Selecting HA glycosylation for improved vaccine responses

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.