The Mumps Virus Neurovirulence Safety Test in Rhesus Monkeys:A Comparison of Mumps Virus Strains

Rubin, Steven A.; Snoy, Philip; Wright, Kathryn; Brown, Earl G.; Reeve, P.; Beeler, Judy A.; Carbone, Kathryn M.

doi:10.1086/314905

Cited by 44 publications

(32 citation statements)

References 11 publications

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“…Preventing infected cells from dying or from dying prematurely is beneficial to virus replication. Interestingly, it has been reported that increased CPE induced by mumps virus infection in vitro (tissue culture cells) seems to correlate with decreased pathogenicity of the virus in a rat model system (35)(36)(37)(38). Not surprisingly, a mutation in SV5 causing increased CPE in infected cells results in a mutant that is attenuated in vivo (14,16).…”

Section: Discussionmentioning

confidence: 99%

Function of Small Hydrophobic Proteins of Paramyxovirus

Wilson¹,

Fuentes²,

Wang

et al. 2006

J Virol

110

108

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Section: Discussionmentioning

confidence: 99%

Function of Small Hydrophobic Proteins of Paramyxovirus

Wilson¹,

Fuentes²,

Wang

et al. 2006

J Virol

110

108

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“…Mumps virus neurovirulence testing as currently performed in monkeys has failed to discriminate between strains with known differences in human neurovirulence (2,8,27,28). Similarly, tests in hamsters have also failed to reliably discriminate neurovirulent from nonneurovirulent human mumps virus strains (12,19,22,34).…”

mentioning

confidence: 99%

“…Recent reports have indicated that the monkey neurovirulence test (MNVT) is not sufficiently predictive of mumps virus neurovirulence in humans (2,27). However, based on the observed influence of virus dose on RNVT scores, it was conceivable that the use of higher or lower doses of mumps virus might yield responses in monkeys better correlating with neurovirulence in humans.…”

mentioning

confidence: 99%

Evaluation of a Neonatal Rat Model for Prediction of Mumps Virus Neurovirulence in Humans

Rubin

Pletnikov²,

Taffs

et al. 2000

J Virol

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Neurovirulence of several mumps virus strains was assessed in a prototype rat neurovirulence test and compared to results obtained in the monkey neurovirulence test. The relative human neurovirulence of these strains was proportional to the severity of hydrocephalus in rats but not to lesion scores in the monkeys.Neurovirulence testing is performed to demonstrate that attenuated mumps virus seeds used in the manufacture of vaccine lack the neurovirulence properties of wild-type mumps virus strains. Mumps virus neurovirulence testing as currently performed in monkeys has failed to discriminate between strains with known differences in human neurovirulence (2,8,27,28). Similarly, tests in hamsters have also failed to reliably discriminate neurovirulent from nonneurovirulent human mumps virus strains (12,19,22,34). The difficulty in evaluating the neurovirulence potential of mumps viruses may be reflected in reports of mumps virus central nervous system (CNS) infection causally linked to vaccination with some mumps virus vaccines (e.g., Urabe-AM 9, Leningrad-3, and Sofia-6) (3,9,10,23,24,32). Thus, a validated mumps virus neurovirulence test with greater relevance to human disease remains an important public health objective.Because neonatal rat brain is particularly sensitive to damage following perinatal virus infection (5,6,11,13,16,25,26,31), it was hypothesized that neuropathology in rats neonatally inoculated with mumps virus may serve as a sensitive indicator of neurovirulence potential in the human CNS. Litters of 1-day-old Lewis rats were inoculated intracranially with 0.02 ml containing 10 2 PFU of the following mumps virus strains: (i) Jeryl Lynn vaccine (JL) (15); (ii) RIT 4385 vaccine (JL-RIT), cloned from JL by limiting dilution (33); (iii) Urabe-AM 9 vaccine (Ur-AM9) (35); (iv) Ur-1004, a cerebrospinal fluid isolate from a case of Ur-AM9 meningitis (7); (v) Kilham, a wild-type strain isolated from human breast milk and serially passaged in suckling hamster brain (20); (vi) Lo1, a wild-type strain isolated from the saliva of a patient with uncomplicated parotitis (1); and (vi) 88-1961, a wild-type strain isolated from the saliva of a patient with parotitis and symptoms of CNS infection.Rats were euthanized on days 3, 6, 9, and 30 postinoculation, and brains were removed and either homogenized to determine viral titer by plaque assay (26) or fixed in 10% formalin for histological analysis. Two 3-to 4-mm-thick sagittal slices were selected at a standard distance from either side of the anatomical midline from a fixed brain, paraffin embedded, sectioned, and stained with hematoxylin and eosin. The severity of hydrocephalus was determined as the percentage of the total brain cross-sectional area (excluding the cerebellum) occupied by the lateral ventricle on each of the two sections per rat using Image Pro Plus image analysis software (Media Cybernetics, Silver Spring, Md.). The mean percentage of hydrocephalus in each experimental group of rats was calculated and designated as the rat neurovirulence test...

