Connors M, Collins P L, Firestone C Y, Sotnikov A V, Waitze A, Davis A R, Hung P P, Chanock R M, Murphy B R
Respiratory Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Vaccine. 1992;10(7):475-84. doi: 10.1016/0264-410x(92)90397-3.
In studies conducted in the 1960s, children previously immunized with a formalin-inactivated respiratory syncytial virus (RSV) vaccine (FI-RSV) developed a greater incidence and severity of pulmonary disease during subsequent natural RSV infection than did controls. It was previously shown that cotton rats immunized with FI-RSV or immunoaffinity-purified fusion (F) glycoprotein developed enhanced pulmonary histopathology following intranasal challenge with RSV. In the present studies, various forms of immunization, including parenteral inoculation of an immunoaffinity-purified F glycoprotein or a chimeric FG glycoprotein produced in insect cells using a baculovirus vector (Bac-FG), intradermal infection with a vaccinia-F recombinant (Vac-F) or intranasal infection with an adenovirus-F recombinant (Ad-F) or RSV, were compared for immunogenicity, efficacy and ability to alter the host so that enhanced pulmonary histopathology developed during RSV infection 3 months after immunization. Immunization of cotton rats with F glycoprotein, Bac-FG, Vac-F, Ad-F or infection with RSV induced high levels of ELISA-F antibodies, but the antibodies induced by purified F glycoprotein of Bac-FG had low levels of neutralizing activity. Immunization with Vac-F or Ad-F, or infection with RSV induced a high level of resistance to pulmonary RSV replication, whereas animals immunized with Bac-FG or FI-RSV were only partially protected. Following RSV challenge, animals immunized with purified F glycoprotein or Bac-FG developed the highest levels of bronchiolar and alveolar histopathology, those immunized with FI-RSV had intermediate levels, and those immunized with Vac-F or RSV had histopathology scores at control levels. Ad-F immunized animals had elevated scores of bronchiolar but not alveolar histopathology; however, this finding was not reproducible. Passive transfer of pooled immune sera from animals infected with RSV or Vac-F and Vac-G was highly protective, whereas pooled sera from animals immunized with Bac-FG failed to protect the lungs against RSV challenge. Increased pulmonary histopathology was not observed in the passively immunized animals following RSV challenge, suggesting that the histopathology was mediated by RSV-specific T cells. These data indicate that subunit F glycoprotein or chimeric FG vaccines share with FI-RSV the properties of (i) induction of F antibodies with low neutralizing activity and (ii) enhancement of pulmonary histopathology during subsequent RSV infection. These observations confirm the need for caution in studies involving the administration of RSV subunit vaccines to seronegative humans.
在20世纪60年代进行的研究中，先前用福尔马林灭活呼吸道合胞病毒（RSV）疫苗（FI-RSV）免疫的儿童在随后自然感染RSV期间发生肺部疾病的发生率和严重程度高于对照组。先前已表明，用FI-RSV或免疫亲和纯化的融合（F）糖蛋白免疫的棉鼠在经鼻内接种RSV后肺部组织病理学增强。在本研究中，比较了各种免疫形式，包括胃肠外接种免疫亲和纯化的F糖蛋白或使用杆状病毒载体（Bac-FG）在昆虫细胞中产生的嵌合FG糖蛋白、用痘苗-F重组体（Vac-F）进行皮内感染或用腺病毒-F重组体（Ad-F）或RSV进行鼻内感染，以评估其免疫原性、效力以及改变宿主的能力，从而使在免疫后3个月的RSV感染期间肺部组织病理学增强。用F糖蛋白、Bac-FG、Vac-F、Ad-F免疫棉鼠或用RSV感染可诱导高水平的ELISA-F抗体，但由Bac-FG的纯化F糖蛋白诱导的抗体具有低水平的中和活性。用Vac-F或Ad-F免疫或用RSV感染可诱导对肺部RSV复制的高度抗性，而用Bac-FG或FI-RSV免疫的动物仅得到部分保护。在RSV攻击后，用纯化F糖蛋白或Bac-FG免疫的动物出现最高水平的细支气管和肺泡组织病理学变化，用FI-RSV免疫的动物变化水平中等，而用Vac-F或RSV免疫的动物组织病理学评分处于对照水平。Ad-F免疫的动物细支气管组织病理学评分升高，但肺泡组织病理学评分未升高；然而，这一发现无法重复。来自感染RSV或Vac-F和Vac-G的动物的混合免疫血清的被动转移具有高度保护作用，而来自用Bac-FG免疫的动物的混合血清未能保护肺部免受RSV攻击。在RSV攻击后，被动免疫的动物未观察到肺部组织病理学变化增加，这表明组织病理学变化是由RSV特异性T细胞介导的。这些数据表明，亚单位F糖蛋白或嵌合FG疫苗与FI-RSV具有共同特性：（i）诱导具有低中和活性的F抗体；（ii）在随后的RSV感染期间增强肺部组织病理学变化。这些观察结果证实，在涉及向血清阴性的人类施用RSV亚单位疫苗的研究中需要谨慎。
