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Proceedings of the National Academy of... Aug 2022With the rapid increase in SARS-CoV-2 cases in children, a safe and effective vaccine for this population is urgently needed. The MMR (measles/mumps/rubella) vaccine has...
With the rapid increase in SARS-CoV-2 cases in children, a safe and effective vaccine for this population is urgently needed. The MMR (measles/mumps/rubella) vaccine has been one of the safest and most effective human vaccines used in infants and children since the 1960s. Here, we developed live attenuated recombinant mumps virus (rMuV)-based SARS-CoV-2 vaccine candidates using the MuV Jeryl Lynn (JL2) vaccine strain backbone. The soluble prefusion SARS-CoV-2 spike protein (preS) gene, stablized by two prolines (preS-2P) or six prolines (preS-6P), was inserted into the MuV genome at the P-M or F-SH gene junctions in the MuV genome. preS-6P was more efficiently expressed than preS-2P, and preS-6P expression from the P-M gene junction was more efficient than from the F-SH gene junction. In mice, the rMuV-preS-6P vaccine was more immunogenic than the rMuV-preS-2P vaccine, eliciting stronger neutralizing antibodies and mucosal immunity. Sera raised in response to the rMuV-preS-6P vaccine neutralized SARS-CoV-2 variants of concern, including the Delta variant equivalently. Intranasal and/or subcutaneous immunization of IFNAR1 mice and golden Syrian hamsters with the rMuV-preS-6P vaccine induced high levels of neutralizing antibodies, mucosal immunoglobulin A antibody, and T cell immune responses, and were completely protected from challenge by both SARS-CoV-2 USA-WA1/2020 and Delta variants. Therefore, rMuV-preS-6P is a highly promising COVID-19 vaccine candidate, warranting further development as a tetravalent MMR vaccine, which may include protection against SARS-CoV-2.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Immunogenicity, Vaccine; Measles-Mumps-Rubella Vaccine; Mesocricetus; Mice; Mumps virus; Proline; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vaccine Efficacy; Vaccines, Attenuated
PubMed: 35895717
DOI: 10.1073/pnas.2201616119 -
Molecular Therapy Oncolytics 2016Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as...
Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as a treatment for human cancer four decades ago in Japan. These clinical studies demonstrated that mumps virus could be a promising cancer therapeutic agent that showed significant antitumor activity against various types of cancers. Since oncolytic virotherapy was not in the limelight until the beginning of the 21(st) century, the interest to pursue mumps virus for cancer treatment slowly faded away. Recent success stories of oncolytic clinical trials prompted us to resurrect the mumps virus and to explore its potential for cancer treatment. We have obtained the Urabe strain of mumps virus from Osaka University, Japan, which was used in the earlier human clinical trials. In this report we describe the development of a reverse genetics system from a major isolate of this Urabe strain mumps virus stock, and the construction and characterization of several recombinant mumps viruses with additional transgenes. We present initial data demonstrating these recombinant mumps viruses have oncolytic activity against tumor cell lines in vitro and some efficacy in preliminary pilot animal tumor models.
PubMed: 27556105
DOI: 10.1038/mto.2016.19 -
BMC Infectious Diseases Jan 2017Mumps emerged among highly vaccinated populations in the Netherlands. This offered a unique opportunity to study mumps virus transmission. In particular the extent to...
BACKGROUND
Mumps emerged among highly vaccinated populations in the Netherlands. This offered a unique opportunity to study mumps virus transmission. In particular the extent to which asymptomatic infections in vaccinated people contribute to ongoing mumps virus transmission is uncertain. Insight into this could help project the future burden of mumps in vaccinated populations. We therefore studied the relative infectiousness of symptomatic and asymptomatic cases.
METHODS
In a cohort study we followed contacts of notified mumps cases (ring 1) and contacts' contacts (ring 2) for 40 days to ascertain symptoms of mumps and social contacts by weekly diaries and questionnaires, and mumps virus infections by taking finger stick dried blood spot specimens (DBS) that were tested for mumps-specific IgG antibodies. Mumps IgG concentrations >1500 RU/ml in a single sample, a four-fold increase in IgG antibody concentration in paired samples, or a positive oral fluid PCR were defined as recent infection.
