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Journal of Virology, October 1998, p. 8037-8042, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Comparison of the Neurovirulence of a Vaccine and a Wild-Type
Mumps Virus Strain in the Developing Rat Brain
Steven A.
Rubin,1
Mikhail
Pletnikov,2 and
Kathryn M.
Carbone1,2,3,*
DVP/OVRR, Center for Biologics Evaluation and
Research, Food and Drug Administration, Bethesda, Maryland
20892,1 and
Departments of
Psychiatry2 and
Medicine,3 Johns Hopkins University,
Baltimore, Maryland 21205
Received 6 May 1998/Accepted 25 June 1998
 |
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.
| |
INTRODUCTION |
Mumps virus, a member of the
Paramyxoviridae family, contains a 15.3-kb enveloped,
nonsegmented, negative-strand RNA virus within a lipid envelope.
Humans are the only natural host of mumps virus infection, although
nonhuman primates, rodents, and other species can be
experimentally infected. Mumps virus is transmitted by droplet spread
to the nasal mucosa or upper respiratory mucosal epithelium,
resulting in viremia and dissemination to most organ systems, including
the brain, with production of acute inflammatory disease
(70). Cerebrospinal fluid pleocytosis has been detected in
more than half of all mumps virus infections, a testament to the
profound neurotropism of the virus (70). Prior to the
widespread use of live, attenuated mumps virus vaccines, mumps virus
was the leading cause of virus-induced central nervous system (CNS) disease (i.e., neurovirulence) (14, 30). The most frequent clinical CNS complication of wild-type mumps virus infection is aseptic meningitis (29, 46); other CNS complications include acute and chronic encephalitis (34, 47), hydrocephalus
(52, 65), transverse myelitis (51, 69), and acute
cerebellar ataxia (17, 28). Although the case fatality
rate is only 1 in 10,000, nonfatal complications of mumps virus
infection often lead to hospitalization and occasionally to permanent
and severe neurological sequelae (25, 42, 50, 59).
Although vaccination programs have decreased the incidence of mumps
virus infection worldwide (13), mumps virus outbreaks have
not been completely eliminated, even in vaccinated populations. Mumps
virus infections in vaccinees are due either to an infection with
wild-type virus following primary vaccine failure (7, 24,
63) or to inoculation of a relatively neurovirulent mumps virus
vaccine (e.g., Urabe AM9) (2, 16, 18, 45). Problems with
excessive neurovirulence of live mumps virus vaccines primarily stem
from the lack of an animal model capable of determining the strain's
neurovirulence potential for the human CNS. The lack of such an animal
model has also hindered studies on the molecular basis for attenuation
of mumps virus neurovirulence.
We previously demonstrated the sensitivity of the developing rat CNS to
damage by perinatal viral infection with Borna disease virus (BDV)
(4, 5, 12). The suggestion that mumps virus was particularly
pathogenic for the rodent CNS was provided by a recent publication
demonstrating enhanced susceptibility of neonatal hamsters to mumps
virus-induced hydrocephalus (68). Here, we report an
analysis of the developing rat CNS following intracranial inoculation
with different strains of mumps virus, revealing that wild-type and
vaccine strains of mumps virus could be discriminated according to
disease induction in the neonatal rat. Also presented are
associated strain-specific differences in in vitro replication in
primate and rat neural and nonneural cell lines. Using these data, we
propose a possible mechanism for the pathogenesis of mumps virus
neurovirulence.
| |
MATERIALS AND METHODS |
Virus.
The hamster-neuroadapted wild-type Kilham (KH) strain
(kindly provided by J. Wolinsky, University of Texas, Houston) and the attenuated Jeryl Lynn (JL) vaccine strain (MumpsVax; Merck Sharp & Dohme, West Point, Pa.) were used. Stocks of each strain were prepared
from virus passaged twice on Vero cells in minimal essential medium
(MEM; Gibco BRL, Gaithersburg, Md.) with 7% fetal bovine serum (FBS;
Gibco BRL) at 37°C.
Plaque assay.
Viral titer was determined by plaque assay.
