Murphy B R, Holley H P, Berquist E J, Levine M M, Spring S B, Maassab H F, Kendal A P, Chanock R M
Infect Immun. 1979 Feb;23(2):253-9. doi: 10.1128/iai.23.2.253-259.1979.
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 degrees 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 degrees 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.
通过将A/安阿伯/6/60（H2N2）冷适应（ca）供体病毒与甲型流感野生型病毒交配制备的甲型流感/苏格兰/74（H3N2）和A/维多利亚/75（H3N2）冷适应重组病毒，在成年血清阴性志愿者（血清血凝抑制抗体效价，≤1:8）中评估了温度敏感和冷适应表型的减毒水平、抗原性和遗传稳定性。在10⁷.⁰至10⁷.⁵ 50%组织培养感染剂量下，A/苏格兰/74和A/维多利亚/75冷适应重组病毒明显减毒且具有抗原性。然而，8名接种10⁷.⁵ 50%组织培养感染剂量A/苏格兰/74冷适应重组病毒的受种者中有1人出现发热反应（39℃）。在高10倍的剂量（10⁸.⁵ 50%组织培养感染剂量）下，12名接种A/苏格兰/74的受种者中有4人出现发热和/或全身反应。接种A/维多利亚/75冷适应重组病毒的志愿者未观察到发热反应，而12名受种者中有3人出现轻度上呼吸道症状，其中1例伴有轻度全身表现。值得注意的是，血清血凝抑制和神经氨酸酶抑制抗体反应与野生型病毒诱导的反应相当。两种冷适应重组病毒在短时间内以低滴度排出。每个分离株都保留了温度敏感表型。然而，有证据表明冷适应标记存在遗传不稳定性，因为24个分离株中有7个表现出冷适应特性的部分丧失，1个分离株在25℃时完全丧失产生蚀斑的能力。A/苏格兰/74冷适应重组病毒中残留的低水平反应原性表明，对于缺乏血凝素免疫力的个体，冷适应重组病毒获得冷适应和温度敏感表型可能并不总能带来令人满意的减毒水平。
