Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.
mBio. 2020 Mar 24;11(2):e00186-20. doi: 10.1128/mBio.00186-20.
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 [rLASV(IGR/S-S)], which is based on the presence of the noncoding intergenic region (IGR) of the small (S) 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. 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 live-attenuated 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.
拉沙病毒（LASV）在西非的拉沙热流行地区构成了重大的公共卫生问题。LASV每年感染数十万人，相当数量的拉沙热病例与高发病率和死亡率有关。目前没有获得批准的 LASV 疫苗，而现有的治疗方法仅限于利巴韦林的标签外使用，这种方法仅部分有效，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 LASV 的有效疫苗的重要性。在这里，我们介绍了一种重组 LASV（rLASV）疫苗候选物[rLASV(IGR/S-S)]的开发和特性，该候选物基于大（L）和 S LASV 片段中小（S）基因组片段的非编码间基因区（IGR）的存在。在培养的细胞中，rLASV(IGR/S-S) 的适应性比野生型 rLASV（rLASV-WT）略差。rLASV(IGR/S-S) 在豚鼠中高度减毒，单次皮下低剂量病毒完全保护免受 LASV-WT 的致命感染。此外，rLASV(IGR/S-S) 在细胞培养中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) 可以开发成一种 LASV 活疫苗（LAV），其具有与 LASV-WT 相同的抗原组成，以及明确的减毒机制，可以克服人们对 LAV 在多次繁殖过程中由于遗传变化而导致毒力增加的担忧。拉沙病毒（LASV）是拉沙热的病原体，它感染了西非的数十万人，导致许多致命的拉沙热病例。没有美国食品和药物管理局批准的对策可用于预防或治疗 LASV 感染。我们描述了一种新型 LASV 活疫苗候选物 rLASV(IGR/S-S) 的产生，该候选物基于用小基因组片段的非编码间基因区（IGR）替换大基因组片段的非编码间基因区（IGR）。rLASV(IGR/S-S) 在细胞培养中的适应性比野生型病毒差，并且不会引起接种豚鼠的临床症状。重要的是，rLASV(IGR/S-S) 可保护免疫豚鼠免受 LASV 的致命暴露。
