Selecting HA glycosylation for improved vaccine responses

选择 HA 糖基化以改善疫苗反应

• 批准号: 10298131
• 负责人: XIUFENG HENRY WAN
• 金额: $ 82.17万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-09 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298131
• 关键词: Adaptive Immune System; Address; Affect; Allosteric Site; Amino Acids; Antibodies; Antigenic Variation; Antigens; Appearance; Attenuated; Avidity; Binding; Binding Sites; Biological Assay; Cessation of life; Communities; Complex; Computer Models; Consensus Sequence; Data; Development; Epitopes; Escape Mutant; Evolution; Genes; Genetic; Genomics; Glycoproteins; Goals; Head; Hemagglutinin; Human; Hybrids; Immune; Immune response; Immunity; Immunodominant Epitopes; Immunologic Surveillance; Influenza A Virus, H1N1 Subtype; Influenza A virus; Knowledge; Lectin; Link; Mannose; Masks; Mass Spectrum Analysis; Measures; Membrane Glycoproteins; Modeling; Mus; Mutation; Natural History; Natural Immunity; Neuraminidase; Outcome; Pattern; Polymerase; Polysaccharides; Population; Population Heterogeneity; Positioning Attribute; Preparation; Property; Proteins; Proteome; Proteomics; Recombinant Vaccines; Recombinants; Research; Site; Specificity; Structure; Surface Antigens; Use Effectiveness; Vaccine Design; Vaccines; Variant; Viral; Virus; Work; base; design; expectation; fitness; glycoproteomics; glycosylation; immunogenic; immunogenicity; improved; influenza virus strain; influenza virus vaccine; influenzavirus; molecular dynamics; molecular modeling; mutant; neutralizing antibody; neutralizing vaccine; pandemic disease; population based; receptor; receptor binding; response; seasonal influenza; sialic acid receptor; stem; universal influenza vaccine; vaccine effectiveness; vaccine response; viral fitness

Selecting HA glycosylation for improved vaccine responses This application responds to PA-18-859 "Advancing Research Needed to Develop a Universal Influenza Vaccine" and addresses the goal to “support rational design of universal influenza vaccines”. The low Influenza A virus (IAV) vaccine effectiveness (VE) stems from the ability of the virus to evade existing immunity. Its error-prone polymerase enables rapid evolution of the surface glycoprotein antigens hemagglutinin (HA) and neuraminidase (NA). Significantly, among the more prevalent mutations that occur as an IAV strain undergoes antigenic drift is the appearance of new N-glycosylation consensus sequences (sequons) on the HA globular domain. The appearance of new glycosites shields underlying amino acid residues from antibody contact. However, because the host receptor binding sites (RBSs) also reside in the HA head group, variations in head group glycosylation have the simultaneous potential to harm viral fitness by interfering with virus binding to its host receptor. HA glycosylation is macro- and micro-heterogeneous, meaning that each HA glycosite has a distribution of glycoforms that differ in their physicochemical and lectin-binding properties. HA therefore consists of heterogeneous populations that differ by glycosylation, antigenicity, and immunogenicity. Unfortunately, the glycosylated structures of HA populations most suited for vaccine use remain unknown for IAV strains. This lack of information results in over-reliance on genomic information that cannot predict the level of glycosylation at a given site, the compositions of the attached glycans, and which glycosylated populations of HA are most immunogenic. We propose to use glycoproteomics, molecular modeling, and antigenic cartography of HA glyco-populations to develop a detailed understanding of the relationship between HA glycosylation and immunogenicity for representative H1N1 strains. This study will enhance our understanding of the natural history of influenza viruses. In addition, we anticipate that this knowledge could be employed to select HA sequences for producing recombinant influenza vaccines with enhanced immunogenicity and VE. Unlike vaccines based on attenuated or inactivated virus, recombinant vaccines are created synthetically and can be prepared in advance of the emergence of a seasonal or pandemic strain of virus. Knowledge of the optimal HA glycosylation pattern would provide important guidance in recombinant vaccine design.

选择HA糖基化以改善疫苗应答 此应用程序响应PA-18-859“开发通用流感所需的推进研究” 疫苗”，并实现“支持合理设计通用流感疫苗”的目标。 甲型流感病毒（IAV）疫苗的低有效性（VE）源于病毒逃避现有免疫缺陷的能力。 免疫力它的易错聚合酶能够快速进化表面糖蛋白抗原血凝素 (HA)和神经氨酸酶（NA）。值得注意的是，在作为IAV毒株发生的更普遍的突变中， HA上出现新的N-糖基化共有序列（序列子） 球状域新糖基的出现保护了抗体的潜在氨基酸残基 contact.然而，由于宿主受体结合位点（RBS）也存在于HA头基中， 在头基糖基化同时具有通过干扰病毒结合而损害病毒适应性的潜力 到它的宿主受体。 HA糖基化是宏观和微观异质性的，这意味着每个HA糖位点具有以下分布： 这些糖型在其物理化学和凝集素结合特性上不同。因此，医管局的成员包括 在一些实施方案中，所述细胞是糖基化、抗原性和免疫原性不同的异质群体。可惜 对于IAV毒株，最适合于疫苗使用的HA群体的糖基化结构仍然未知。这种缺乏 信息的缺乏导致过度依赖基因组信息，无法预测糖基化水平。 给定的位点，连接的聚糖的组成，以及HA的糖基化群体最多 免疫原性。 我们建议使用HA糖群的糖蛋白组学、分子建模和抗原制图， 详细了解HA糖基化和免疫原性之间的关系， 代表性的H1N1病毒株。 这项研究将加强我们对流感病毒自然史的了解。此外，我们预计， 这些知识可以用来选择HA序列来生产重组流感疫苗 具有增强的免疫原性和VE。与基于减毒或灭活病毒的疫苗不同， 疫苗是合成的，可以在季节性或大流行出现之前制备 病毒株。最佳HA糖基化模式的知识将在以下方面提供重要指导： 重组疫苗设计