Influenza virus infection in newborn rats: A possible marker of attenuation for man

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Abstract
The growth of parent influenza viruses A/England/939/69 and A/PR/8/34, and clones 6, 7, and 64C, derived by recombination, was studied in newborn rats. Using an inoculum of 104.0 EID50, influenza virus A/England/939/69 produced the highest titres of virus in rat turbinates at 48 hours after inoculation; clones 6 and 7 and A/PR/8/34 grew to lower titres; and clone 64C grew to the lowest titre. These differences were less apparent when 102.0 EID50 of virus was used as an inoculum, and rats were not infected by smaller inoculum of any of the virus strains. Infection with 104.0 EID50 of all viruses produced lung infection; at 48 hours after infection, the highest titres were recovered from rats infected with A/PR/8/34 and A/England/939/69 virus. Prior infection with A/England/939/69 or A/PR/8/34 increased the incidence of bacteraemia and meningitis following intranasal inoculation of Haemophilus influenzae type b; infection with clone 64C did not enhance bacterial meningitis, while infection with clone 6 gave an intermediate result. Volunteer studies with these viruses have shown that influenza virus A/England/939/69 was virulent, clones 6 and 7 were attenuated, clone 64C was overattenuated, and A/PR/8/34 virus was noninfective for man. The relative titres of virus recovered from turbinates taken 48 hours after infection with 104.0 EID50 of virus and the ability of virus infection to enhance bacterial infection correlated with the property of virus attenuation for man for four of the five strains tested; however, no correlation was seen for A/PR/8/34 virus, which is a result also found in other laboratory tests designed to measure virulence for man.