Neurovirulence.

Alternatives to the standard WHO neurovirulence test (nvt) in simians for live attenuated poliovirus vaccines are highly developed, at least for poliovirus type 3. The alternatives are MAPREC, a molecular biological assay, and transgenic mice that express the human cellular receptor for polioviruses (TgPVR mice). The MAPREC assay quantifies reversion of key mutations that may accumulate during vaccine manufacture. Collaborative studies organised by WHO showed that the assay is sensitive, robust and standardised. WHO International Standard and Reference Reagents are established. Samples that fail the MAPREC assay need not be tested for neurovirulence in monkeys. The assay is now being used by both manufacturers and national control laboratories to characterise virus seeds and to monitor the consistency of production at the molecular level. A regulatory decision-making model has also been developed in the TgPVR21 mouse line. The model has been found a valuable indicator of neurovirulence in a WHO collaborative study. These alternative methods are the fruits of a long-term basic research programme on the molecular biology of polioviruses and provide an excellent example of co-ordinated regulatory research.