A live olfactory MCMV vaccine attenuated for systemic spread, protects against superinfection.

2021 ◽  
Author(s):  
Helen E Farrell ◽  
Kimberley Bruce ◽  
Philip G Stevenson
Keyword(s):  
Animal Models ◽  
Human Cytomegalovirus ◽  
Congenital Infection ◽  
Vaccine Design ◽  
Virus Challenge ◽  
Health Goal ◽  
Systemic Spread ◽  
Hcmv Disease ◽  
Public Health Goal ◽  
Vaccine Potential

Vaccination against the β-herpesvirus, human cytomegalovirus (HCMV) is a public health goal. However, HCMV has proved difficult to vaccinate against. Vaccination against single HCMV determinants has not worked, suggesting that immunity to a wider antigenic profile may be required. Live attenuated vaccines provide the best prospects for protection, but the question remains as to how to balance vaccine virulence with safety. Animal models of HCMV infection provide insights into identifying targets for virus attenuation and understanding how host immunity blocks natural, mucosal infection. Here we evaluated the vaccine potential of a mouse cytomegalovirus (MCMV) vaccine deleted of a viral G protein-coupled receptor (GPCR), designated M33, that renders it attenuated for systemic spread. A single non-invasive olfactory ΔM33 MCMV vaccine replicated locally, but as a result of the loss of the M33 GPCR, it failed to spread systemically and was attenuated for latent infection. Vaccination did not prevent host entry of a superinfecting MCMV but spread from the mucosa was blocked. This approach to vaccine design may provide a viable alternative for a safe and effective β-herpesvirus vaccine. IMPORTANCE Human cytomegalovirus (HCMV) is the most common cause of congenital infection for which a vaccine is not yet available. Subunit vaccine candidates have failed to achieve licensure. A live HCMV vaccine may prove more efficacious, but it faces safety hurdles which include its propensity to persist and to establish latency. Understanding how pathogens infect guide rational vaccine design. However, HCMV infections are asymptomatic and thus difficult to capture. Animal models of experimental infection provide insight. Here we investigated the vaccine potential of a MCMV attenuated for systemic spread and latency. We used olfactory vaccination and virus challenge to mimic its natural acquisition. We provide proof-of-concept that a single olfactory MCMV that is deficient in systemic spread, can protect against wild type MCMV superinfection and dissemination. This approach of deleting functional counterpart genes in HCMV may provide safe and effective vaccination against congenital HCMV disease.

scholarly journals Diagnosis and Management of Human Cytomegalovirus Infection in the Mother, Fetus, and Newborn Infant

2002 ◽  
Vol 15 (4) ◽  
pp. 680-715 ◽  
Author(s):  
Maria Grazia Revello ◽  
Giuseppe Gerna
Keyword(s):  
Prenatal Diagnosis ◽  
Human Cytomegalovirus ◽  
Primary Infection ◽  
Hcmv Infection ◽  
Prognostic Markers ◽  
Recurrent Infection ◽  
Congenital Infection ◽  
Immunoglobulin M ◽  
Hcmv Disease ◽  
The Impact

SUMMARY Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection and mental retardation. HCMV infection, while causing asymptomatic infections in most immunocompetent subjects, can be transmitted during pregnancy from the mother with primary (and also recurrent) infection to the fetus. Hence, careful diagnosis of primary infection is required in the pregnant woman based on the most sensitive serologic assays (immunoglobulin M [IgM] and IgG avidity assays) and conventional virologic and molecular procedures for virus detection in blood. Maternal prognostic markers of fetal infection are still under investigation. If primary infection is diagnosed in a timely manner, prenatal diagnosis can be offered, including the search for virus and virus components in fetal blood and amniotic fluid, with fetal prognostic markers of HCMV disease still to be defined. However, the final step for definite diagnosis of congenital HCMV infection is detection of virus in the blood or urine in the first 1 to 2 weeks of life. To date, treatment of congenital infection with antiviral drugs is only palliative both prior to and after birth, whereas the only efficacious preventive measure seems to be the development of a safe and immunogenic vaccine, including recombinant, subunit, DNA, and peptide-based vaccines now under investigation. The following controversial issues are discussed in the light of the most recent advances in the field: the actual perception of the problem; universal serologic screening before pregnancy; the impact of correct counseling on decision making by the couple involved; the role of prenatal diagnosis in ascertaining transmission of virus to the fetus; the impact of preconceptional and periconceptional infections on the prevalence of congenital infection; and the prevalence of congenitally infected babies born to mothers who were immune prior to pregnancy compared to the number born to mothers undergoing primary infection during pregnancy.

