Comparison of the Neurovirulence of a Vaccine and a Wild-Type Mumps Virus Strain in the Developing Rat Brain

ABSTRACT Prior to the adoption of widespread vaccination programs, mumps virus was the leading cause of virus-induced central nervous system (CNS) disease. Mumps virus-associated CNS complications in vaccinees continue to be reported; outside the United States, some of these complications have been attributed to vaccination with insufficiently attenuated neurovirulent vaccine strains. The development of potentially neurovirulent, live, attenuated mumps virus vaccines stems largely from the lack of an animal model that can reliably predict the neurovirulence of mumps virus vaccine candidates in humans. The lack of an effective safety test with which to measure mumps virus neurovirulence has also hindered analysis of the neuropathogenesis of mumps virus infection and the identification of molecular determinants of neurovirulence. In this report we show, for the first time, that mumps virus infection of the neonatal rat leads to developmental abnormalities in the cerebellum due to cerebellar granule cell migration defects. The incidence of the cerebellar abnormalities and other neuropathological and clinical outcomes of mumps virus infection of the neonatal rat brain demonstrated the ability of this model to distinguish neurovirulent (Kilham) from nonneurovirulent (Jeryl Lynn) mumps virus strains. Thus, this neonatal rat model may prove useful in evaluating the neurovirulence potential of new live, attenuated vaccine strains and may also be of value in elucidating the molecular basis of mumps virus neurovirulence.

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Changes in Mumps Virus Gene Sequence Associated with Variability in Neurovirulent Phenotype

Journal of Virology ◽

10.1128/jvi.77.21.11616-11624.2003 ◽

2003 ◽

Vol 77 (21) ◽

pp. 11616-11624 ◽

Cited By ~ 27

Author(s):

Steven A. Rubin ◽

Georgios Amexis ◽

Mikhail Pletnikov ◽

Jacqueline Vanderzanden ◽

Jeremy Mauldin ◽

...

Keyword(s):

Amino Acid ◽

Matrix Protein ◽

The United States ◽

Viral Meningitis ◽

Mumps Virus ◽

Wild Type Virus ◽

Neural Cells ◽

Wild Type ◽

Virus Variant ◽

Vaccination Programs

ABSTRACT Mumps virus is highly neurotropic and, prior to widespread vaccination programs, was the major cause of viral meningitis in the United States. Nonetheless, the genetic basis of mumps virus neurotropism and neurovirulence was until recently not understood, largely due to the lack of an animal model. Here, nonneurovirulent (Jeryl Lynn vaccine) and highly neurovirulent (88-1961 wild type) mumps virus strains were passaged in human neural cells or in chicken fibroblast cells with the goal of neuroadapting or neuroattenuating the viruses, respectively. When tested in our rat neurovirulence assay against the respective parental strains, a Jeryl Lynn virus variant with an enhanced propensity for replication (neurotropism) and damage (neurovirulence) in the brain and an 88-1961 wild-type virus variant with decreased neurotropic and neurovirulent properties were recovered. To determine the molecular basis for the observed differences in neurovirulence and neuroattenuation, the complete genomes of the parental strains and their variants were fully sequenced. A comparison at the nucleotide level associated three amino acid changes with enhanced neurovirulence of the neuroadapted vaccine strain: one each in the nucleoprotein, matrix protein, and polymerase and three amino acid changes with reduced neurovirulence of the neuroattenuated wild-type strain: one each in the fusion protein, hemagglutinin-neuraminidase protein, and polymerase. The potential role of these amino acid changes in neurotropism, neurovirulence, and neuroattenuation is discussed.

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Effects of X-Irradiation on Susceptibility of Neonatal Rat Brain and Muscle to Goxsackie B1 Virus Infection.

Experimental Biology and Medicine ◽

10.3181/00379727-118-29932 ◽

1965 ◽

Vol 118 (3) ◽

pp. 658-661 ◽

Cited By ~ 2

Author(s):

L. Schneck ◽

S. Berkovich

Keyword(s):

Virus Infection ◽

Rat Brain ◽

Neonatal Rat ◽

X Irradiation ◽

Neonatal Rat Brain

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Development and Use of an Endpoint Titration Assay To Characterize Mumps IgG Avidity following Measles, Mumps, and Rubella Vaccination and Wild-Type Mumps Infection

mSphere ◽

10.1128/msphere.00320-18 ◽

2018 ◽

Vol 3 (5) ◽

Cited By ~ 3

Author(s):

Sara Mercader ◽

Marcia McGrew ◽

Sun B. Sowers ◽

Nobia J. Williams ◽

William J. Bellini ◽

...

