Stott E J, Taylor G, Ball L A, Anderson K, Young K K, King A M, Wertz G W
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27514.
J Virol. 1987 Dec;61(12):3855-61. doi: 10.1128/JVI.61.12.3855-3861.1987.
Previous reports have established that vaccinia virus (VV) recombinants expressing G, F, or N protein of respiratory syncytial (RS) virus protect small animals against intranasal challenge with live RS virus. This work demonstrates that a variety of parameters affect the protection induced by recombinant viruses. The route of vaccination, the subtype of challenge virus, and the species used influenced the antibody titers and extent of protection. During these studies, observations were also made on the subclass of antibody generated, and pulmonary histopathological changes induced by challenge after vaccination were noted. The effect of route of inoculation on host response was examined by vaccinating mice intranasally, intraperitoneally, or by scarification with a recombinant VV expressing the RS virus G glycoprotein. Intranasal vaccination induced 25-fold-higher titers of antibody to RS virus in the lung than the intraperitoneal route did, but both routes resulted in complete suppression of virus replication after intranasal challenge 21 days after vaccination. Scarification was a less effective method of vaccination. The antibody induced by recombinant VV in mice was mostly immunoglobulin G2a (IgG2a) with some IgG2b. No antibody to RS virus was detected in the IgA, IgM, IgG1, or IgG3 subclass irrespective of the vaccination route. The G and F glycoproteins were shown to elicit similar subclasses of antibody. However, animals vaccinated with the G and F vectors differed strikingly in their response to challenge by heterologous virus. Mice or cotton rats vaccinated with recombinant VV carrying the G gene of RS virus were protected against challenge only with homologous subtype A virus. Vaccination with a recombinant VV expressing the F glycoprotein induced protection against both homologous and heterologous subtype B virus challenge. The protection induced in mice was greater than that detected in cotton rats, indicating that the host may also affect immunity. Finally, this report describes histological examination of mouse lungs after vaccination and challenge. Vaccinated mice that were subsequently challenged had significantly greater lung lesion scores than unvaccinated challenged mice. The lesions were primarily peribronchiolar and perivascular infiltrations of polymorphonuclear cells and lymphocytes. Further work will establish whether these pulmonary changes are a desirable immune response to virus invasion or a potential immunopathogenic hazard. The results have important implications for planning a strategy of vaccination against RS virus and emphasize potential dangers that may attend the use of recombinant VV as vaccines.
先前的报告已证实，表达呼吸道合胞（RS）病毒G、F或N蛋白的痘苗病毒（VV）重组体可保护小动物免受活RS病毒的鼻内攻击。这项研究表明，多种参数会影响重组病毒诱导的保护作用。接种途径、攻击病毒的亚型以及所用物种都会影响抗体滴度和保护程度。在这些研究过程中，还对产生的抗体亚类进行了观察，并记录了接种疫苗后攻击所诱导的肺部组织病理学变化。通过给小鼠进行鼻内、腹腔内接种或用表达RS病毒G糖蛋白的重组VV划痕接种，来研究接种途径对宿主反应的影响。鼻内接种诱导的肺中针对RS病毒的抗体滴度比腹腔内接种高25倍，但两种途径在接种疫苗21天后鼻内攻击后均导致病毒复制完全受到抑制。划痕接种是一种效果较差的接种方法。重组VV在小鼠中诱导的抗体主要是免疫球蛋白G2a（IgG2a），还有一些IgG2b。无论接种途径如何，在IgA、IgM、IgG1或IgG3亚类中均未检测到针对RS病毒的抗体。G和F糖蛋白诱导产生相似的抗体亚类。然而，用G和F载体接种疫苗的动物在对异源病毒攻击的反应上有显著差异。用携带RS病毒G基因的重组VV接种的小鼠或棉鼠仅对同源A亚型病毒攻击有保护作用。用表达F糖蛋白的重组VV接种可诱导对同源和异源B亚型病毒攻击的保护作用。在小鼠中诱导的保护作用大于在棉鼠中检测到的保护作用，表明宿主也可能影响免疫。最后，本报告描述了接种疫苗和攻击后小鼠肺部的组织学检查。随后受到攻击的接种疫苗小鼠的肺部病变评分明显高于未接种疫苗的受攻击小鼠。病变主要是多形核细胞和淋巴细胞的支气管周围和血管周围浸润。进一步的研究将确定这些肺部变化是对病毒入侵的理想免疫反应还是潜在的免疫致病危险。这些结果对规划RS病毒疫苗接种策略具有重要意义，并强调了使用重组VV作为疫苗可能存在的潜在危险。
