Cold-Adapted Variants of Influenza A Virus: Evaluation in Adult Seronegative Volunteers of A/Scotland/840/74 and A/Victoria/3/75 Cold-Adapted Recombinants Derived from the Cold-Adapted A/Ann Arbor/6/60 Strain

Abstract

Influenza A/Scotland/74 (H3N2) and A/Victoria/75 (H3N2) cold-adapted ( ca ) recombinant viruses, prepared by mating the A/Ann Arbor/6/60 (H2N2) ca donor virus and influenza A wild-type virus, were evaluated in adult seronegative volunteers (serum hemagglutination-inhibiting antibody titer, ≤1:8) for level of attenuation, antigenicity, and genetic stability of the temperature-sensitive and ca phenotypes. At 10 7.0 to 10 7.5 50% tissue culture infective doses the A/Scotland/74 and A/Victoria/75 ca recombinant viruses were clearly attenuated and antigenic. However, one of eight vaccinees infected with 10 7.5 50% tissue culture infective doses of the A/Scotland/74 ca recombinant had a febrile reaction (39°C). At a 10-fold higher dose (10 8.5 50% tissue culture infective doses), 4 of 12 A/Scotland/74 vaccinees had a febrile and/or systemic reaction. Febrile reactions were not observed in volunteers who received the A/Victoria/75 ca recombinant virus, whereas 3 of the 12 vaccinees had mild upper respiratory tract symptoms, in one instance associated with mild systemic manifestations. Significantly, the serum hemagglutination- and neuraminidase-inhibiting antibody responses were comparable to those induced by wild-type virus. Both ca recombinant viruses were shed in low titer for a short period of time. Each isolate retained the temperature-sensitive phenotype. However, there was evidence of genetic instability of the ca marker in that 7 of 24 isolates exhibited some loss of the ca property, and one isolate completely lost the capacity to produce plaques at 25°C. The retention of a low level of residual reactogenicity in the A/Scotland/74 ca recombinant suggests that acquisition of the ca and temperature-sensitive phenotypes by a ca recombinant virus may not always bring about a satisfactory level of attenuation for individuals lacking hemagglutinin immunity.