Keyword(s):

Virus Infection ◽

Characteristic Curve ◽

Vaccine Dose ◽

The United States ◽

Mumps Virus ◽

Igg Antibody ◽

Avidity Assay ◽

Igg Avidity ◽

Specific Igg ◽

Avidity Maturation

ABSTRACTWaning mumps IgG antibody and incomplete IgG avidity maturation may increase susceptibility to mumps virus infection in some vaccinees. To measure mumps IgG avidity, serum specimens serially diluted to the endpoint were incubated on a commercial mumps-specific IgG enzyme immunoassay and treated with the protein denaturant diethylamine (60 mM, pH 10). End titer avidity indices (etAIs [percent ratio of detected diethylamine-resistant IgG at endpoint]) were calculated. Unpaired serum specimens (n= 108) from 15-month-old children living in a low-incidence setting were collected 1 month and 2 years after the first measles, mumps, and rubella vaccine dose (MMR1) and tested for mumps avidity. Per the receiver operating characteristic curve, the avidity assay is accurate (area under the curve, 0.994; 95% confidence interval [CI], 0.956 to 1.000), 96.5% sensitive (95% CI, 87.9 to 99.6%), and 92.2% specific (95% CI, 81.1 to 97.8%) at an etAI of 30%. When 9 sets of paired serum specimens collected 1 to 60 months post-MMR1 were tested for mumps and measles IgG avidity using comparable methods, the mumps etAI increased from 11% to 40 to 60% in 6 months. From 6 to 60 months, avidity was sustained at a mean etAI of 50% (95% CI, 46 to 54%), significantly lower (P < 0.0001) than the mean measles etAI of 80% (95% CI, 74 to 86%). Mean etAIs in children 2 years post-MMR1 (n= 51), unvaccinated adults with distant mumps disease (n= 29), and confirmed mumps cases (n= 23) were 54, 62, and 57%, respectively. A mumps-specific endpoint avidity assay was developed and validated, and mumps avidity was determined to be generally sustained at etAIs of 40 to 60%, reaching etAIs of >80% in some individuals.IMPORTANCENumerous outbreaks of mumps have occurred in the United States among two-dose measles-mumps-rubella (MMR)-vaccinated populations since 2006. The avidity of mumps-specific IgG antibodies may affect susceptibility to mumps virus infection in some vaccinated individuals. To accurately measure mumps avidity, we developed and validated a mumps-specific IgG avidity assay that determines avidity at the endpoint titer of serially diluted serum specimens, providing results that are independent of IgG concentration. At low antibody titers, endpoint methods are considered more accurate than methods that determine avidity at a single dilution. We determined that 6 months after the first MMR dose, mumps IgG avidity is high and generally sustained at avidity indices of 40 to 60%, reaching values of >80% in some individuals. Additionally, 4% (4/103) of individuals had avidity indices of ≤30% (low avidity) 2 years after vaccination. Inadequate mumps avidity maturation may be one factor influencing susceptibility to mumps virus infection among previously vaccinated or naturally infected individuals.

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Wild-type and attenuated influenza virus infection of the neonatal rat brain

Journal of NeuroVirology ◽

10.1080/13550280490499579 ◽

2004 ◽

Vol 10 (5) ◽

pp. 305-314 ◽

Cited By ~ 7

Author(s):

Steven A Rubin ◽

Dong Liu ◽

Mikhail Pletnikov ◽

Jonathan A McCullers ◽

Zhiping Ye ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Rat Brain ◽

Influenza Virus Infection ◽

Neonatal Rat ◽

Wild Type ◽

Neonatal Rat Brain

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Vaccine waning and mumps re-emergence in the United States

10.1101/185454 ◽

2017 ◽

Cited By ~ 1

Author(s):

Joseph A. Lewnard ◽

Yonatan H. Grad

Keyword(s):

