37711

Special Issue Editor


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Guest Editor
Department of Hematology/HCT, Beckman Research Institute of the City of Hope, Duarte, CA, USA
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

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Keywords

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

Published Papers (9 papers)

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Editorial

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4 pages, 182 KiB  
Editorial
Exciting Times for Cytomegalovirus (CMV) Vaccine Development: Navigating the Pathways toward the Goal of Protecting Infants against Congenital CMV Infection
by Mark R. Schleiss and Don J. Diamond
Vaccines 2020, 8(3), 526; https://doi.org/10.3390/vaccines8030526 - 14 Sep 2020
Cited by 10 | Viewed by 2382
Abstract
The congenital transmission of cytomegalovirus (cCMV) is the most common infectious cause of disability in children in the developed world, and probably globally [...] Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)

Research

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19 pages, 1939 KiB  
Article
MVA-Vectored Pentameric Complex (PC) and gB Vaccines Improve Pregnancy Outcome after Guinea Pig CMV Challenge, but Only gB Vaccine Reduces Vertical Transmission
by Heidi Contreras, Felix Wussow, Claudia Fernández-Alarcón, Craig Bierle, Jenny Nguyen, Don J. Diamond and Mark R. Schleiss
Vaccines 2019, 7(4), 182; https://doi.org/10.3390/vaccines7040182 - 14 Nov 2019
Cited by 10 | Viewed by 3744
Abstract
(1) Background: A congenital cytomegalovirus (cCMV) vaccine is a major research priority, but the essential glycoprotein target(s) remain unclear. We compared CMV gB (gpgB), gH/gL (gp75/gL), and pentameric complex (gpPC, composed of gH/gL/GP129/GP131/GP133) vaccines in a guinea pig CMV (GPCMV) congenital infection model. [...] Read more.
(1) Background: A congenital cytomegalovirus (cCMV) vaccine is a major research priority, but the essential glycoprotein target(s) remain unclear. We compared CMV gB (gpgB), gH/gL (gp75/gL), and pentameric complex (gpPC, composed of gH/gL/GP129/GP131/GP133) vaccines in a guinea pig CMV (GPCMV) congenital infection model. (2) Methods: Modified vaccinia virus Ankara (MVA) vaccines expressing GPCMV glycoproteins were used to immunize GPCMV-seronegative, female Hartley guinea pigs (three-dose series, 3 × 107 pfu/dose). After pregnancy was established, the dams underwent an early third-trimester challenge with salivary gland (SG)-adapted GPCMV. (3) Results: All vaccines elicited GPCMV-specific binding and neutralizing antibodies. Preconception immunization resulted in 19.5-, 4.9-, and 698-fold reductions in maternal DNAemia in MVA-gp75/gL, MVA-gpPC and MVA-gpgB groups, respectively, at day 14, post-SG challenge. Vaccination improved pups’ birth weight and reduced mortality and congenital CMV transmission. In controls, cCMV infection was observed in 100% of pups (mean viral load in all visceral organs, 2.4 × 104 genomes/mg), versus 50% in the gB group (visceral viral load, 9.4 × 102 genomes/mg; p < 0.05). No significant reductions in congenital transmission were noted in the MVA-gp75/gL and MVA-gpPC groups. (4) Conclusions: MVA-vectored gB, gH/gL, and PC vaccines were immunogenic, and protected against maternal DNAemia and pup mortality. These results support the inclusion of multiple glycoprotein complexes in a cCMV vaccine. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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24 pages, 16087 KiB  
Article
Neutralizing Monoclonal Antibodies Reduce Human Cytomegalovirus Infection and Spread in Developing Placentas
by Takako Tabata, Matthew Petitt, June Fang-Hoover, Daniel C. Freed, Fengsheng Li, Zhiqiang An, Dai Wang, Tong-Ming Fu and Lenore Pereira
Vaccines 2019, 7(4), 135; https://doi.org/10.3390/vaccines7040135 - 29 Sep 2019
Cited by 25 | Viewed by 5049
Abstract
Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects worldwide, yet the most effective strategies for preventing virus transmission during pregnancy are unknown. We measured the efficacy of human monoclonal antibodies (mAbs) to HCMV attachment/entry factors glycoprotein B (gB) and [...] Read more.
Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects worldwide, yet the most effective strategies for preventing virus transmission during pregnancy are unknown. We measured the efficacy of human monoclonal antibodies (mAbs) to HCMV attachment/entry factors glycoprotein B (gB) and the pentameric complex, gH/gL-pUL128–131, in preventing infection and spread of a clinical strain in primary placental cells and explants of developing anchoring villi. A total of 109 explants from five first-trimester placentas were cultured, and infection was analyzed in over 400 cell columns containing ~120,000 cytotrophoblasts (CTBs). mAbs to gB and gH/gL, 3-25 and 3-16, respectively, neutralized infection in stromal fibroblasts and trophoblast progenitor cells. mAbs to pUL128-131 of the pentameric complex, 1-103 and 2-18, neutralized infection of amniotic epithelial cells better than mAbs 3-25 and 3-16 and hyperimmune globulin. Select mAbs neutralized infection of cell column CTBs, with mAb 2-18 most effective, followed by mAb 3-25. Treatment of anchoring villi with mAbs postinfection reduced spread in CTBs and impaired formation of virion assembly compartments, with mAb 2-18 achieving better suppression at lower concentrations. These results predict that antibodies generated by HCMV vaccines or used for passive immunization have the potential to reduce transplacental transmission and congenital disease. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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19 pages, 3403 KiB  
Article
Production Strategies for Pentamer-Positive Subviral Dense Bodies as a Safe Human Cytomegalovirus Vaccine
by Patricia Gogesch, Inessa Penner, Steffi Krauter, Nicole Büscher, Leander Grode, Inci Aydin and Bodo Plachter
Vaccines 2019, 7(3), 104; https://doi.org/10.3390/vaccines7030104 - 1 Sep 2019
Cited by 13 | Viewed by 4200
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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Review