Virus was serially diluted 10-fold, and 0.5 ml of each dilution was
incubated for 1 h at 37°C on Vero cell monolayers in six-well
plates. Viral inoculum was removed by aspiration; cell monolayers were
rinsed with MEM, immediately covered with warm 0.5% Noble agar in 2× MEM (Quality Biologicals, Gaithersburg, Md.) supplemented with 7% FBS,
and incubated at 37°C for 4 days. A second layer of agar containing
0.01% neutral red (Quality Biologicals) was subsequently added and
incubated overnight, allowing for visualization of the plaques the
following day. Virus was quantitated by counting the number of PFU and
multiplying by the reciprocal of the dilution factor and volume plated.
Rats.
One-day-old Lewis rats (Harlan, Indianapolis, Ind.)
were inoculated intracranially with 20 µl of either JL
(n = 40) or KH (n = 60) containing
4 × 103 PFU. All inoculations were performed at the
coronal suture approximately 1 to 2 mm left of midline. Duplicate
litters of rats were inoculated with an equivalent volume of uninfected
Vero cell supernatant (n = 20) to serve as controls. On
days 3, 6, 9, 12, 19, and 26 postinoculation (p.i.), rats were weighed,
and two control and six infected rats were deeply anesthetized and
killed. Brains were removed aseptically and divided sagitally. Half of
the brain, used for plaque assay for infectious virus titration, was
homogenized into a 20% (wt/vol) suspension in MEM with 2% FBS by
Dounce homogenization, followed by brief pulses of ultrasonic
treatment, and clarified by centrifugation at 2,000 × g for 10 min. Rat body weights and viral titers were
analyzed by two-way repeated-measures analysis of variance.
Histology and avidin-biotin immunohistochemistry.
The
remainder of the brain was processed for histopathological and
immunohistochemical analysis by fixation in 4% formalin overnight,
paraffin embedding, and sagittal sectioning. Sectioned brain tissue was
stained with hematoxylin and eosin and observed under light microscopy
for the presence or absence of ventriculitis, hydrocephalus,
meningitis, encephalitis, and developmental abnormalities. Avidin-biotin immunohistochemistry (Vector Laboratories, Burlingame, Calif.) was also performed by using a previously described method to
identify inflammatory and glial cells in the cerebellum
(11). Briefly, brain sections were incubated in blocking
buffer (2% normal goat serum in phosphate-buffered saline) followed by
incubation with either monoclonal mouse anti-major histocompatibility
complex Ia (Chemicon, Temecula, Calif.) for detection of inflammatory cells or polyclonal rabbit anti-glial fibrillary acidic protein (Dako,
Carpenteria, Calif.) for detection of glial cells. After being rinsed
in phosphate-buffered saline, slides were incubated with secondary
biotinylated anti-species immunoglobulin G antibodies and
avidin-biotin-horseradish peroxidase complex (Vector Laboratories). A
hydrogen peroxide-diaminobenzidine solution (Sigma, St. Louis, Mo.) was
added, and the resultant brown precipitate was detected by light
microscopy.
In vitro virus characterization.
Cultures of SK-N-SY5Y
(human neuroblastoma; Joan Schwartz, National Institutes of Health,
Bethesda, Md.), C6 (rat astrocytoma; American Type Culture
Collection, Rockville, Md.), and Vero (monkey kidney; American Type
Culture Collection) cells in six-well plates were infected with either
JL or KH at a multiplicity of infection of 0.01 PFU/cell in MEM with
7% FBS. Supernatant was removed every 24 h over a 6- to 8-day
period following infection, and the virus titer was determined by
plaque assay. The onset and extent of cell fusion and lysis were
evaluated qualitatively in the SK-N-SY5Y and C6 cell
cultures and quantitatively in the Vero cell cultures.
