Jeryl-Lynn Research Articles

Mumps Outbreaks in Canada and the United States: Time for New Thinking on Mumps Vaccines

Mumps epidemics in Canada and the United States prompted us to review evidence for the effectiveness of 5 different vaccine strains. Early trials with the Jeryl Lynn vaccine strain demonstrated an efficacy of approximately 95%, but in epidemic conditions, the effectiveness has been as low as 62%; this is still considerably better than the effectiveness of another safe strain, Rubini (which has an effectiveness of close to 0% in epidemic conditions). The Urabe vaccine strain has an effectiveness of 54%-87% but is prone to cause aseptic meningitis. Little epidemiological information is available for other vaccines. The Leningrad-Zagreb vaccine strain, which is widely used in developing countries and costs a fraction of what vaccines cost in the developed world, seems to have encouraging results; in 1 study, the effectiveness of this vaccine exceeded 95%. Aseptic meningitis has also been reported in association with this vaccine, but the benign nature of the associated meningitis was shown recently in Croatia. Also, the Leningrad-3 strain seems to be effective but causes less-benign meningitis. No mumps vaccine equals the best vaccines in quality, but the virtually complete safety of some strains may not offset their low effectiveness. Epidemiological data are pivotal in mumps, because serological testing is subject to many interpretation problems.

Neurovirulence of mumps virus: intraspinal inoculation test in marmosets

An intraspinal inoculation test of mumps virus using marmosets was performed in order to develop a neurovirulence test of mumps vaccines. In the group inoculated with non-neurovirulent Jeryl Lynn vaccine strain at 10 2.0 pfu/dose, there were only minimal histopathological changes in 3 of the 5 marmosets. In contrast, all marmosets inoculated with neurovirulent Urabe and NK-M46 vaccine strains developed extensive encephalitis and meningitis. Thus, this marmoset model, which can distinguish between non-neurovirulent and neurovirulent vaccine strains, is useful for evaluating neurovirulence of vaccine strains and elucidating the molecular pathogenesis of mumps.

Changes in mumps virus gene sequence associated with variability in neurovirulent phenotype.

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.

Antigenic relationships between six genotypes of the small hydrophobic protein gene of mumps virus.

Six different genotypes of mumps virus, A, C, D, G, H and I, genotyped on the basis of the small hydrophobic protein gene sequence, were subjected to antigenic comparison. Monoclonal antibodies directed against the haemagglutinin-neuraminidase protein of the SBL-1 strain of genotype A were used in immunofluorescence tests with different mumps virus strains. In addition, the six virus genotypes were compared by cross-neutralization tests with human post-vaccination sera after vaccination with the Jeryl Lynn (JL) strain of mumps virus and with rabbit hyperimmune sera directed against the A or D genotypes of mumps virus. Genotypes C, D, G, H and I could not be antigenically separated. In contrast, three different virus strains of genotype A, SBL-1, JL and Kilham, were distinct and were found to represent three different serotypes within the A genotype of mumps virus. Vaccination of Swedish children with the JL strain of mumps virus resulted in clearly lower neutralization titres against the SBL-1 strain, which is endemic in Sweden, compared to the homologous vaccine titres.

Sequence Diversity of Jeryl Lynn Strain of Mumps Virus: Quantitative Mutant Analysis for Vaccine Quality Control

The Jeryl Lynn strain of mumps vaccine live (MVL) was developed in 1966 by Merck Co. and has been widely used in the U.S. and other countries since the early 1970s. Partial sequencing has recently shown that the vaccine contains a mixture of two substrains with substantially different nucleotide sequences. We have determined the complete genomic sequences of both substrains and identified 414 nucleotide differences (2.69%), leading to 87 amino acid substitutions (1.67%). We used this information to develop methods for quantification of the substrain components in vaccine samples based on PCR and restriction enzyme cleavage and oligonucleotide microarray hybridization and monitored their dynamics in viral populations propagated in different conditions. Passaging Jeryl Lynn strain in Vero or CEF cell cultures resulted in rapid selection of the major component JL1, while growth in embryonated chicken eggs (ECE) favored accumulation of the minor component JL2. Based on the findings presented here, it is proposed that the substrain composition of Jeryl Lynn vaccine can be monitored as a part of its quality control to ensure consistency of the vaccine.

Pathogenicity of mumps virus in the marmoset.