RESULTS
We recruited 99 contacts (40 in ring 1 and 59 in ring 2) of 10 mumps index cases. The median age of participants was 23 years (range 18-57 years), 31 (31%) were male. At study entry, DBS of 4 out of 78 (5%) participants with samples showed serological evidence of recent mumps virus infection. Three of these reported mumps symptoms. Among the 59 participants who provided DBS at the beginning and end of the follow-up period, none had serological evidence of infection during this period. Of 72 participants who provided at least one oral fluid sample, one participant (1%) who also reported mumps symptoms, was found PCR positive. Of all 99 participants, the attack rate of self-reported mumps was 4% (95% CI 1.1-10.0%). Of the 5 laboratory confirmed mumps cases, 1 reported no mumps symptoms (percentage asymptomatic 20% (95% CI 0-71%)). Compared to non-students, students had larger households and more household members who were born after 1980 (p < 0.01 and <0.01, respectively).
CONCLUSIONS
We demonstrated that this prospective cohort study design allows for inference of the proportion of asymptomatic mumps infections. Because we only detected one asymptomatic mumps virus infection, we could not assess the relative infectiousness of asymptomatic mumps. Household characteristics of students differed from non-students. This may partly explain recent mumps epidemiology in the Netherlands.
Topics: Adolescent; Adult; Antibodies, Viral; Cohort Studies; Family Characteristics; Female; Humans; Immunoglobulin G; Incidence; Male; Middle Aged; Mumps; Mumps virus; Netherlands; Prospective Studies; RNA, Viral; Residence Characteristics; Saliva; Students; Surveys and Questionnaires; Young Adult
PubMed: 28068914
DOI: 10.1186/s12879-016-2135-5 -
Epidemiology and Infection Aug 2021On 16-17 January 2020, four suspected mumps cases were reported to the local Public Health Authorities with an epidemiological link to a local school and football club....
On 16-17 January 2020, four suspected mumps cases were reported to the local Public Health Authorities with an epidemiological link to a local school and football club. Of 18 suspected cases identified, 14 were included in this study. Laboratory results confirmed mumps virus as the cause and further sequencing identified genotype G. Our findings highlight that even with a high MMR vaccine coverage, mumps outbreaks in children and young adults can occur. Since most of the cases had documented immunity for mumps, we hypothesise that waning immunity or discordant mumps virus strains are likely explanations for this outbreak.
Topics: Adolescent; Child; Disease Outbreaks; Female; Genotype; Humans; Male; Measles-Mumps-Rubella Vaccine; Mumps; Mumps virus; Portugal; Vaccination; Young Adult
PubMed: 34446124
DOI: 10.1017/S0950268821002028 -
Frontiers in Microbiology 2021Many efforts have been dedicated to the discovery of antiviral drug candidates against the mumps virus (MuV); however, no specific drug has yet been approved. The...
Many efforts have been dedicated to the discovery of antiviral drug candidates against the mumps virus (MuV); however, no specific drug has yet been approved. The development of efficient screening methods is a key factor for the discovery of antiviral candidates. In this study, we evaluated a screening method using an green fluorescent protein-expressing MuV infectious molecular clone. The application of this system to screen for active compounds against MuV replication revealed that CD437, a retinoid acid receptor agonist, has anti-MuV activity. The point of antiviral action was a late step(s) in the MuV life cycle. The replication of other paramyxoviruses was also inhibited by CD437. The induction of retinoic acid-inducible gene (RIG)-I expression is a reported mechanism for the antiviral activity of retinoids, but our results indicated that CD437 did not stimulate RIG-I expression. Indeed, we observed antiviral activity despite the absence of RIG-I, suggesting that CD437 antiviral activity does not require RIG-I induction.
PubMed: 34867872
DOI: 10.3389/fmicb.2021.751909 -
PloS One 2020Mumps cases continue to occur, also in countries with a relatively high vaccination rate. The last major outbreaks of mumps in the Netherlands were in 2009-2012 and...