For quantitative analysis, Vero cell monolayers were fixed in 100%
ethanol at 20°C for 10 min, stained with KaryoMAX Giemsa stain (Gibco
BRL) for 5 min, rinsed under tap water, and air dried. Stained Vero
cell monolayers were examined by light microscopy, and the extent of
cell-to-cell fusion and syncytium formation was determined by a
modification of a previously described method (44). Briefly,
four random 2.0- by 2.67-mm fields were examined by bright-field
microscopy, and each field was scored as 0 (absence of cytopathic
effects), 1+ (presence of discrete syncytium foci with 4 to 10 nuclei
per polykaryocyte), 2+ (partially confluent syncytium foci containing
10 to 25 nuclei per polykaryocyte), or 3+ (confluent syncytia
encompassing the entire field of view). The mean score was used to
represent the overall fusion score. The time p.i. of the development of
cell lysis (involving >50% of the monolayer) was also recorded.
Statistical analysis was performed by one-way analysis of variance on
data from four to six repetitions.
| |
RESULTS |
In vivo measurements of virulence. (i) Viral titers in rat
brain.
One-day-old rats were inoculated with either the attenuated
JL or the neurovirulent wild-type KH strain of mumps virus. Viral replication was confirmed by recovery of infectious virus from the
brains of all mumps virus-inoculated rats between days 3 and 12 p.i. Maximum viral titers (PFU/milliliter) were recovered on day 3 p.i. from JL-infected rat brain (3.5 × 102 ± 62) and
on day 6 p.i. from KH-infected rat brain (1.9 × 103 ± 152). Little to no virus was recovered after day
12 p.i. (a time coincident with the onset of neuroanatomical
abnormalities) from any of the mumps virus-infected rats. Maximum viral
titers in the KH-infected rats were significantly greater
(P < 0.001) than those in the JL-infected rats. Virus
was not recovered from any of the uninfected rats.
(ii) Rat weights.
Inhibition of normal weight gain in
virus-infected neonatal rats compared to uninfected neonatal rats is a
physiological indication of viral disease (57). Table
1 shows the mean weights of KH- and
JL-infected rats and of uninfected rats at all time points tested.
KH-infected rats weighed significantly less (P < 0.05) than uninfected rats from days 3 through 19 p.i. In contrast, no
significant differences in weights between JL-infected and uninfected
rats were measured at any time point. The mean percent inhibition of
normal weight gain between days 3 and 19 p.i. in KH-infected rats
was 16.6 ± 1.2, compared to 4.8 ± 0.7 in JL-infected rats
(P < 0.001).
(iii) Neuropathology.
The increased virulence of KH relative
to JL was also evident upon neuropathological evaluation of
hematoxylin- and eosin-stained sagittal brain sections. The most
striking neuroanatomical findings were (i) hydrocephalus of the lateral
and third ventricles, first observed on day 12 p.i. (Fig.
1), with incidences of 72%
(n = 18) in KH-infected rats and 12%
(n = 17) in JL-infected rats, and (ii) abnormal
cerebellar development, first observed on day 19 p.i. (Fig.
2), with incidences of 67%
(n = 12) in KH-infected rats and 9% (n = 11) in JL-infected rats. The mumps virus-associated cerebellar
abnormality was characterized by the anomalous retention of masses of
granule cell neurons at the external germinal layer and scattered
throughout the molecular layer. In these same rat brains, the
cerebellar Bergmann glial fibers, normally arrayed in an orderly and
parallel fashion, were disorganized and distorted (Fig.
3).
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FIG. 1.
Sagittal sections through the brains of sham (A)-, KH
(B)-, and JL (C)-inoculated rats on day 19 p.i. Note the
hydrocephalus of the lateral (arrows) and third (arrowheads) ventricles
in the KH-inoculated rat brain. Hematoxylin and eosin stained;
magnification, ×40.
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FIG. 2.
Sagittal sections through sham-, KH-, and JL-inoculated
rat brains on day 19 p.i. Panels A (magnification, ×11), B
(magnification, ×34), and C (magnification, ×85) show the
cerebellum of a representative sham-inoculated rat. Note the smoothness
and regularity of the external germinal layer (EGL), molecular layer
(ML), and internal granule cell layer (IGL). Panels D to F (same
magnifications as panels A to C, respectively) show the cerebellum of a
representative KH-inoculated rat. Note the irregularity of the EGL, ML,
and IGL and the anomalous masses of granule cell neurons (arrows).