Animal models of human cytomegalovirus congenital infection

2015 ◽  
Vol 36 (4) ◽  
pp. 196
Author(s):  
Helen Farrell
Keyword(s):  
Animal Models ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Phylogenetic Analyses ◽  
Congenital Infection ◽  
Host Responses ◽  
Laboratory Animals ◽  
Natural Hosts ◽  
Congenital Hcmv Infection ◽  
Species Specific

Human cytomegalovirus (HCMV) infection is highly species-specific, which means that it is unable to productively infect laboratory animals. Despite this caveat, studies of animal CMV counterparts in their natural hosts have revealed significant correlations with observed neuropathological effects of congenital HCMV infection and have improved our understanding of host responses to vaccination. The biological relatedness between human and animal CMVs has been confirmed by phylogenetic analyses; the conservation of ‘core' genes that are essential for virus replication as well as genes that contribute similar mechanisms for virus persistence in their respective host species. The common animal models of HCMV congenital infection include Rhesus CMV (RhCMV), guinea-pig CMV (GPCMV) and mouse CMV (MCMV). Whilst animal models of CMV do not fully recapitulate HCMV infection, they each offer specific advantages in understanding HCMV congenital/perinatal infection (summarised in Table 1).

scholarly journals Development of a Vaccine against Human Cytomegalovirus: Advances, Barriers, and Implications for the Clinical Practice

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 551
Author(s):  
Sara Scarpini ◽  
Francesca Morigi ◽  
Ludovica Betti ◽  
Arianna Dondi ◽  
Carlotta Biagi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Human Cytomegalovirus ◽  
Congenital Infection ◽  
Health Concern ◽  
Live Vaccines ◽  
Target Populations ◽  
Immune Correlates ◽  
Common Causes ◽  
The Status ◽  
Life Threatening

Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymptomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, unclear immune correlates for protection, low number of available animal models, and insufficient general awareness. Moreover, there is a need to determine which may be the best target populations for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines undergoing clinical trials and understand barriers limiting their development.

scholarly journals California sets public health goal for perchlorate

2004 ◽  
Vol 38 (10) ◽  
pp. 177A-178A ◽  
Author(s):  
Rebecca Renner
Keyword(s):  
Public Health ◽  
Health Goal ◽  
Public Health Goal

scholarly journals Human Cytomegalovirus UL144 Is Associated with Viremia and Infant Development Sequelae in Congenital Infection

2010 ◽  
Vol 48 (11) ◽  
pp. 3956-3962 ◽  
Author(s):  
A. Waters ◽  
J. Hassan ◽  
C. deGascun ◽  
G. Kissoon ◽  
S. Knowles ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Infant Development ◽  
Congenital Infection

scholarly journals Human Cytomegalovirus Genomes Sequenced Directly from Clinical Material: Variation, Multiple-Strain Infection, Recombination and Mutation

2018 ◽  
Author(s):  
Nicolás M. Suárez ◽  
Gavin S. Wilkie ◽  
Elias Hage ◽  
Salvatore Camiolo ◽  
Marylouisa Holton ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
High Throughput Sequencing ◽  
Clinical Pathology ◽  
Congenital Infection ◽  
Population Based ◽  
Single Strain ◽  
Natural Mutation ◽  
Future Population

ABSTRACTThe genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination and natural mutation. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analysed, in the process facilitating the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating diversity, (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination, (iii) mutants with non-functional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae, and (iv) intrahost diversity in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology and pathogenesis of HCMV.

scholarly journals Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection

2020 ◽  
Author(s):  
Matthew L. Goodwin ◽  
Helen S. Webster ◽  
Hsuan-Yuan Wang ◽  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Effector Cell ◽  
Natural Infection ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Domain Specificity ◽  
Cell Functions ◽  
The Impact

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection, and the leading nongenetic cause of sensorineural hearing loss (SNHL) in newborns globally. A gB subunit vaccine administered with adjuvent MF59 (gB/MF59) is the most efficacious tested to-date, achieving 50% efficacy in preventing infection of HCMV-seronegative mothers. We recently discovered that gB/MF59 vaccination elicited primarily non-neutralizing antibody responses, that HCMV strains acquired by vaccinees more often included strains with gB genotypes that are distinct from the vaccine antigen, and that protection against HCMV acquisition correlated with ability of vaccine-elicited antibodies to bind to membrane associated gB. Thus, we hypothesized that gB-specific non-neutralizing antibody binding breadth and function are dependent on their epitope and genotype specificity as well as their ability to interact with membrane-associated gB. Twenty-four gB-specific monoclonal antibodies (mAbs) isolated from naturally HCMV-infected individuals were mapped for gB domain specificity by binding antibody multiplex assay (BAMA) and for genotype preference binding to membrane-associated gB presented on transfected cells. We defined their non-neutralizing functions including antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC). The isolated gB-specific non-neutralizing mAbs were primarily specific for Domain II and linear antigenic domain 2 site 2 (AD2). We observed variability in mAb gB genotype binding preference, with increased binding to gB genotypes 2 and 4. Functional studies identified two gB-specific mAbs that facilitate ADCP and have binding specificities of AD2 and Domain II. This investigation provides novel understanding on the impact of gB domain specificity and antigenic variability on gB-specific non-neutralizing antibody responses.ImportanceHCMV is the most common congenital infection worldwide, but development of a successful vaccine remains elusive. gB-specific non-neutralizing mAbs, represent a distinct anti-HCMV Ab subset implicated in the protection against primary infection during numerous phase-II gB/MF59 vaccine trials. By studying non-neutralizing gB-specific mAbs from naturally infected individuals, this study provides novel characterization of binding site specificity, genotypic preference, and effector cell functions mediated by mAbs elicited in natural infection. We found that a panel of twenty-four gB-specific non-neutralizing mAbs bind across multiple regions of the gB protein, traditionally through to be targeted by neutralizing mAbs only, and bind differently to gB depending if the protein is soluble versus embedded in a membrane. This investigation provides novel insight into the gB-specific binding characteristics and effector cell functions mediated by non-neutralizing gB-specific mAbs elicited through natural infection, providing new endpoints for future vaccine development.