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28 pages, 2298 KiB  
Review
Vaccine Vectors Harnessing the Power of Cytomegaloviruses
by Mario Alberto Ynga-Durand, Iryna Dekhtiarenko and Luka Cicin-Sain
Vaccines 2019, 7(4), 152; https://doi.org/10.3390/vaccines7040152 - 17 Oct 2019
Cited by 16 | Viewed by 5217
Abstract
Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. [...] Read more.
Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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13 pages, 683 KiB  
Review
Impact of Maternal Immunity on Congenital Cytomegalovirus Birth Prevalence and Infant Outcomes: A Systematic Review
by Tiziana Coppola, Jesse F. Mangold, Sarah Cantrell and Sallie R. Permar
Vaccines 2019, 7(4), 129; https://doi.org/10.3390/vaccines7040129 - 26 Sep 2019
Cited by 34 | Viewed by 3784
Abstract
Congenital cytomegalovirus (cCMV) is the leading non-genetic cause of sensorineural hearing loss (SNHL), and efforts are geared towards prevention through vaccine development. Transmission rates following primary maternal infection occur at rates of 30–40%, however reported placental rates upon non-primary maternal infection is reported [...] Read more.
Congenital cytomegalovirus (cCMV) is the leading non-genetic cause of sensorineural hearing loss (SNHL), and efforts are geared towards prevention through vaccine development. Transmission rates following primary maternal infection occur at rates of 30–40%, however reported placental rates upon non-primary maternal infection is reported to be less than <4%. There is significant debate about whether this reduction in transmission rate is due to pre-existing maternal immunity, which could identify possible immunologic targets for vaccines. To address this question, we performed a systemic review of the literature using Preferred Reporting Items for Systematic Review and Analysis (PRISMA) guidelines. We identified cohort studies in high CMV seroprevalent (>80%) areas or in developing regions that examined a cohort of at least 50 infants for congenital CMV acquisition. We identified 19 articles that met criteria and were further categorized based on pre-conception serology, maternal seroprevalence, or previously known seroprevalence. Birth prevalence rates ranged from 0.4% to 6% (median 1.1%), with the studies reporting on clinical outcome (16/19 studies) noting the majority of infected infants as asymptomatic. We also utilized a recent study that differentiated primary maternal infections from chronic infections in a highly seropositive population to calculate a placental transmission rate in women with pre-existing immunity compared to that of no pre-existing immunity. This work confirms a low cCMV birth prevalence in highly seropositive populations, indicates via a calculated placental transmission rate that the CMV placental transmission rate is lower in non-primary infection than that of primary infection, and reveals gaps in data for further research aiming to identify targets for vaccine development. Full article
(This article belongs to the Special Issue Cytomegalovirus Infection and Vaccine Development)
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18 pages, 4748 KiB  
Review
Human Cytomegalovirus Cell Tropism and Host Cell Receptors
by Giuseppe Gerna, Anna Kabanova and Daniele Lilleri
Vaccines 2019, 7(3), 70; https://doi.org/10.3390/vaccines7030070 - 22 Jul 2019
Cited by 57 | Viewed by 5487
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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14 pages, 247 KiB  
Review
The Humoral Immune Response Against the gB Vaccine: Lessons Learnt from Protection in Solid Organ Transplantation
by Ariane C. Gomes, Paul D. Griffiths and Matthew B. Reeves
Vaccines 2019, 7(3), 67; https://doi.org/10.3390/vaccines7030067 - 17 Jul 2019
Cited by 12 | Viewed by 3150
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)
15 pages, 635 KiB  
Review
From Vaccine Vector to Oncomodulation: Understanding the Complex Interplay between CMV and Cancer
by Nicole A. Wilski and Christopher M. Snyder
Vaccines 2019, 7(3), 62; https://doi.org/10.3390/vaccines7030062 - 9 Jul 2019
Cited by 18 | Viewed by 3979
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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