High crossreactivity of human T cell responses between Lassa virus lineages

Lassa virus infects hundreds of thousands of people each year across rural West Africa, resulting in a high number of cases of Lassa fever (LF), a febrile disease associated with high morbidity and significant mortality. The lack of approved treatments or interventions underscores the need for an effective vaccine. At least four viral lineages circulate in defined regions throughout West Africa with substantial interlineage nucleotide and amino acid diversity. An effective vaccine should be designed to elicit Lassa virus specific humoral and cell mediated immunity across all lineages. Most current vaccine candidates use only lineage IV antigens encoded by Lassa viruses circulating around Sierra Leone, Liberia, and Guinea but not Nigeria where lineages I-III are found. As previous infection is known to protect against disease from subsequent exposure, we sought to determine whether LF survivors from Nigeria and Sierra Leone harbor memory T cells that respond to lineage IV antigens. Our results indicate a high degree of cross-reactivity of CD8+ T cells from Nigerian LF survivors to lineage IV antigens. In addition, we identified regions within the Lassa virus glycoprotein complex and nucleoprotein that contributed to these responses while T cell epitopes were not widely conserved across our study group. These data are important for current efforts to design effective and efficient vaccine candidates that can elicit protective immunity across all Lassa virus lineages.

拉沙病毒（Lassa virus）每年在西非农村地区感染数十万人，引发大量拉沙热（Lassa fever, LF）病例——拉沙热是一种伴随高发病率与显著死亡率的发热性疾病。目前尚无获批的治疗手段或干预措施，这凸显了研发有效疫苗的迫切需求。西非各地至少存在四种病毒谱系，各谱系间核苷酸与氨基酸多样性水平显著。一款有效的疫苗应能够诱导针对所有谱系的拉沙病毒特异性体液免疫与细胞介导免疫。当前多数候选疫苗仅采用塞拉利昂、利比里亚及几内亚周边流行的拉沙病毒IV型谱系编码的抗原，未覆盖存在I-III型谱系的尼日利亚地区。鉴于既往感染可预防后续暴露引发的疾病，本研究旨在探究尼日利亚与塞拉利昂的拉沙热幸存者体内是否存在可识别IV型谱系抗原的记忆T细胞。研究结果显示，尼日利亚拉沙热幸存者的CD8+ T细胞对IV型谱系抗原具有高度交叉反应性。此外，我们还鉴定出拉沙病毒糖蛋白复合物与核蛋白内参与此类免疫应答的区域，但本研究队列中的T细胞表位并未广泛保守。上述数据对于当前开发能够诱导覆盖所有拉沙病毒谱系的保护性免疫的高效疫苗候选物的研究工作具有重要意义。