Induction of broadly neutralizing antibodies using a secreted form of the hepatitis C virus E1E2 heterodimer as a vaccine candidate.
Induction of broadly neutralizing antibodies using a secreted form of the hepatitis C virus E1E2 heterodimer as a vaccine candidate.
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DOI：
10.1073/pnas.2112008119
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发表时间：
2022-03-15
影响因子：
11.1
通讯作者：
Fuerst TR
中科院分区：
文献类型：
--
作者：
Wang R;Suzuki S;Guest JD;Heller B;Almeda M;Andrianov AK;Marin A;Mariuzza RA;Keck ZY;Foung SKH;Yunus AS;Pierce BG;Toth EA;Ploss A;Fuerst TR
丙型肝炎病毒慢性感染约1%的世界人口，使丙型肝炎病毒的有效疫苗成为一个主要的未满足的公共卫生需求。膜相关的E1E2包膜糖蛋白已在临床研究中用作候选疫苗。然而，有限的中和宽度和难以产生大量的均质膜相关的E1E2阻碍了开发基于E1E2的疫苗的努力。我们先前的工作描述了天然样可溶性分泌型E1E2（sE1E2）的设计和生化验证。在这里，我们描述的sE1E2复合物的免疫原性表征。sE1E2在免疫小鼠中引起广泛中和抗体，相对于膜相关的E1E2具有增加的中和宽度，从而验证该平台作为疫苗开发的有前景的模型系统。丙型肝炎病毒（HCV）是一种全球性疾病负担，需要预防性疫苗来控制或根除病毒。尽管出现了有效的抗病毒治疗，但许多患者无法获得这种治疗，并且不能防止再感染，使慢性丙型肝炎成为持续的全球健康问题。因此，预防性疫苗的开发将代表全球根除HCV的重要一步。HCV具有高度的遗传变异性，这经常导致免疫逃逸。然而，HCV疫苗开发中面临的一个相当大的挑战是设计一种能激发广泛中和抗体的抗原。在这里，我们表征了基于可溶性分泌形式的E1E2包膜异源二聚体（sE1E2.LZ）的疫苗的免疫原性。来自用sE1E2.LZ免疫的小鼠的血清表现出与用膜结合E1E2（mbE1E2）或可溶性E2胞外域（sE2）免疫的小鼠相当的抗E1E2特异性应答。在使用抗原结构域特异性中和和非中和抗体的竞争抑制ELISA中，与mbE1E2相比，sE1E2. LZ免疫小鼠的血清显示出几乎相同或更强的中和抗体竞争。与此相反，从小鼠血清免疫sE2，并在较小程度上mbE1E2，更有效地与非中和抗体竞争。使用HCV假颗粒和细胞培养物衍生的感染性HCV的中和活性评估显示，用sE1E2.LZ免疫引起三种抗原中最广泛的中和活性，并且sE1E2.LZ诱导针对所有基因型的中和活性。这些结果表明，我们的天然样可溶性糖蛋白设计，sE1E2.LZ，诱导广泛的中和抗体，并作为一个有前途的疫苗候选进一步发展。
Hepatitis C virus chronically infects approximately 1% of the world’s population, making an effective vaccine for hepatitis C virus a major unmet public health need. The membrane-associated E1E2 envelope glycoprotein has been used in clinical studies as a vaccine candidate. However, limited neutralization breadth and difficulty in producing large amounts of homogeneous membrane-associated E1E2 have hampered efforts to develop an E1E2-based vaccine. Our previous work described the design and biochemical validation of a native-like soluble secreted form of E1E2 (sE1E2). Here, we describe the immunogenic characterization of the sE1E2 complex. sE1E2 elicited broadly neutralizing antibodies in immunized mice, with increased neutralization breadth relative to the membrane-associated E1E2, thereby validating this platform as a promising model system for vaccine development. Hepatitis C virus (HCV) is a global disease burden, and a preventive vaccine is needed to control or eradicate the virus. Despite the advent of effective antiviral therapy, this treatment is not accessible to many patients and does not prevent reinfection, making chronic hepatitis C an ongoing global health problem. Thus, development of a prophylactic vaccine will represent a significant step toward global eradication of HCV. HCV exhibits high genetic variability, which leads frequently to immune escape. However, a considerable challenge faced in HCV vaccine development is designing an antigen that elicits broadly neutralizing antibodies. Here, we characterized the immunogenicity of a vaccine based on a soluble, secreted form of the E1E2 envelope heterodimer (sE1E2.LZ). Sera from mice immunized with sE1E2.LZ exhibited an anti-E1E2–specific response comparable to mice immunized with membrane-bound E1E2 (mbE1E2) or a soluble E2 ectodomain (sE2). In competition-inhibition ELISA using antigenic domain-specific neutralizing and nonneutralizing antibodies, sera from sE1E2.LZ-immunized mice showed nearly identical or stronger competition toward neutralizing antibodies when compared with mbE1E2. In contrast, sera from mice immunized with sE2, and to a lesser extent mbE1E2, competed more effectively with nonneutralizing antibodies. An assessment of neutralization activity using both HCV pseudoparticles and cell culture–derived infectious HCV showed that immunization with sE1E2.LZ elicited the broadest neutralization activity of the three antigens, and sE1E2.LZ induced neutralization activity against all genotypes. These results indicate that our native-like soluble glycoprotein design, sE1E2.LZ, induces broadly neutralizing antibodies and serves as a promising vaccine candidate for further development.
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影响因子：
4.8
作者：
De Beeck, AO;Montserret, R;Dubuisson, J
通讯作者：
Dubuisson, J
影响因子：
5.4
作者：
Falson, Pierre;Bartosch, Birke;Penin, Francois
通讯作者：
Penin, Francois
大致中和抗体消除了乙型肝炎病毒感染。
影响因子：
17.1
作者：
de Jong YP;Dorner M;Mommersteeg MC;Xiao JW;Balazs AB;Robbins JB;Winer BY;Gerges S;Vega K;Labitt RN;Donovan BM;Giang E;Krishnan A;Chiriboga L;Charlton MR;Burton DR;Baltimore D;Law M;Rice CM;Ploss A
通讯作者：
Ploss A
影响因子：
64.5
作者：
de Taeye SW;Ozorowski G;Torrents de la Peña A;Guttman M;Julien JP;van den Kerkhof TL;Burger JA;Pritchard LK;Pugach P;Yasmeen A;Crampton J;Hu J;Bontjer I;Torres JL;Arendt H;DeStefano J;Koff WC;Schuitemaker H;Eggink D;Berkhout B;Dean H;LaBranche C;Crotty S;Crispin M;Montefiori DC;Klasse PJ;Lee KK;Moore JP;Wilson IA;Ward AB;Sanders RW
通讯作者：
Sanders RW
影响因子：
4.7
作者：
Andrianov AK;Marin A;Wang R;Karauzum H;Chowdhury A;Agnihotri P;Yunus AS;Mariuzza RA;Fuerst TR
通讯作者：
Fuerst TR