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Changes in mumps virus neurovirulence phenotype associated with quasispecies heterogeneity
Christian J Sauder1, Kari M Vandenburgh, Rebecca C Iskow
1DVP/Office of Vaccines Research and Review, Center for Biologics, Evaluation and Research, Food and Drug Administration, Building 29A, Room 1A-21, 8800 Rockville Pike, Bethesda, MD 20892, USA.
Abstract:
Mumps virus is a highly neurotropic virus with evidence of central nervous system invasion (CNS) in approximately half of all cases of infection. In countries where live attenuated mumps virus vaccines were introduced, the number of mumps cases declined dramatically; however, recently, the safety of some vaccine strains has been questioned. For example, one of the most widely used vaccines, the Urabe AM9 strain, was causally associated with meningitis, leading to the withdrawal of this product from the market in several countries. This highlights the need for a better understanding of the attenuation process and the identification of markers of attenuation. To this end, we further attenuated the Urabe AM9 strain by serial passage in cell culture and compared the complete nucleotide sequences of the parental and passaged viruses. Interestingly, despite a dramatic decrease in virus virulence (as assayed in rats), the only genomic changes were in the form of changes in the level of genetic heterogeneity at specific genome sites, i.e., either selection of one nucleotide variant at positions where the starting material exhibited nucleotide heterogeneity or the evolution of an additional nucleotide to create a heterogenic site. This finding suggests that changes in the level of genetic heterogeneity at specific genome sites can have profound neurovirulence phenotypic consequences and, therefore, caution should be exercised when evaluating genetic markers of virulence or attenuation based only on a consensus sequence.
Insights
Further attenuating the Urabe AM9 mumps virus strain by cell culture passage reduced virulence. Genomic changes involved altered genetic heterogeneity, not consensus sequence shifts, suggesting caution in identifying attenuation markers.
Area of Science:
- Virology
- Neuroscience
- Vaccine Development
Background:
- Mumps virus is neurotropic, causing central nervous system (CNS) invasion in about half of infections.
- Live attenuated mumps virus vaccines significantly reduced disease, but safety concerns have arisen.
- The Urabe AM9 vaccine strain was linked to meningitis, leading to its market withdrawal in several countries.
Purpose of the Study:
- To understand the attenuation process of mumps virus vaccine strains.
- To identify genetic markers associated with mumps virus attenuation.
- To investigate genomic changes in a passaged, attenuated Urabe AM9 strain.
Main Methods:
- Serial passage of the Urabe AM9 mumps virus strain in cell culture to achieve further attenuation.
- Comparison of the complete nucleotide sequences of the parental and passaged Urabe AM9 viruses.
- Assay of virus virulence in rats.
Main Results:
- Further passage in cell culture dramatically decreased the virulence of the Urabe AM9 strain in rats.
- Genomic analysis revealed no consensus sequence changes, but alterations in genetic heterogeneity at specific sites.
- Observed changes included selection of nucleotide variants and creation of new heterogeneous sites.
Conclusions:
- Changes in the level of genetic heterogeneity at specific genome sites can significantly impact mumps virus neurovirulence.
- Evaluating genetic markers of virulence or attenuation solely based on consensus sequences may be misleading.
- Further research is needed to understand the role of genetic heterogeneity in mumps virus attenuation and neurotropism.
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