Panels G to I (same magnifications as panels A to C, respectively)
show the cerebellum of a representative JL-inoculated rat. Note the
similarity of the EGL, ML, and IGL to those of the sham-inoculated
rats. All sections were stained with hematoxylin and eosin.
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FIG. 3.
Bergmann glia, immunohistochemically stained with glial
fibrillary acidic protein, in sagittal sections through the cerebella
of sham-, KH-, and JL-inoculated rat brains on day 19 p.i. Panels
A (magnification, ×100) and B (magnification, ×200) show the Bergmann
glia (arrows) in the molecular layer of the cerebellum of a
representative sham-inoculated rat. Note the smoothness of the
molecular layer and the orderly parallel arrangement of the Bergmann
glia. Panels C and D (same magnification as panels A and B,
respectively) show the Bergmann glia (arrowheads) in the molecular
layer of the cerebellum of a representative KH-inoculated rat. Note the
irregularity of the molecular layer and the disorganization of the
Bergmann glia. Panels E and F (same magnifications as panels A and B,
respectively) show the Bergmann glia in the molecular layer of the
cerebellum of a representative JL-inoculated rat. Note the similarity
of the smoothness of the molecular layer and the orderly parallel
arrangement of the Bergmann glia to those of the sham-inoculated
rats.
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There was little to no ventriculitis, meningitis, or encephalitis in
any of the KH- or JL-infected rats at any time point.
None of the
sham-inoculated age-matched control rats exhibited
either of these
neuroanatomical findings.
In vitro measurements of virulence.
To determine the relative
virulence of JL and KH in vitro, virus production and cytopathology
were assessed in KH- and JL-infected neural (C6 and
SK-N-SY5Y) and nonneural (Vero) cells. Peak viral titers in KH
(1.8 × 105 ± 4.7 × 104)- and JL
(1.3 × 105 ± 5.1 × 104)-infected
Vero cells were not significantly different (P = 0.40) (Fig. 4A). In contrast, significant
differences between peak viral titers were seen in KH (1.05 × 106 ± 7.9 × 104)- and JL (9.5 × 104 ± 3.6 × 104)-infected C6
cells (P < 0.001) (Fig. 4B) and in KH (2.6 × 106 ± 1.7 × 105)- and JL (6.9 × 105 ± 1.3 × 104)-infected SK-N-SY5Y
cells (P < 0.001) (Fig. 4C). Results represent the
averages of four determinations.
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FIG. 4.
Amount of infectious virus recovered from supernatant of
KH (solid squares)- and JL (open circles)-infected Vero (A),
C6 astrocytoma (B), and SK-N-SY5Y neuroblastoma (C) cell
lines over several days p.i.
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When the virus-specific cytopathic effects were evaluated following KH
and JL infection of SK-N-SY5Y, C
6, and Vero cells,
in all
three cell types, KH infection led to earlier evidence
of infection
(fusion) but slower progression to lysis than in
JL-infected cells.
Vero cells were chosen to quantitate the virus-specific
cytopathic
changes since, unlike the neural cells, Vero cells
grow in uniform
monolayers and replicate KH and JL to equivalent
peak titers. A
comparison of the time courses of cell fusion and
cell lysis in Vero
cell cultures infected with JL and KH is shown
in Fig.
5. The early stages of cell fusion in
KH-infected cultures
were observed within 24 h p.i. and gradually
increased to a point
where the entire monolayer was fused (3+) by day
5 p.i. The fused
monolayer remained intact until succumbing to
cell lysis by day
8 p.i. In contrast, cell fusion in JL-infected
cultures was not
observed until day 2 p.i. and attained 3+ fusion
by day 4 p.i.,
followed by rapid lysis the next day. Results
represent the averages
of data obtained from three to four infections.
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FIG. 5.
Time course of cell fusion and cell lysis in Vero cell
cultures infected with KH (solid squares) and JL (open circles). The
day on which cell lysis was observed is represented by the last time
point for each curve.
