SARS-CoV-2 vaccines based on RBDs with engineered glycosylation sites

基于带有工程化糖基化位点的 RBD 的 SARS-CoV-2 疫苗

基本信息

批准号：
10867558
负责人：
MICHAEL DAVID ALPERT
金额：
$ 100万
依托单位：
EMMUNE, INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10867558
关键词：
2019-nCoV ACE2 Address Antibody Response Antibody titer measurement Antigens B-Cell Antigen Receptor COVID-19 vaccine Cells Collaborations Communities Cytoplasmic Tail Data Engineering Engraftment Epitopes Face Future Goals Grant Human Hydrophobicity Immune response In Vitro Length Link Lymphoid Mann-Whitney U Test Mesocricetus auratus Messenger RNA Moderna COVID-19 vaccine Muscle Phase Polysaccharides Population Positioning Attribute Primates Protein Subunits Proteins RNA vaccine Research Rodent SARS-CoV-2 antigen SARS-CoV-2 variant Site Tail Testing Transfection Transmembrane Domain Vaccine Antigen Vaccines Variant Viral crosslink design exosome experimental study glycosylation immunogenic immunogenicity improved industry partner lipid nanoparticle nanoparticle delivery neutralizing antibody public health relevance receptor binding vaccine development vaccine efficacy variants of concern

项目摘要

We are developing vaccine antigens for SARS-CoV-2 that focus the antibody response onto neutralizing epitopes in the receptor binding domain (RBD) of the viral Spike (S) protein. Booster antigens derived from variants of SARS-CoV-2 would especially benefit from being limited to the RBD, due to the preponderance of conserved but non-neutralizing epitopes in the full-length S protein. However, RBD-only vaccines face the technical limitations of aggregation and poor expression, due to hydrophobic patches on the RBD that form the inter-subunit interfaces in the native S protein. We have overcome these limitations by engineering N- linked glycosylation sites into the RBD. These glycans also help to focus the immune response away from off-target faces of the RBD, and onto the targets for potent neutralizing antibody responses. We will extend this strategy further, to focus the antibody response onto neutralizing epitopes in the RBD that are conserved among variants of SARS-CoV-2. The RBD antigens will be tested as lipid nanoparticle (LNP)-mRNA vaccines. In Phase I of this project, we will enhance the intrinsic immunogenicity of RBD antigens delivered as LNP-mRNA vaccines. In Phase II, we will build upon this platform to compare boosters based on variant- derived RBD versus variant-derived full-length S, and to optimize RBD antigens for focusing antibody responses onto neutralizing epitopes that are conserved among variants of SARS-CoV-2. The antigens generated by this project will exploit four levels of immunofocusing to elicit or boost antibody responses that recognize conserved epitopes in the RBD and neutralize antigenically-distinct variants of SARS-CoV-2.

我们正在开发针对 SARS-CoV-2 的疫苗抗原，该抗原将抗体反应集中在病毒刺突 (S) 蛋白的受体结合域 (RBD) 中的中和表位上。由于全长 S 蛋白中保守但非中和性表位占优势，源自 SARS-CoV-2 变体的加强抗原将特别受益于 RBD 的限制。然而，由于 RBD 上的疏水斑块在天然 S 蛋白中形成亚基间界面，因此仅 RBD 疫苗面临聚集和表达不良的技术限制。我们通过将 N 连接糖基化位点设计到 RBD 中克服了这些限制。这些聚糖还有助于将免疫反应从 RBD 的脱靶面集中到目标上，以产生有效的中和抗体反应。我们将进一步扩展这一策略，将抗体反应集中在 RBD 中的中和表位上，这些表位在 SARS-CoV-2 变体中是保守的。 RBD 抗原将作为脂质纳米颗粒 (LNP)-mRNA 疫苗进行测试。在该项目的第一阶段，我们将增强作为 LNP-mRNA 疫苗提供的 RBD 抗原的内在免疫原性。在第二阶段，我们将基于该平台来比较基于变体衍生的 RBD 与变体衍生的全长 S 的加强剂，并优化 RBD 抗原，以将抗体反应集中在 SARS-CoV 变体中保守的中和表位上。 2.该项目产生的抗原将利用四个级别的免疫聚焦来引发或增强抗体反应，识别 RBD 中的保守表位并中和 SARS-CoV-2 的抗原独特变体。