Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity.
Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity.
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从mRNA疫苗传递的丙型肝炎病毒E1和修饰的E2可诱导保护性免疫。
DOI：
10.1038/s41541-023-00635-9
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发表时间：
2023-03-18
期刊：
影响因子：
9.2
通讯作者：
中科院分区：
文献类型：
--
作者：
丙型肝炎病毒（HCV）的特征在于由于保护性先天和适应性免疫应答受损而导致大量慢性病例。在这里，我们研究了E1、E2或具有降低的CD 81结合和插入的N-连接糖基化位点的修饰的E2的单个胞外域组合作为疫苗抗原mRNA-脂质纳米颗粒（LNP）的贡献。在BALB/c小鼠模型中观察到对表达同源HCV糖蛋白的替代重组痘苗病毒（VV）攻击感染的保护性免疫应答的诱导。用表达可溶性E1（sE 1）的mRNA-LNP接种显著降低小鼠卵巢中的vv/HCV滴度。然而，添加sE 2 mRNA-LNP用于免疫损害了sE 1构建体的功效。进一步的分析表明，在共同免疫后，在sE 2存在下，对sE 1 mRNA-LNP的Th 1相关细胞因子应答显著改变。免疫原性评价显示，使用修饰的sE 2F 442 NYT核苷mRNA-LNP疫苗导致改善的细胞免疫应答、IgG 2a同种型转换、增强的总IgG和针对HCV假型病毒的中和抗体应答的增加。HCV跨基因型特异性反应的肽代表保守的E2特异性线性表位增强在修改E2疫苗接种的动物血清。在没有合适的HCV感染的免疫活性小动物模型的情况下，与单独的sE 1或未修饰的sE 2 mRNA-LNP疫苗相比，在免疫小鼠中观察到对替代HCV牛痘攻击感染模型的保护。包含具有修饰的sE 2F 442 NYT的sE 1作为mRNA-LNP疫苗候选物似乎有利于保护。
Hepatitis C virus (HCV) is characterized by a high number of chronic cases due to an impairment of protective innate and adaptive immune responses. Here, we examined the contribution of the individual ectodomains of E1, E2, or a modified E2 with reduced CD81 binding and an inserted N-linked glycosylation site in combination as vaccine antigen mRNA-lipid nanoparticles (LNPs). The induction of a protective immune response to surrogate recombinant vaccinia virus (VV) expressing homologous HCV glycoprotein(s) challenge infection in a BALB/c mouse model was observed. Vaccination with a mRNA-LNP expressing soluble E1 (sE1) significantly reduced vv/HCV titer in the mouse ovary. However, the addition of sE2 mRNA-LNP for immunization impaired the efficacy of the sE1 construct. Further analysis showed that Th1 related cytokine responses to the sE1 mRNA-LNP were significantly altered in the presence of sE2 following co-immunization. Evaluation of immunogenicity revealed that the use of modified sE2F442NYT nucleoside mRNA-LNP vaccine results in an improved cellular immune response, IgG2a isotype switching, enhanced total IgG, and an increase in the neutralizing antibody response against HCV pseudotype virus. HCV cross genotype specific reactivity to peptides representing conserved E2 specific linear epitopes were enhanced in modified E2 vaccinated animal sera. In the absence of a suitable immunocompetent small animal model for HCV infection, protection from surrogate HCV vaccinia challenge infection model was observed in the immunized mice as compared to sE1 alone or an unmodified sE2 mRNA-LNP vaccine. Inclusion of sE1 with modified sE2F442NYT as mRNA-LNP vaccine candidate appeared to be beneficial for protection.
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影响因子：
32.4
作者：
Alameh MG;Tombácz I;Bettini E;Lederer K;Sittplangkoon C;Wilmore JR;Gaudette BT;Soliman OY;Pine M;Hicks P;Manzoni TB;Knox JJ;Johnson JL;Laczkó D;Muramatsu H;Davis B;Meng W;Rosenfeld AM;Strohmeier S;Lin PJC;Mui BL;Tam YK;Karikó K;Jacquet A;Krammer F;Bates P;Cancro MP;Weissman D;Luning Prak ET;Allman D;Locci M;Pardi N
通讯作者：
Pardi N
影响因子：
5.5
作者：
Leroux-Roels, G;Depla, E;Maertens, G
通讯作者：
Maertens, G
影响因子：
5.9
作者：
Kong, Leopold;Jackson, Kelli N.;Law, Mansun
通讯作者：
Law, Mansun
影响因子：
5.4
作者：
Alexander, Jason;Wong, Ji-Xhin;Houghton, Michael
通讯作者：
Houghton, Michael
DOI：
10.1073/pnas.1131929100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Murata, K;Lechmann, M;Liang, TJ
通讯作者：
Liang, TJ