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DISCUSSION |
A major obstacle to the development of new live, attenuated mumps
virus strains for use in vaccines is the assessment of the strains'
potential neurovirulence in humans. These concerns stem from historical
and recent experience, as following use in countries outside the United
States, new mumps vaccine strains were found to have unacceptable
neurovirulence in humans. The risk of production of potentially
neurovirulent new mumps virus vaccines may continue unless an animal
model capable of reliably discriminating neurovirulent from
nonneurovirulent human strains is developed. Neurovirulence testing of
mumps virus vaccine strains is currently performed in monkeys
(Macacus rhesus and Cercopithecus); however, in
these animals clinical and pathological manifestations often do not correlate with the strain's known neurovirulence in humans (36, 58). Similarly, the hamster, the most widely studied small-animal model of mumps virus pathogenesis, also lacks the ability to reliably discriminate neurovirulent from nonneurovirulent human strains (22, 32, 41, 71).
In the work described here, we developed a neonatal rat model of mumps
virus infection that, based on clinical and pathological outcomes of
infection, was capable of discriminating between two mumps virus
strains of widely disparate neurovirulence, the neurovirulent KH strain
and the nonneurovirulent JL vaccine strain. Our major findings in
KH-infected rats were a reduction in weight gain and a high incidence
of hydrocephalus and cerebellar abnormalities. In contrast, rats
inoculated with the JL strain did not show statistically significant reductions in weight gain and exhibited only a small fraction of the incidence of neuroanatomical abnormalities.
Validation of this rat model as a means of assessing
the neurovirulence potential of new vaccine strains will
require additional testing with a wide range of known human
neurovirulent and nonneurovirulent mumps virus strains. Nevertheless,
the potential applicability of the rat as an in vivo model for
neurovirulence testing appears promising, since both monkeys (10,
58) and hamsters (22, 41, 71) have not been uniformly
capable of distinguishing the attenuated JL strain from more virulent
mumps virus strains.
This model also demonstrates the first evidence for mumps
virus-associated developmental brain damage not linked to
hydrocephalus, e.g., cerebellar neuron migration defects in mumps
virus-infected rats. The delayed and inefficient cerebellar
neuron migration was manifested by the prolonged presence of granule
cells at the external germinal layer and deposits of ectopic
granule cell neurons scattered throughout the molecular layer.
Although the abnormally retained external germinal layer
eventually dissipated, the retention of granule cells in the molecular
layer persisted through at least 3 months p.i. (data not shown). In all
cerebella displaying such abnormalities, Bergmann glial cells were
morphologically abnormal, appearing tangled and distorted, unlike the
uniform and parallel arrangement seen in uninfected or in unaffected
KH- and JL-infected rats. Since Bergmann glial cells are
responsible for guiding the migration of cerebellar granule cell
neurons from the external germinal layer through the molecular layer to
the internal granule cell layer (26, 27, 61), it is tempting
to speculate that the morphologically abnormal Bergmann glia may be
functionally abnormal as well and thus may have interrupted the normal
migration of granule cells.
The granule cell migration abnormality reported here differs from the
only other reported mumps virus-induced cerebellar abnormality, the
Chiari type I malformation. The Chiari type I malformation is a
secondary effect of the mumps virus-induced hydrocephalus and is
manifested by elongation of the cerebellar vermis and flattening of the
molecular layer and granule cell layers due to increased intracranial
pressure (64). Unlike the Chiari type I malformation, the
cerebellar neuronal migration abnormality reported here (Fig. 2)
occurred in animals with and without hydrocephalus, suggesting that the
development of ectopic granule cells is independent of the development
of hydrocephalus.