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“…Any live viral vaccines for human use must pass the neurovirulence test in nonhuman primates (16)(17)(18)(19). In order to take advantage of live rVSVs as a vaccine vector for their high yield and for their induction of strong and long-lasting immune responses, it is necessary to make the live vaccine vector safe to use in humans without losing its immunogenicity.…”

Section: Esicular Stomatitis Virus (Vsv) Is a Rapidly Replicating Vmentioning

confidence: 99%

Creation of Matrix Protein Gene Variants of Two Serotypes of Vesicular Stomatitis Virus as Prime-Boost Vaccine Vectors

Kim

Hong

et al. 2015

J Virol

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To take advantage of live recombinant vesicular stomatitis viruses (rVSVs) as vaccine vectors for their high yield and for their induction of strong and long-lasting immune responses, it is necessary to make live vaccine vectors safe for use without losing their immunogenicity. We have generated safer and highly efficient recombinant VSV vaccine vectors by combining the M51R mutation in the M gene of serotype VSV-Indiana (VSV Ind ) with a temperature-sensitive mutation (tsO23) of the VSV Ind Orsay strain. In addition, we have generated two new serotype VSV-New Jersey (VSV NJ ) vaccine vectors by combining M48R and M51R mutations with G22E and L110F mutations in the M gene, rVSV NJ (G22E M48R M51R) [rVSV NJ (GMM)] and VSV NJ (G22E M48R M51R L110F) [rVSV NJ (GMML)]. The combined mutations G21E, M51R, and L111F in the M protein of VSV Ind significantly reduced the burst size of the virus by up to 10,000-fold at 37°C without affecting the level of protein expression. BHK 21 cells and SH-SY5Y human neuroblastoma cells infected with rVSV Ind (GML), rVSV NJ (GMM), and rVSV NJ (GMML) showed significantly reduced cytopathic effects in vitro at 37°C, and mice injected with 1 million infectious virus particles of these mutants into the brain showed no neurological dysfunctions or any other adverse effects. In order to increase the stability of the temperaturesensitive mutant, we have replaced the phenylalanine with alanine. This will change all three nucleotides from UUG (leucine) to GCA (alanine). The resulting L111A mutant showed the temperature-sensitive phenotype of rVSV Ind (GML) and increased stability. Twenty consecutive passages of rVSV Ind (GML) with an L111A mutation did not convert back to leucine (UUG) at position 111 in the M protein gene. V esicular stomatitis virus (VSV) is a rapidly replicating virus.Eventually humoral and cellular immune responses against VSV are elicited in the animal host, like any other viral vectors (1-3). Animals infected with VSV develop immune responses within 2 weeks and start to neutralize the VSV (1). This hinders the efficacy of boost immunizations for vaccination with the same vector. Serotype-specific antibodies against the viral surface glycoprotein G neutralize VSV. Two different serotypes of VSV, VSV-Indiana (VSV Ind ) and VSV-New Jersey (VSV NJ ), show 50% amino acid homologies in glycoprotein G (4). Antibodies raised against one serotype of VSV do not neutralize the other serotype of VSV (5). Accordingly, other investigators have used VSV Ind with its own surface glycoprotein G and VSV Ind carrying the G gene from other serotypes as a vaccine vector (6, 7).VSV causes self-limiting disease in animals such as pigs, cows, and horses, whereby vesicular lesions on the mouth, nose, teats, and hooves are cleared in a couple of weeks after the onset (8).Although it is very rare, human infections with VSV have been reported mostly in animal care workers, veterinarians, and laboratory personnel who were in close contact with the diseased animals or with the viruses (9-11)....

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The Mumps Virus Neurovirulence Safety Test in Rhesus Monkeys:A Comparison of Mumps Virus Strains

Cited by 44 publications

References 11 publications

Function of Small Hydrophobic Proteins of Paramyxovirus

Function of Small Hydrophobic Proteins of Paramyxovirus

Evaluation of a Neonatal Rat Model for Prediction of Mumps Virus Neurovirulence in Humans

Creation of Matrix Protein Gene Variants of Two Serotypes of Vesicular Stomatitis Virus as Prime-Boost Vaccine Vectors

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