Dose‐Response Assessment for Influenza A Virus Based on Data Sets of Infection with its Live Attenuated Reassortants

Reported data sets on infection of volunteers challenged with wild‐type influenza A virus at graded doses are few. Alternatively, we aimed at developing a dose‐response assessment for this virus based on the data sets for its live attenuated reassortants. Eleven data sets for live attenuated reassortants that were fit to beta‐Poisson and exponential dose‐response models. Dose‐response relationships for those reassortants were characterized by pooling analysis of the data sets with respect to virus subtype (H1N1 or H3N2), attenuation method (cold‐adapted or avian‐human gene reassortment), and human age (adults or children). Furthermore, by comparing the above data sets to a limited number of reported data sets for wild‐type virus, we quantified the degree of attenuation of wild‐type virus with gene reassortment and estimated its infectivity. As a result, dose‐response relationships of all reassortants were best described by a beta‐Poisson model. Virus subtype and human age were significant factors determining the dose‐response relationship, whereas attenuation method affected only the relationship of H1N1 virus infection to adults. The data sets for H3N2 wild‐type virus could be pooled with those for its reassortants on the assumption that the gene reassortment attenuates wild‐type virus by at least 63 times and most likely 1,070 times. Considering this most likely degree of attenuation, 10% infectious dose of H3N2 wild‐type virus for adults was estimated at 18 TCID50 (95% CI = 8.8–35 TCID50). The infectivity of wild‐type H1N1 virus remains unknown as the data set pooling was unsuccessful.