The neurovirulence of two mumps virus strains was compared using marmosets. Marmosets were inoculated intravenously with the wild-type mumps virus Odate strain, resulting in evident meningitis in 1 of 3 marmosets at each of the weeks 3, 4, and 5 postinoculation, representing a total of 3 out of 9 marmosets. Nephritis, parotitis, pancreatitis, and tonsillitis were manifest in addition to central nervous system (CNS) sequelae. On the other hand, the Jeryl Lynn vaccine strain did not induce histopathological changes in the CNS and multiplication of the Jeryl Lynn strain was distinctly lower compared to that of the Odate strain in the marmoset. This is the first report to describe the induction of meningitis in non-human primates after peripheral inoculation of a wild-type mumps virus, presenting findings useful for the elucidation of the mechanism of infection and pathology of mumps virus in the CNS. The distinction observed between the Odate and Jeryl Lynn strains suggests the applicability of the marmoset model for the evaluation of any neurovirulence potential of vaccine strains.

Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system.

Amplification of viral nucleic acids from the cerebrospinal fluid (CSF) has considerably improved the diagnosis of several acute, subacute and chronic viral infections of the nervous system. In herpes simplex virus (HSV) encephalitis (HSE) the polymerase chain reaction (PCR) has become the method of choice for the rapid, non invasive diagnosis. Other herpes virus associated diseases which can now be reliably diagnosed are encephalitis, ventriculoencephalitis, polymyeloradiculitis, myelitis and an inflammatory polyradiculoneuropathy caused by cytomegalovirus (CMV), HSV, varicella-zoster virus (VZV) or Epstein-Barr virus (EBV), EBV associated primary B-cell-lymphoma of the brain, acute aseptic meningitis in young adults allied with VZV, and meningoencephalitis with recurrent seizures due to human herpes virus type 6 (HHV-6). In AIDS patients, PCR has helped to differentiate lesions either due to the human immunodeficiency virus (HIV) itself or to opportunistic infections such as progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) or CMV related complications. HIV can be detected early in the course of infection in the CSF and the amount of proviral DNA in CSF cells seems to be correlated with the severity and/or progression of neurological signs and symptoms. Acute epidemic aseptic meningitis caused by enterovirus infections can now be reliably diagnosed and typed by reverse transcriptase PCR (RT-PCR). Meningitis cases caused by vaccination with the Jeryl Lynn and Urabe vaccine strain of mumps virus have been identified using RT-PCR and sequencing of the amplified products (amplicon).

Vaccine against mumps containing a jeryl-lynn virus strain (NM Harford et al, BE)

Vaccine against mumps containing a jeryl-lynn virus strain (NM Harford et al, BE)

The Jeryl Lynn vaccine strain of mumps virus is a mixture of two distinct isolates.

Sequence analysis of the region of the mumps virus genome encoding the putative small hydrophobic protein gene confirms that it is a highly variable region. Jeryl Lynn, the mumps vaccine strain used in the U.K., is shown to be a mixture of two closely related viruses, both probably of American origin.

Vaccine safety versus vaccine efficacy in mass immunisation programmes

In community-wide immunisation programmes against childhood infections there is a conflict between the interests of the individual (vaccine safety and efficacy) and the interests of the community (vaccine uptake and level of herd immunity). Studies suggesting that the complication rate is greater with the high efficacy Urabe Am 9 mumps vaccine than with the lower efficacy Jeryl Lynn vaccine, have led to concern about whether the higher efficacy mumps vaccine should be introduced or retained in nationwide mass immunisation programmes. We describe the use of a mathematical model to assess benefits and risks to both individual and community, and illustrate this method by reference to immunisation programmes based on these vaccines. On the basis of current epidemiological data on viral transmission and vaccine coverage in England and Wales, data on vaccine-associated and infection-associated complication rates, and vaccine efficacies estimated from clinical trials, our analyses suggest there is little to chose between the two vaccines, but that overall performance depends on the level of vaccine coverage in a defined population. In community-based programmes, the greater apparent safety of the Jeryl Lynn vaccine (fewer vaccine-included complications) is offset by the greater apparent efficacy of the Urabe Am 9 vaccine (fewer complications due to natural infection). The findings suggest that it may not always be in the interests of the community to use the vaccine with the lowest complication rate.

