Genetic studies on a mumps vaccine strain associated with meningitis

Vaccination with mumps measles and rubella (MMR) vaccine containing the live attenuated mumps strain, Urabe AM9, is associated with an increased incidence of meningitis. The isolation of mumps virus from CSF and subsequent identification as Urabe AM9-like by sequence analysis confirmed the causative role of Urabe AM9 vaccine in meningitis. To assess the role of genetic reversion in vaccine failure, sequence comparisons were made between several genes of Urabe AM9 vaccine and post-vaccination meningitis mumps isolates. An amino acid substitution in the Urabe AM9 HN gene Lys335Glu was not detected in the post-vaccination meningitis isolates suggesting that reversion to wild type sequence was associated with vaccine failure. However, further analysis showed that the vaccine was a mixture of viruses that differed at aa 335 of HN, possessing either the wild type Lys335 or the mutant Glu335, whereas the clinical isolates were homogeneous and possessed the wild type Lys335. Passage of the Urabe AM9 vaccine preparations in Vero cells resulted in the amplification of the Glu335 virus, however the post-vaccination meningitis isolates (Lys335) grew better in Vero cells than Urabe AM9 vaccine. A virus isolate, similar to the post-vaccination isolates was obtained from the vaccine suggesting that the strain responsible for vaccine failure was a pre-existing component of the vaccine and was not necessarily the result of reversion. The Urabe AM9 vaccine is a heterogeneous mixture of genotypes that differ in virulence with the HN Glu335 viruses being attenuated and at least a subset of the HN Lys335 viruses that are associated with disease. The Glu335 mutation may be among a class of attenuating mutations identified in several neurotropic viruses that involve charged amino acids in neutralising epitopes of receptor binding proteins. Copyright 1998 John Wiley & Sons, Ltd.