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 糖基化以改善疫苗反应 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”并提出了“支持通用流感疫苗的合理设计”的目标。 甲型流感病毒 (IAV) 疫苗有效性 (VE) 较低源于病毒逃避现有疫苗的能力 其容易出错的聚合酶使表面糖蛋白抗原血凝素能够快速进化。 (HA) 和神经氨酸酶 (NA) 是 IAV 毒株中最常见的突变。 经历抗原漂移是在 HA 上出现新的 N-糖基化共有序列（序列片段） 新糖位点的出现保护了潜在的氨基酸残基免受抗体的影响。 然而，由于宿主受体结合位点 (RBS) 也位于 HA 头基中，因此存在差异。 头基糖基化同时有可能通过干扰病毒结合来损害病毒适应性 对其宿主受体。 HA 糖基化在宏观和微观上是异质的，这意味着每个 HA 糖基化位点的分布为 因此，其物理化学和凝集素结合特性不同的糖型由以下部分组成。 不幸的是，在糖基化、抗原性和免疫原性方面存在差异的异质群体。 对于 IAV 毒株来说，最适合疫苗使用的 HA 群体的糖基化结构仍然未知。 信息的过度依赖无法预测糖基化水平的基因组信息 给定位点、附着聚糖的组成以及哪些 HA 的糖基化群体是最多的 具有免疫原性。 我们建议使用糖蛋白组学、分子建模和 HA 糖群抗原制图来 详细了解 HA 糖基化与免疫原性之间的关系 代表性 H1N1 毒株。 此外，我们预计这项研究将增强我们对流感病毒自然史的了解。 该知识可用于选择用于生产重组流感疫苗的 HA 序列 与基于减毒或灭活病毒、重组疫苗的疫苗相比，具有增强的免疫原性和VE。 疫苗是合成制造的，可以在季节性或大流行病出现之前准备好 病毒株的最佳 HA 糖基化模式的知识将为研究提供重要指导。 重组疫苗设计。