United States ◽

Vaccine Coverage ◽

Age Distribution ◽

Age Groups ◽

The United States ◽

Epidemiological Studies ◽

Mumps Virus ◽

Live Attenuated Vaccine ◽

Virus Genotypes ◽

Heterologous Virus

AbstractFollowing decades of declining mumps incidence amid widespread vaccination, the United States and other high-income countries have experienced a resurgence in mumps cases over the last decade. Outbreaks affecting vaccinated individuals—and communities with high vaccine coverage—have prompted concerns about the effectiveness of the live attenuated vaccine currently in use: it is unclear if immune protection wanes, or if the vaccine protects inadequately against mumps virus lineages currently circulating. Synthesizing data from epidemiological studies, we estimate that vaccine-derived protection wanes at a timescale of 27 (95%CI: 16 to 51) years. After accounting for this waning, we identify no evidence of changes in vaccine effectiveness over time associated with the emergence of heterologous virus genotypes. Moreover, a mathematical model of mumps transmission validates our findings about the central role of vaccine waning in the re-emergence of cases: outbreaks from 2006 to the present among young adults, and outbreaks occurring in the late 1980s and early 1990s among adolescents, align with peaks in the susceptibility of these age groups attributable to loss of vaccine-derived protection. In contrast, evolution of mumps virus strains escaping pressure would be expected to cause a higher proportion of cases among children. Routine use of a third dose at age 18y, or booster dosing throughout adulthood, may enable mumps elimination and should be assessed in clinical trials.One Sentence SummaryThe estimated waning rate of vaccine-conferred immunity against mumps predicts observed changes in the age distribution of mumps cases in the United States since 1967.

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Rabies Encephalitis With Myocarditis Mimicking ST-Elevation Myocardial Infarction

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz260 ◽

2019 ◽

Vol 6 (6) ◽

Cited By ~ 2

Author(s):

Stacy C Park ◽

Ian M Crane ◽

Kavita Pal ◽

R Elaine Cagnina

Keyword(s):

Myocardial Infarction ◽

Virus Infection ◽

Rabies Virus ◽

The United States ◽

St Elevation Myocardial Infarction ◽

Human Rabies ◽

Vaccination Programs ◽

Significant Public Health ◽

Rabies Virus Infection ◽

St Elevation

AbstractRabies virus infection remains a significant public health threat particularly in developing countries without effective canine vaccination programs. After symptoms develop, there is no effective treatment and mortality approaches 100%. In countries such as the United States where human rabies remains rare, initial diagnosis is often delayed. In this study, we describe a case of rabies encephalitis presenting with concern for acute ST-elevation myocardial infarction (STEMI) based on electrocardiogram, laboratory, and exam findings and briefly review the known literature on cardiac involvement of rabies virus infection.

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Hyperbiofilm Formation by Bordetella pertussis Strains Correlates with Enhanced Virulence Traits

Infection and Immunity ◽

10.1128/iai.00373-17 ◽

2017 ◽

Vol 85 (12) ◽

Cited By ~ 11

Author(s):

Natalia Cattelan ◽

Jamie Jennings-Gee ◽

Purnima Dubey ◽

Osvaldo M. Yantorno ◽

Rajendar Deora

Keyword(s):

Bordetella Pertussis ◽

Biofilm Formation ◽

Whooping Cough ◽

Bacterial Colonization ◽

The United States ◽

Content Type ◽

Vaccination Programs ◽

First Time ◽

Reciprocal Expression ◽

Country Specific

ABSTRACT Pertussis, or whooping cough, caused by the obligate human pathogen Bordetella pertussis is undergoing a worldwide resurgence. The majority of studies of this pathogen are conducted with laboratory-adapted strains which may not be representative of the species as a whole. Biofilm formation by B. pertussis plays an important role in pathogenesis. We conducted a side-by-side comparison of the biofilm-forming abilities of the prototype laboratory strains and the currently circulating isolates from two countries with different vaccination programs. Compared to the reference strain, all strains examined herein formed biofilms at high levels. Biofilm structural analyses revealed country-specific differences, with strains from the United States forming more structured biofilms. Bacterial hyperaggregation and reciprocal expression of biofilm-promoting and -inhibitory factors were observed in clinical isolates. An association of increased biofilm formation with augmented epithelial cell adhesion and higher levels of bacterial colonization in the mouse nose and trachea was detected. To our knowledge, this work links for the first time increased biofilm formation in bacteria with a colonization advantage in an animal model. We propose that the enhanced biofilm-forming capacity of currently circulating strains contributes to their persistence, transmission, and continued circulation.

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