Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection
Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection
复制标题
DOI：
10.3389/fimmu.2020.01673
复制
发表时间：
2020-07-29
影响因子：
7.3
通讯作者：
Empey, Kerry M.
中科院分区：
文献类型：
--
作者：
Eichinger, Katherine M.;Kosanovich, Jessica L.;Empey, Kerry M.
呼吸道合胞病毒（RSV）仍然是全世界儿童下呼吸道感染的最常见原因。由于自然接触病毒后存在罹患增强型呼吸道疾病（ERD）的风险，疫苗的开发受到阻碍。已提出用稳定的融合前 F 蛋白抗原生成更高质量的中和抗体作为预防 ERD 的策略。我们试图测试用无佐剂的、稳定的融合前 F 蛋白免疫并用 RSV 19 系攻击的初始 BALB/c 小鼠是否存在 ERD 证据。我们进一步试图确定含有 Th2 偏向（明矾）或更 Th1/Th2 平衡（Advax-SM）佐剂的制剂对细胞反应和肺病理学的影响程度。当暴露于 RSV 时，单独使用融合前 F 蛋白 (PreF) 免疫的小鼠表现出气道嗜酸性粒细胞增多和粘液积聚增加。 PreF 与 Alum（氢氧化铝）的配方进一步加剧了这种情况。相反，PreF 与 Th1/Th2 平衡佐剂 Advax-SM 的配方不仅抑制 RSV 病毒复制，而且抑制气道嗜酸性粒细胞增多和粘液积聚。这与产生 IL-5+ 或 IL-13+ 的肺固有淋巴细胞 (ILC2) 和 CD4+ T 细胞数量减少以及 IFN gamma+ CD4+ 和 CD8+ T 细胞以及 RSV F 特异性 CD8+ T 细胞增加有关。这些数据表明，在缺乏预免疫的情况下，稳定的 PreF 抗原可能仍与异常 Th2 反应相关，异常 Th2 反应会诱导 RSV 感染引起的肺部病理学变化，并且可以通过配制更多 Th1/Th2 平衡佐剂（增强 CD4+ 和 CD8+ IFN γ+ T 细胞反应）来预防。这可能支持使用稳定的 PreF 抗原与 Th1/Th2 平衡佐剂（如 Advax-SM）作为 RSV 候选疫苗中明矾的更安全替代品。
Respiratory syncytial virus (RSV) remains the most common cause of lower respiratory tract infections in children worldwide. Development of a vaccine has been hindered by the risk of developing enhanced respiratory disease (ERD) upon natural exposure to the virus. Generation of higher quality neutralizing antibodies with stabilized pre-fusion F protein antigens has been proposed as a strategy to prevent ERD. We sought to test whether there was evidence of ERD in naive BALB/c mice immunized with an unadjuvanted, stabilized pre-fusion F protein, and challenged with RSV line 19. We further sought to determine the extent to which formulation with a Th2-biased (alum) or a more Th1/Th2-balanced (Advax-SM) adjuvant influenced cellular responses and lung pathology. When exposed to RSV, mice immunized with pre-fusion F protein alone (PreF) exhibited increased airway eosinophilia and mucus accumulation. This was further exacerbated by formulation of PreF with Alum (aluminum hydroxide). Conversely, formulation of PreF with a Th1/Th2-balanced adjuvant, Advax-SM, not only suppressed RSV viral replication, but also inhibited airway eosinophilia and mucus accumulation. This was associated with lower numbers of lung innate lymphocyte cells (ILC2s) and CD4+ T cells producing IL-5+ or IL-13+ and increased IFN gamma+ CD4+ and CD8+ T cells, in addition to RSV F-specific CD8+ T cells. These data suggest that in the absence of preimmunity, stabilized PreF antigens may still be associated with aberrant Th2 responses that induce lung pathology in response to RSV infection, and can be prevented by formulation with more Th1/Th2-balanced adjuvants that enhance CD4+ and CD8+ IFN gamma+ T cell responses. This may support the use of stabilized PreF antigens with Th1/Th2-balanced adjuvants like, Advax-SM, as safer alternatives to alum in RSV vaccine candidates.