Mumps cases continue to occur, also in countries with a relatively high vaccination rate. The last major outbreaks of mumps in the Netherlands were in 2009-2012 and thereafter, only small clusters and single cases were reported. Molecular epidemiology can provide insights in the circulation of mumps viruses. The aims of the present study were to analyze the molecular epidemiology of mumps viruses in the Netherlands in 2017-2019 and to compare the phylogenetic trees built from sequence data of near complete mumps virus genomes or from the SH gene and non-coding regions (SH+NCRs). To this end, Sanger sequence data from SH+NCRs were analyzed from 82 mumps genotype G viruses. In addition, near complete genomes were obtained from 10 mumps virus isolates using next-generation sequencing. Analysis of SH+NCRs sequences of mumps genotype G viruses revealed the presence of two major genetic lineages in the Netherlands, which was confirmed by analysis of near complete genomes. Comparison of phylogenetic trees built with SH+NCRs or near complete genomes indicated that the topology was similar, while somewhat longer branches were present in the phylogenetic tree with near complete genomes. These results confirm that analysis of SH + NCRs sequence data is a useful approach for molecular surveillance. Furthermore, data from recent mumps genotype G viruses might indicate (intermittent) circulation of mumps genotype G viruses in the Netherlands in 2017-2019.
Topics: Disease Outbreaks; Genes, Viral; Humans; Molecular Epidemiology; Mumps; Mumps virus; Netherlands; Phylogeny; Viral Proteins
PubMed: 32925979
DOI: 10.1371/journal.pone.0233143 -
Enfermedades Infecciosas Y... Oct 2020This study describes a mumps outbreak among a group of young people who shared a same narghile to smoking. Saliva and blood samples were obtained from 3cases for RT-PCR...
INTRODUCTION
This study describes a mumps outbreak among a group of young people who shared a same narghile to smoking. Saliva and blood samples were obtained from 3cases for RT-PCR and serology respectively.
METHODS
The notification of a mumps case started an epidemiological investigation. Information of other 6additional symptomatic persons who had gathered with the case in a discotheque where they smoking in a same narghile was achieved. RT-PCR positive samples were genotyped by sequencing.
RESULTS
The 7patients resided in 3different municipalities, and they do not have get together for more than a month until the meeting in the discotheque. Four cases were confirmed by RT-PCR and/or IgM determinations. The genomic investigation showed identical nucleic sequences.
CONCLUSIONS
This outbreak is consequence of the common use of a narghile to smoking. The public usage of these water pipes should be regulated.
PubMed: 33059946
DOI: 10.1016/j.eimc.2020.08.015 -
Nature Communications May 2024The viral polymerase complex, comprising the large protein (L) and phosphoprotein (P), is crucial for both genome replication and transcription in non-segmented...
The viral polymerase complex, comprising the large protein (L) and phosphoprotein (P), is crucial for both genome replication and transcription in non-segmented negative-strand RNA viruses (nsNSVs), while structures corresponding to these activities remain obscure. Here, we resolved two L-P complex conformations from the mumps virus (MuV), a typical member of nsNSVs, via cryogenic-electron microscopy. One conformation presents all five domains of L forming a continuous RNA tunnel to the methyltransferase domain (MTase), preferably as a transcription state. The other conformation has the appendage averaged out, which is inaccessible to MTase. In both conformations, parallel P tetramers are revealed around MuV L, which, together with structures of other nsNSVs, demonstrates the diverse origins of the L-binding X domain of P. Our study links varying structures of nsNSV polymerase complexes with genome replication and transcription and points to a sliding model for polymerase complexes to advance along the RNA templates.
Topics: Cryoelectron Microscopy; Mumps virus; Viral Proteins; Models, Molecular; RNA, Viral; DNA-Directed RNA Polymerases; Protein Domains; Phosphoproteins; RNA-Dependent RNA Polymerase; Virus Replication; Transcription, Genetic; Protein Conformation
PubMed: 38760379
DOI: 10.1038/s41467-024-48389-9 -
Journal of Virology Aug 1971Ribonucleic acid (RNA) species in mumps virions and in infected cells were compared. The predominant RNA species in virions labeled with (3)H-uridine sedimented at 50S;...
