A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response
A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response
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DOI：
10.1128/jvi.06048-11
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Baric, Ralph S.
中科院分区：
文献类型：
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作者：
Bolles, Meagan;Deming, Damon;Baric, Ralph S.
严重急性呼吸道综合征冠状病毒（SARS-CoV）是一种重要的新型病毒，在老年人群中具有高致病性，并在人畜共患病宿主中保持着巨大的多样性。虽然多种疫苗平台已在动物模型中显示出针对同源病毒株的功效，但尚未使用复制人类流行期间所见的急性终末期肺病表型的高致病性变体来彻底评估疫苗功效。使用佐剂和无佐剂的双重灭活SARS-CoV（DIV）疫苗，我们证明了嗜酸性粒细胞免疫病理学在老年小鼠中看到的SARS核衣壳蛋白免疫小鼠，并对非致死性异源性挑战的保护差。在年轻和1岁的动物，我们证明，佐剂DIV疫苗提供保护，防止致命的疾病在年轻的动物同源和异源的挑战，虽然增强免疫病理学和嗜酸性粒细胞增多症是明显的异源挑战。在不存在明矾的情况下，DIV疫苗在用致死性同源或异源菌株攻击的年幼动物中表现不佳。相比之下，DIV疫苗（含佐剂和无佐剂）在老龄动物模型中表现较差。重要的是，老年动物在肺中显示出嗜酸性粒细胞免疫病理学增加，并且不能防止显著的病毒复制。这些数据引起了对DIV疫苗安全性的重大关注，并强调需要对DIV诱导的嗜酸性粒细胞增多和疫苗失效的分子机制进行额外研究，特别是在更脆弱的人类疾病老年动物模型中。
Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.