LASSA FEVER VACCINE EFFICACY IN MARMOSETS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 拉沙病毒（LASV）是一种旧大陆沙粒病毒，也是拉沙出血热（LHF）的病原体，在西非每年造成多达30万例感染。 大约30%的感染导致疾病，从轻微的流感样疾病到致命的LHF，每年造成数千人死亡。 LASV巨大的疾病负担、严重的并发症、致命性和可用作生物战剂的可能性，为有效的疫苗开发提供了有力的理由。 携带LASV和非致病性Mopeia的RdRp的突变主要结构蛋白的ML 29拉沙热候选疫苗在豚鼠和恒河猴中减毒。 我们已经证明，ML 29疫苗保护豚鼠免受同源和异源LASV毒株的致死性感染。 在这里，我们报告了疫苗在非人灵长类动物中的有效性。 用1000 PFU的ML 29接种6只绒猴（Callithrix jacchus），并在第30天用致死剂量的LASV-Josiah进行攻击。第二组绒猴（n=4），即未接种疫苗的对照组，用相同剂量的LASV感染。观察动物的疾病临床体征，并采集血液用于血液学和血液化学。 在未接种疫苗的动物中，LASV感染诱导体重减轻、发热、组织中的高病毒血症和病毒负荷、肝酶升高、血浆中白蛋白水平降低以及感染后15-20天的严重发病率。显著的组织病理学结果包括肝坏死和靶组织细胞的免疫表型改变，证实了致死性人LHF的免疫抑制表型。 相反，接种疫苗的绒猴在攻毒后存活，无临床表现，而血液学和生化参数正常。重要的是，攻毒后16、21和28天采集的血浆样本中未检测到LASV水平。 这项工作证实了先前在LHF品系13豚鼠模型中获得的ML 29疗效、安全性和免疫原性数据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lassa virus (LASV), an Old World Arenavirus and the etiological agent of Lassa hemorrhagic fever (LHF), causes up to 300,000 annual infections in West Africa. Approximately 30% of infections result in disease varying from mild influenza-like illness to lethal LHF causing several thousand deaths per year. The large disease burden, severe complications, lethality and the possibility that LASV can be used as a biological warfare agent make a strong case for effective vaccine development. A ML29 Lassa fever vaccine candidate carrying mutated major structural proteins of LASV and RdRp of non-pathogenic Mopeia is attenuated in guinea pigs and rhesus macaques. We have shown that ML29 vaccine protects guinea pigs from lethal infection with homologous and heterologous LASV strains. Here we report the efficacy of the vaccine in nonhuman primates. Six Marmosets (Callithrix jacchus) were vaccinated with 1000 PFU of ML29 and challenged on day 30 with lethal dose of LASV-Josiah. A second group of marmosets (n=4), the unvaccinated control group, was infected with the same dose of LASV. Animals were observed for clinical signs of disease and blood was collected for hematology and blood chemistry. LASV infection induced weight loss, fever, high viremia and viral burden in tissues, elevated liver enzymes, decreased levels of albumin in plasma, and severe morbidity 15-20 days after infection in non vaccinated animals. Prominent histopathology findings included hepatic necrosis and immunophenotypic alterations of cells in target tissues confirming immunosuppressive phenotype of fatal human LHF. In contrast, vaccinated marmosets survived after challenge with no clinical manifestations while hematology and biochemical parameters were normal. Importantly, plasma samples collected 16, 21, and 28 days after challenge had no detectable levels of LASV. This work confirms the ML29 efficacy, safety and immunogenicity data previously obtained in the strain 13 guinea pig model of LHF.