Temperature-sensitive mutants of influenza A virus. XII. Safety, antigenicity, transmissibility, and efficacy of influenza A/Udorn/72-ts-1[E] recombinant viruses in human adults

Abstract

The influenza A/Hong Kong/68-ts-1[E] virus (shutoff temperature, 38 C), which possesses many characteristics desirable in a vaccine virus, was used as a donor of its two temperature-sensitive (ts) lesions to the antigenically divergent influenza A/Udorn/72 wild-type virus. Two subsets of Udorn/72-ts-1[E] recombinant viruses were evaluated in seronegative volunteers (serum titer of hemagglutination-inhibiting antibody, less than or equal 1:8). The first subset, represented by clone 13, possessed a shutoff temperature of 39 C and only one of the two ts lesions; this virus was insufficiently attenuated for use in humans. The other subset, represented by clones 16 and 24, possessed both ts lesions and a shutoff temperature of 38 C, like that of its Hong Kong/68-ts-1[E] parent. This subset, also like its ts-1[E] parent, was adequately attenuated, nontransmissible, and protective against intranasal challenge with wild-type Udorn/72 virus. The attenuation manifested by the ts mutants was not a result of their cloning in bovine kidney tissue or replication in eggs. The results suggest that the Hong Kong/68-ts-1[E] virus can be considered for use as a master strain for donation of ts lesions and thus could bring about predictable attenuation of new wild-type influenza A viruses.