Selecting HA glycosylation for improved vaccine responses

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“，并针对”支持合理设计通用流感疫苗“的目标。 甲型流感病毒(IAV)疫苗效力低(VE)源于病毒逃避现有病毒的能力 豁免权。其容易出错的聚合酶使表面糖蛋白抗原血凝素快速进化 (HA)和神经氨酸酶(NA)。值得注意的是，在作为IAV毒株出现的更普遍的突变中 经历抗原漂移是在HA上出现新的N-糖基化共识序列(Sequon) 球状域。新糖基的出现保护了潜在的氨基酸残基免受抗体的侵害。 联系。然而，由于宿主受体结合位点(RBSS)也驻留在HA头部群中，所以变异 在头部群中，糖基化同时可能通过干扰病毒结合而损害病毒的适合性 到它的宿主受体。 HA糖基化是宏观和微观非均相的，这意味着每个HA糖基都有一个分布 具有不同的物理化学和凝集素结合特性的糖类。因此，医管局由以下部分组成 糖基化、抗原性和免疫原性不同的异质种群。不幸的是， 对于IAV毒株，最适合疫苗使用的HA群体的糖基化结构仍然未知。这种缺失 导致对基因组信息的过度依赖，而基因组信息无法预测糖基化水平 在特定的位置，连接的多糖的组成以及HA的糖基化基团最多 免疫原性。 我们建议使用糖蛋白组学、分子建模和HA糖群的抗原图来 详细了解HA糖基化与免疫原性之间的关系 有代表性的H1N1病毒株。 这项研究将增进我们对流感病毒自然历史的了解。此外，我们预计 这一知识可用于选择HA序列以生产重组流感疫苗 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，重组 疫苗是人工合成的，可以在季节性或大流行出现之前准备好 病毒株。对最佳HA糖基化模式的了解将对 重组疫苗设计。

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.