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Prior to 1967, attenuation of influenza virus was achieved by gradually lowering the incubation temperature until optimal growth at 25 degrees C was obtained. The process of attenuation of a Hong Kong strain was modified and considerably shortened. The temperature of incubation was changed abruptly from 35 degrees C to 25 degrees C and a cold variant was selected using the plaque-assay system.A set of genetic markers was developed for assessing the potential virulence of cold-passaged variants. The cold variant of the Hong Kong strain was temperature-sensitive, acid-labile and produced a small plaque in primary chick kidney cells incubated at 35 degrees C. Additional differentiating biological properties relating to the adaptation of the virus to growth at 25 degrees C and to loss of virulence in a susceptible host are presented.The cold-adapted variant was found to be relatively avirulent and highly antigenic for mice and ferrets, and virus was recovered from the nasopharynx of infected ferrets during the first 3 days. The virus recovered was still unable to grow well at 41 degrees C (rct/41-), was sensitive to acid pH and produced small plaques at 35 degrees C and larger ones at 25 degrees C.After a series of plaque purifications, the cold variant showed further loss of virulence to mice, more vigorous growth at 25 degrees C, complete failure to grow at 41 degrees C and good antigenic potency.The genetic markers were stable in the plaque-purified cold variant after at least 10 consecutive passages either in tissue culture at 35 degrees C, or in mice.Cold variants of type B influenza virus have a narrower range of temperature sensitivity compared with type A strains. Reduced plaquing efficiency and reproductive capacity occurred at 35 degrees C (rct/35-) with the attenuated type B strains instead of at 41 degrees C as with the type A strains.Clinical trials with the attenuated Hong Kong strain of influenza virus (A2/Aichi/2/68) have demonstrated the acceptability and immunogenicity of the strain in man.
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