A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
A Lassa Virus Live-Attenuated Vaccine Candidate Based on Rearrangement of the Intergenic Region
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DOI：
10.1128/mbio.00186-20
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发表时间：
2020-03-01
期刊：
影响因子：
6.4
通讯作者：
de la Torre, Juan Carlos
中科院分区：
文献类型：
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作者：
Cai, Yingyun;Iwasaki, Masaharu;de la Torre, Juan Carlos
拉沙病毒（LASV）在西非拉沙热流行区域内构成一个重大的公共卫生问题。每年有数十万人感染拉沙病毒，相当多的拉沙热病例具有高发病率和高致死率。没有批准的LASV疫苗可用，目前的治疗仅限于利巴韦林的超说明书使用，仅部分有效并伴有明显的副作用。拉沙热对人类健康的影响，以及现有的有限对策，突出了开发针对拉沙病毒的有效疫苗的重要性。在这里，我们提出了一种重组LASV（rLASV）候选疫苗ErLASV（IGR/S-S）的开发和表征，它是基于大(L)和S LASV片段中小(5)基因组片段（S-IGR）的非编码基因间区（IGR）的存在。在培养细胞中，rLASV（IGR/S-S）的拟合程度略低于野生型rLASV（rLASV- wt）。rLASV（IGR/S-S）在豚鼠体内被高度减毒，单次皮下低剂量的病毒完全保护豚鼠免受LASV-WT的致命感染。此外，rLASV（IGR/S-S）在培养细胞的连续传代过程中具有遗传稳定性。这些发现表明，rLASV（IGR/S-S）可以发展成LASV减毒活疫苗（LAV），具有与LASV- wt相同的抗原组成，并具有明确的衰减机制，克服了多轮增殖过程中LAV遗传变化可能引起的毒力增加的担忧。拉沙病毒（LASV）是拉沙热的病原体，在西非感染数十万人，导致许多致命的拉沙热病例。没有美国食品和药物管理局许可的对策可用于预防或治疗LASV感染。我们描述了一种新的LASV减毒活疫苗候选rLASV（IGR/S-S）的产生，它基于用小基因组片段替代大基因组片段非编码基因间区（IGR）。rLASV（IGR/S-S）在细胞培养中比野生型病毒更不适合，并且在接种的豚鼠中不会引起临床症状。重要的是，rLASV（IGR/S-S）可以保护免疫的豚鼠免受LASV的致命暴露。
Lassa virus (LASV) poses a significant public health problem within the regions of Lassa fever endemicity in Western Africa. LASV infects several hundred thousand individuals yearly, and a considerable number of Lassa fever cases are associated with high morbidity and lethality. No approved LASV vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. The impact of Lassa fever on human health, together with the limited existing countermeasures, highlights the importance of developing effective vaccines against LASV. Here, we present the development and characterization of a recombinant LASV (rLASV) vaccine candidate ErLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (5) genome segment (S-IGR) in both large (L) and S LASV segments. In cultured cells, rLASV(IGR/S-S) was modestly less fit than wild-type rLASV (rLASV-WT). rLASV(IGR/S-S) was highly attenuated in guinea pigs, and a single subcutaneous low dose of the virus completely protected against otherwise lethal infection with LASV-WT. Moreover, rLASV(IGR/S-S) was genetically stable during serial passages in cultured cells. These findings indicate that rLASV(IGR/S-S) can be developed into a LASV live-attenuated vaccine (LAV) that has the same antigenic composition as LASV-WT and a well-defined mechanism of attenuation that overcomes concerns about increased virulence that could be caused by genetic changes in the LAV during multiple rounds of multiplication.IMPORTANCE Lassa virus (LASV), the causative agent of Lassa fever, infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever cases. No U.S. Food and Drug Administration-licensed countermeasures are available to prevent or treat LASV infection. We describe the generation of a novel LASV liveattenuated vaccine candidate rLASV(IGR/S-S), which is based on the replacement of the large genomic segment noncoding intergenic region (IGR) with that of the small genome segment. rLASV(IGR/S-S) is less fit in cell culture than wild-type virus and does not cause clinical signs in inoculated guinea pigs. Importantly, rLASV(IGR/S-S) protects immunized guinea pigs against an otherwise lethal exposure to LASV.