Nucleotide sequence analysis of Urabe mumps vaccine strain that caused meningitis in vaccine recipients

Mumps virus was isolated from the cerebrospinal fluid of eight patients who acquired meningitis within 4 weeks of immunization with live Trivirix vaccine that contains mumps (Urabe Am 9), measles (Schwarz), and rubella (RA 27/3) viruses. Part of the haemagglutinin-neuraminidase (HN) gene from three postvaccination isolates of mumps virus, three wild strains and the Urabe and Jeryl Lynn vaccine strains was cloned following polymerase chain reaction (PCR) amplification, for the purpose of sequence analysis. A 200-nucleotide portion of the cloned HN genes was sequenced and compared to published sequences of two other strains (RW and SBL-1). The postvaccination mumps strains were identical in sequence to Urabe and were distinguishable from the wild and the Jeryl Lynn vaccine strains. Twenty-two out of 200 position were seen to vary among the group of viruses. It was concluded that the Urabe vaccine strain was the cause of postvaccination meningitis. Therefore, with effect from 1990, Trivirix measles, mumps and rubella vaccine is no longer licensed for sale in Canada.

Differentiation of vaccine and wild mumps viruses using the polymerase chain reaction and dideoxynucleotide sequencing

Parts of the F gene from 16 mumps viruses derived from vaccines and clinical isolates were amplified using the polymerase chain reaction and their nucleotide sequences were determined. Over a region of 111 nucleotides, eight regions of variability were detected with a maximum of six (5.4%) changes occurring between any two virus strains. The Jeryl Lynn and Urabe vaccine strains were clearly different from each other and from wild virus isolated from cases of non-vaccine-associated mumps. In contrast, viruses isolated from the cerebrospinal fluid and throat in cases of meningitis and parotitis following vaccination with the Urabe strain were identical to this strain. We conclude that the vaccine was the source of these infections.

Antigenic Variation of Envelope and Internal Proteins of Mumps Virus Strains Detected with Monoclonal Antibodies

Antigenic characteristics of nine mumps virus strains were determined by immunofluorescence and radioimmunoprecipitation assay (RIPA) using a collection of 44 monoclonal antibodies. These antibodies were directed against five different structural components of mumps virus, the haemagglutinin-neuraminidase (HN), fusion (F), matrix (M), phospho- (P) and nucleocapsid (NP) proteins. The nine mumps virus strains could be divided into two groups according to their antigenic characteristics. One group included two strains isolated more than a decade ago and the Jeryl Lynn vaccine strain. These three strains reacted with a wider range of monoclonal antibodies than the second group of six recently isolated strains of different geographical origin. In the F, M and P proteins variations were only found in single antigenic determinants. In the HN and NP components, RIPA revealed variations in three and seven determinants respectively. The Jeryl Lynn vaccine strain showed a unique lack of reaction with one anti-HN antibody clone in the RIPA.

The immunizing effect and reactogenicity of two live attenuated mumps virus vaccines in Swedish schoolchildren

An evaluation of the seroconversion and booster effects after vaccination with two different mumps vaccines, the Urabe Am 9 strain and the Jeryl Lynn strain, was carried out in schoolchildren. Four hundred and fifty-four schoolchildren aged 11 to 12 years with no previous history of mumps or mumps vaccination were enrolled for the study. The antibody responses were measured by serum neutralization (SN) and haemolysis-in-gel (HIG) tests. Of the 454 subjects, 130 were found to be initially seronegative. Two lots of different strengths of each vaccine were used to evaluate the relationships. The Urabe Am 9 vaccine lots had infectivity titres of 100 000 and 19 000 TCID50 per dose and the Jeryl Lynn vaccine titres of 59 000 and 28 000 TCID50 per dose. Only slight differences in seroconversion rates were seen between the lots. The overall seroconversion rate, measured by SN, was 94% for the Urabe Am 9 vaccine and 91% for the Jeryl Lynn vaccine, whereas the geometric mean titre for virus-neutralizing antibody in seroconverting children was 7.4 with the Urabe Am 9 vaccine and 10.7 with the Jeryl Lynn vaccine. In children who were seropositive prior to vaccination, a marked rise in antibody titre was found 8 weeks after vaccine injection indicating a booster effect. The miscellaneous post-vaccination side-effects were mild and inconsequential.

Evaluation of Enzyme-Linked Immunosorbent Assay (ELISA) for Mumps Virus Antibodies

SummaryPre- and postvaccination sera from individuals who had been vaccinated with live Jeryl-Lynn vaccine were assayed for mumps antibodies by using serum neutralization (NT), enzymed-linked immun...