Ribonucleic acid (RNA) species in mumps virions and in infected cells were compared. The predominant RNA species in virions labeled with (3)H-uridine sedimented at 50S; RNA species sedimenting at 28, 18, and about 10S were also present. The virion-associated RNA species sedimenting slower than 50S contained some nucleotide sequences similar to 50S virion RNA. Although mumps virus replication was severely inhibited by high concentrations of actinomycin D, some virus was made, and virus-specific RNA species accumulated in infected cells. Mumps virus resembled other paramyxoviruses in inducing, in infected cells, synthesis not only of 50S RNA but also of slower sedimenting RNA species with a peak distribution at about 18S, complementary in base sequences to 50S virion RNA. In addition, base sequences of the parental type were relatively abundant in the RNA species sedimenting slower than 50S; these may represent precursors of the slowly sedimenting RNA species associated with virions. Ribonuclease-resistant RNA was detected in infected cells; this may represent replicative or transcriptive intermediates. Inhibition of protein synthesis with cycloheximide severely depressed accumulation of labeled 50S RNA in infected cells but did not interfere with accumulation of RNA species sedimenting slower than 50S. Actinomycin D treatment had a similar effect. Annealing of genomes and virus-induced complementary RNA species of Newcastle disease virus, Sendai virus, and mumps virus did not reveal any base sequence homologies.
Topics: Animals; Base Sequence; Cells, Cultured; Centrifugation, Density Gradient; Centrifugation, Zonal; Chick Embryo; Culture Techniques; Cycloheximide; Cytopathogenic Effect, Viral; Dactinomycin; Fibroblasts; Hot Temperature; Lung; Mumps virus; Nucleic Acid Denaturation; Nucleic Acid Hybridization; Parainfluenza Virus 1, Human; RNA; RNA, Viral; Ribonucleases; Sucrose; Tritium; Uridine; Virus Replication
PubMed: 4329967
DOI: 10.1128/JVI.8.2.161-173.1971 -
Virology Journal Oct 2010Mumps virus V protein has the ability to inhibit the interferon-mediated antiviral response by inducing degradation of STAT proteins. Two virus variants purified from...
BACKGROUND
Mumps virus V protein has the ability to inhibit the interferon-mediated antiviral response by inducing degradation of STAT proteins. Two virus variants purified from Urabe AM9 mumps virus vaccine differ in their replication and transcription efficiency in cells primed with interferon. Virus susceptibility to IFN was associated with insertion of a non-coded glycine at position 156 in the V protein (VGly) of one virus variant, whereas resistance to IFN was associated with preservation of wild-type phenotype in the V protein (VWT) of the other variant.
RESULTS
VWT and VGly variants of mumps virus were cloned and sequenced from Urabe AM9 vaccine strain. VGly differs from VWT protein because it possesses an amino acid change Gln103Pro (Pro103) and the Gly156 insertion. The effect of V protein variants on components of the interferon-stimulated gene factor 3 (ISGF3), STAT1 and STAT2 proteins were experimentally tested in cervical carcinoma cell lines. Expression of VWT protein decreased STAT1 phosphorylation, whereas VGly had no inhibitory effect on either STAT1 or STAT2 phosphorylation. For theoretical analysis of the interaction between V proteins and STAT proteins, 3D structural models of VWT and VGly were predicted by comparing with simian virus 5 (SV5) V protein structure in complex with STAT1-STAT2 heterodimer. In silico analysis showed that VWT-STAT1-STAT2 complex occurs through the V protein Trp-motif (W174, W178, W189) and Glu95 residue close to the Arg409 and Lys415 of the nuclear localization signal (NLS) of STAT2, leaving exposed STAT1 Lys residues (K85, K87, K296, K413, K525, K679, K685), which are susceptible to proteasome degradation. In contrast, the interaction between VGly and STAT1-STAT2 heterodimer occurs in a region far from the NLS of STAT2 without blocking of Lys residues in both STAT1 and STAT2.
CONCLUSIONS
Our results suggest that VWT protein of Urabe AM9 strain of mumps virus may be more efficient than VGly to inactivate both the IFN signaling pathway and antiviral response due to differences in their finest molecular interaction with STAT proteins.
Topics: Cell Line; Humans; Interferons; Models, Molecular; Mumps virus; Mutagenesis, Insertional; Protein Binding; Protein Interaction Mapping; Protein Structure, Tertiary; STAT1 Transcription Factor; STAT2 Transcription Factor; Viral Proteins
PubMed: 20937132
DOI: 10.1186/1743-422X-7-263