Cerebellar developmental abnormalities have also been described for
several other viral systems. Cerebellar neuronal migration abnormalities following BDV infection of neonatal rats are also likely
to be due in part to disruption of normal migration of granule cell
neurons. However, unlike the case for mumps virus-infected rats,
granule cells from persistently BDV-infected rats that fail to migrate
from the external germinal layer to the internal granule cell layer
appear to die in situ and are not seen in the molecular layer
(4). In neonatal infection of chicken embryos with influenza C virus, developmental defects are seen in conjunction with abnormal Purkinje cell arborization, attachment of granule cells, and migration (54). In other viral systems, direct lysis of cerebellar
granule cell neurons (e.g., parvovirus [53]) or
immune-mediated lysis of infected granule cells (e.g., lymphocytic
choriomeningitis virus [19, 48] or reovirus type III
[40, 56]) has also been associated with cerebellar
developmental abnormalities.
To establish that the enhanced neurovirulence of KH was due to
preferred replication in neural cells and not adaptation to the rodent,
we examined in vitro virus replication and cytopathology kinetics of KH
and JL in primate and rat neural and nonneural cell lines. In vitro, KH
and JL replicated to similar titers in Vero cells, demonstrating that
the two viral strains were equally replication competent in nonneural
primate cells. In contrast, KH was able to replicate to significantly
higher titers compared to JL in both rat astrocytoma (C6)
and human neuroblastoma (SK-N-SY5Y) cell lines. These findings are
consistent with the in vivo observation that neurovirulence may be
associated with adaptation of the virus for replication in neural
cells. The ability of JL to replicate well in nonneural primate cells
and its apparent restriction of replication in neural cells from
rodents and primates suggest that the relative nonneurovirulence of JL
in the neonatal rat model is not due to a simple species restriction
for this virus.
There is some indication that the increased in vivo neurovirulence of
KH may be due to KH's ability to persist and replicate in neurons with
delayed lysis relative to JL. Delayed host cell lysis by KH may allow
enhanced spread to and infection of neighboring neurons. Conversely,
the rapidly lysed JL-infected neurons would likely result in a
restricted ability to spread and replicate in the brain. This
hypothesis is supported by in vitro data demonstrating KH's tendency
toward a relatively persistent infection compared to JL. Further data
will be needed to confirm this hypothesis as a possible mechanism for
the pathogenesis of mumps virus neurovirulence.
A related advantage of the development of the neonatal rat model of
mumps virus pathogenesis is the elucidation of molecular determinants
of mumps virus neurovirulence. To date, the majority of work in this
area has focused on the analysis of the mumps virus
hemagglutinin-neuraminidase surface protein, a glycoprotein responsible
for viral attachment to cellular receptors and activation of the viral
fusion protein. However, the association between alterations in the
hemagglutinin-neuraminidase glycoprotein and changes in neurovirulence
has been modest at best (1, 8, 9, 35, 38). Although
alterations in similarly functioning proteins of many other RNA viruses
(3, 20, 21, 31, 37, 55, 66, 67) have been linked to altered
virulence, it is unlikely that any single gene is solely responsible
for the neurovirulence potential of the virus. In fact, mutations in
other coding and noncoding regions have also been linked to altered
neurovirulence (6, 15, 23, 33, 39, 43, 49, 60, 62). The
development of a clinically predictive model of mumps virus
neurovirulence may allow for these and other changes at the molecular
level to be evaluated in a biological disease model.
Additionally, by testing several other human CNS wild-type and vaccine
strains, we may be able to validate the neonatal rat model as a means
of preclinical neurovirulence safety testing and reduce or eliminate
the use of monkeys for such purposes. With such a model and a better
understanding of the molecular mechanisms of neurovirulence due to
mumps virus, it may be possible to facilitate the production of safer,
nonneurovirulent live, attenuated mumps virus vaccines.
| |
ACKNOWLEDGMENTS |
We thank Jerry Wolinsky for providing the Kilham virus strain and
Ronald Lundquist and Kathleen Clouse for critical review of the
manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
DVP/OVRR/CBER/FDA, Building 29A, Room 1A-21, 8800 Rockville Pike,
Bethesda, MD 20892. Phone: (301) 827-1973. Fax: (301)
480-5679. E-mail: carbonek{at}a1.cber.fda.gov.
| |
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Journal of Virology, October 1998, p. 8037-8042, Vol. 72, No. 10
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Abstract
Introduction
