Scientific Publications by FDA Staff

Virology 2006 Jun 20;350(1):48-57

Changes in mumps virus neurovirulence phenotype associated with quasispecies heterogeneity.

Sauder CJ, Vandenburgh KM, Iskow RC, Malik T, Carbone KM, Rubin SA

Rubin SA, US FDA, Ctr Biol Evaluat & Res, DVP, Off Vaccines Res & Review, Bldg 29A,Room 1A-21,8800 Rockville Pike, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, DVP, Off Vaccines Res & Review, Bethesda, MD 20892 USA

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.