Evaluation of a Phenotypic Revertant of the A/Alaska/77-ts-1A2 Reassortant Virus in Hamsters and in Seronegative Adult Volunteers: Further Evidence That the Temperature-sensitive Phenotype is Responsible for Attenuation of Ts-1A2 Reassortant Viruses

In a previous study, a seronegative child to whom attenuated A/Alaska/77-ts-1A2 virus was administered (37 degrees C shutoff temperature for plaque formation) shed virus with an altered temperature-sensitive (ts) phenotype (40 degrees C shutoff temperature) (Murphy et al., Ann. N.Y. Acad. Sci. 354:172-182, 1980; Tolpin et al., Virology 112:505-517, 1981). This ts+ virus (FV1319) was evaluated for its level of replication in hamsters and for its virulence for humans. In hamsters, FV1319 ts+ virus replicated to the same level in the nasal turbinates as that of which the A/Alaska/77 wild-type virus replicated, but its replication in the lungs was reduced 40-fold. In contrast, the A/Alaska/77-ts-1A2 reassortant achieved a titer in hamster nasal turbinates that was significantly lower (P less than 0.005) than those achieved by the wild-type and the FV1319 viruses; the A/Alaska/77-ts-1A2 reassortant was not recoverable from the lungs. In seronegative adult volunteers, the pattern of replication of the FV1319 virus was similar to that of the A/Alaska/77 wild-type virus. The illness induced by the FV1319 ts+ virus was also similar to that caused by the wild-type virus. In contrast, the A/Alaska/77-ts-1A2 reassortant was satisfactorily attenuated in adult volunteers. These results suggest that attenuation of the A/Alaska/77-ts-1A2 reassortant virus in humans is a function of the ts phenotype: loss of this phenotype restored virulence. The ability of the A/Alaska/77-ts-1A2 reassortant to lose its ts phenotype and regain virulence during growth in a permissive host limits the usefulness of the ts-1A2 reassortants as vaccine viruses for humans.