Temperature-sensitive mutants of influenza A virus: evaluation of the Alaska/77-ts-1A2 temperature-sensitive recombinant virus in seronegative adult volunteers.

An influenza A virus recombinant bearing the surface antigens of the A/Alaska/6/77 (H3N2) wild type virus ands the two ts genes of the A/Udorn/72-ts-1A2 (H3N2) virus was evaluated for attenuation, antigenicity, and transmissibility in 28 adult volunteers all of whom possessed a preinoculation serum hemagglutination-inhibiting (HAI) antibody titer of less than or equal to 1:8 and 18 of whom also possessed a serum neuraminidase-inhibiting (NI) antibody titer of less than or equal to 1:4. The Alaska/77-ts-1A2 recombinant, which had a 37 degrees C shutoff temperature for plaque formation and ts mutations on the genes thought to code for the P1 and P3 polymerase proteins, infected 71 percent of the vaccinees when administered at a dose of 10(6.5) TCID50. Only 3 percent of the vaccinees developed symptoms in contrast to 50 percent of volunteers who received 10(4.2) TCID50 of wild type virus. Vaccinees shed virus for a shorter interval and at a lower titer than the volunteers who received wild type virus. Each ts-1A2 isolate retained the ts phenotype indicating that the recombinant was stable genetically in seronegative adults. An immunological response, as measured by a rise in serum HAI and/or NI antibody, was detected in 71 percent of the vaccinees and 87 percent of the recipients of wild type virus. Transmission of vaccine virus to susceptible contacts was not observed. The two ts-1A2 ts genes have now been transferred to two variants within the H3N2 subtype, the Vic/75 and Alaska/77 viruses, and have rendered the viruses satisfactorily attenuated for adults. The level of infectivity of the Alaska/77-ts-1A2 virus appeared to be low, however.