Carey Brian D, Yu Shuiqing, Geiger Jillian, Ye Chengjin, Huzella Louis M, Reeder Rebecca J, Mehta Monika, Hirsch Shawn, Bernbaum Rebecca, Cubitt Beatrice, Pahar Bapi, Anthony Scott M, Marketon Anthony, Bernbaum John G, Tran Julie P, Crozier Ian, Martínez-Sobrido Luis, Worwa Gabriella, de la Torre Juan Carlos, Kuhn Jens H
Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
Department of Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, Texas, USA.
NPJ Vaccines. 2024 Nov 17;9(1):220. doi: 10.1038/s41541-024-01012-w.
Lassa virus (LASV) is a rodent-borne mammarenavirus that causes tens to hundreds of thousands of human infections annually in Western Africa. Approximately 20% of these infections progress to Lassa fever (LF), an acute disease with case-fatality rates from ≈20-70%. Currently, there are no approved vaccines or specific therapeutics to prevent or treat LF. The LASV genome consists of a small (S) segment that has two genes, GP and NP, and a large (L) segment that has two genes, L and Z. In both segments, the two genes are separated by non-coding intergenic regions (IGRs). Recombinant LASVs (rLASVs), in which the L segment IGR was replaced with the S segment IGR or in which the GP gene was codon-deoptimized, lost fitness in vitro, were highly attenuated in vivo, and, when used as vaccines, protected domesticated guinea pigs from otherwise lethal LASV exposure. Here, we report the generation of rLASV/IGR-CD, which includes both determinants of attenuation and further enhances the safety of the vaccine compared with its predecessors. rLASV/IGR-CD grew to high titers in Vero cells, which are approved for human vaccine production, but did not cause signs of disease or pathology in guinea pigs. Importantly, guinea pigs vaccinated with rLASV/IGR-CD were completely protected from disease and death after a typically lethal exposure to wild-type LASV. Our data support the development of rLASV/IGR-CD as a live-attenuated LF vaccine with stringent safety features.
拉沙病毒（LASV）是一种由啮齿动物传播的沙粒病毒，每年在西非导致数万至数十万例人类感染。这些感染中约20%会发展为拉沙热（LF），这是一种急性疾病，病死率约为20%-70%。目前，尚无批准用于预防或治疗拉沙热的疫苗或特效疗法。拉沙病毒基因组由一个小（S）片段和一个大（L）片段组成，小片段有两个基因，即糖蛋白（GP）基因和核蛋白（NP）基因，大片段有两个基因，即聚合酶（L）基因和Z基因。在这两个片段中，两个基因均由非编码基因间隔区（IGR）隔开。重组拉沙病毒（rLASV），其中L片段的IGR被S片段的IGR取代，或者GP基因进行了密码子去优化，在体外失去了适应性，在体内高度减毒，并且用作疫苗时，可保护家养豚鼠免受致死性拉沙病毒感染。在此，我们报告了rLASV/IGR-CD的构建，它包含两种减毒决定因素，与之前的疫苗相比进一步提高了疫苗的安全性。rLASV/IGR-CD在经批准用于人类疫苗生产的Vero细胞中生长至高滴度，但在豚鼠中未引起疾病或病理迹象。重要的是，用rLASV/IGR-CD接种疫苗的豚鼠在受到典型致死剂量的野生型拉沙病毒攻击后完全受到保护，未发病和死亡。我们的数据支持将rLASV/IGR-CD开发为一种具有严格安全特性的减毒活拉沙热疫苗。
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