scholarly journals Overview on Cigarettes and Other Tobacco Products Act and its implementation: current update

2020 ◽  
Vol 8 (1) ◽  
pp. 463
Author(s):  
Dhwanit Thakore ◽  
Mahesh Chavda ◽  
Girish Parmar ◽  
Tejal Sheth
Keyword(s):  
Public Health ◽  
Tobacco Control ◽  
Tobacco Use ◽  
Control Measures ◽  
Public Health Issue ◽  
Tobacco Products ◽  
Health Goal ◽  
The Status ◽  
Public Health Goal ◽  
Almost All

Tobacco use- a major public health issue in India has an enormous effect on the lower SES population. . There is an evident link between tobacco use or consumption and poverty. The widespread use of almost all forms of tobacco among the Indian population can be attributed to the social and cultural acceptance in the country. Cigarette and Other Tobacco Products Act, 2003 (COTPA) is the legislation that regulates tobacco in India. The prime objective of this review is to compile the literature with information about the laws regulating tobacco use and the status of implementation of tobacco control provisions covered under COTPA. Since effective tobacco control measures involve multi-stakeholders i.e public health, law, trade and commerce, industry, consumer, human rights and child development, coordinated efforts are required to successful enforcement. The outcome of the current literature is bridging the gaps to make the tobacco control a very important public health goal and thereby protect the population from the consequent morbidity and mortality due to tobacco use.

A Novel Peptide Aldehyde with Activity against Human Cytomegalovirus in Two Different in Vivo Models

2000 ◽  
Vol 11 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Olaf Weber ◽  
Jürgen Reefschläger ◽  
Helga Rübsamen-Waigmann ◽  
Siegfried Raddatz ◽  
Matthias Hesseling ◽  
...  
Keyword(s):  
Animal Models ◽  
Antiviral Activity ◽  
Clinical Isolate ◽  
Human Cytomegalovirus ◽  
Murine Cytomegalovirus ◽  
Human Tissues ◽  
In Vivo Models ◽  
Peptide Aldehydes

Novel peptide aldehydes (PAs) were identified as potent inhibitors of human cytomegalovirus (HCMV) in vitro. Although these compounds were highly effective against HCMV, they did not exhibit any activity against murine cytomegalovirus (MCMV). The purpose of this study was to test the antiviral activity of PA 8 as a representative of this novel class of inhibitors against HCMV in vivo. Because of the strict species specificity of HCMV we had to use two artificial animal models. In the first model, HCMV-infected human cells were entrapped into agarose plugs and transplanted into mice. In the second model, SCID mice were transplanted with human tissues that were subsequently infected with a clinical isolate of HCMV. In these two models the antiviral activity of PA 8 was clearly demonstrated, ganciclovir only being slightly superior in its in vivo antiviral activity.

scholarly journals Human Cytomegalovirus Genomes Sequenced Directly From Clinical Material: Variation, Multiple-Strain Infection, Recombination, and Gene Loss

2019 ◽  
Vol 220 (5) ◽  
pp. 781-791 ◽  
Author(s):  
Nicolás M Suárez ◽  
Gavin S Wilkie ◽  
Elias Hage ◽  
Salvatore Camiolo ◽  
Marylouisa Holton ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
High Throughput Sequencing ◽  
Gene Loss ◽  
Clinical Pathology ◽  
Congenital Infection ◽  
Population Based ◽  
Single Strain ◽  
Future Population

AbstractThe genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination, and gene loss. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analyzed, in the process enabling the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating variation; (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination; (iii) mutants with nonfunctional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae; and (iv) intrahost variation in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology, and pathogenesis of HCMV.

Sign in / Sign up

Export Citation Format

Share Document