Norovirus dose-response in sewage-related QMRA: The importance of virus aggregation

Norovirus infection and illness are increasingly used as end-points in sewage-related health risk assessments, especially as data from clinical trials outbreak studies have recently become available. The authors of a very recent clinical trial have inferred that the human median infectious dose is higher than previous estimates and similar to that of other RNA viruses. This finding has the potential to cause a revision of previous risk assessments. However, in reaching this conclusion, the potential role of aggregation of these viruses seems not to have been accounted for, although it was accounted for in an earlier trial. In fitting (hypergeometric) dose-response curves to data from Norovirus clinical trials, the potential for the laboratory-stored stock of this non-culturable virus to have become aggregated onto storage matrix substances, as observed in a clinical trial, must be addressed. That is because standard dilution series calculations for doses are based on the assumption of uniform mixing of disaggregated particles. "Low" doses derived in this manner may therefore actually be "No" doses and lack of an infection response in trial participants at such doses may reflect absence of the virus in inocula, rather than reflecting its infectivity status. The possible consequences of including aggregation in a re-analysis of such data is explored. Research into the potential for sewage treatment processes to promote aggregation would be of benefit to sewagerelated QMRAs.