Better influenza vaccines: an industry perspective

Abstract

Vaccination is the most effective measure at preventing influenza virus infections. However, current seasonal influenza vaccines are only protective against closely matched circulating strains. Even with extensive monitoring and annual reformulation our efforts remain one step behind the rapidly evolving virus, often resulting in mismatches and low vaccine effectiveness. Fortunately, many next-generation influenza vaccines are currently in development, utilizing an array of innovative techniques to shorten production time and increase the breadth of protection. This review summarizes the production methods of current vaccines, recent advances that have been made in influenza vaccine research, and highlights potential challenges that are yet to be overcome. Special emphasis is put on the potential role of glycoengineering in influenza vaccine development, and the advantages of removing the glycan shield on influenza surface antigens to increase vaccine immunogenicity. The potential for future development of these novel influenza vaccine candidates is discussed from an industry perspective.

Keywords: Influenza virus; Monoglycosylated HA; Monoglycosylated split vaccine; Universal vaccine.

Fig. 1

Timeline of current influenza vaccine production methods. Schematic overview of egg-based, cell-based and protein-based influenza vaccine production. Vaccine strains that match circulating influenza viruses for the upcoming flu season are selected by the World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS). High yielding vaccine strains for egg- or cell-based production are generated by either classic or reverse genetic reassortment. These adapted viruses go into mass production, either in embryonated chicken eggs or MDCK cells with a production timeline of approximately six to eight months. In recombinant HA (rHA) vaccines, the HA sequence is cloned into baculovirus and expressed by insect cells, significantly shortening production time

Fig. 2

The production and immune response of monoglycosylated influenza vaccine. The production of monoglycosylated split virus vaccine adds two key steps to the traditional egg-based platform. Kifunensine, a mannosidase I inhibitor, is added during egg inoculation to arrest viral glycoprotein processing, resulting in a uniformly high mannose composition. Endoglycosidase H is added after harvest to trim high mannose residues down to a single GlcNAc. The resultant monoglycosylated split vaccine provides a more diverse immune response and more effective cross-strain protection than conventional egg-based vaccines. HA_fg, non-modified egg-based vaccine with complex type N-glycans attached to HA; HA_hm, HA with only high mannose type N-glycans; HA_mg, HA with a single GlcNAc at its N-glycosylation sites. Models of HA_fg, HA_hm and HA_mg are created with Protein Data Bank ID code 3LZG and 6FYT by adding glycan with GlyProt (http://www.glycosciences.de/modeling/glyprot/php/main.php), coot (https://www2.mrc-lmb.cam.ac.uk/personal/pemsley/coot/) and PDB of lipid bilayer from Lipid Bilayer Membranes for RasMol (https://www.umass.edu/microbio/rasmol/bilayers.htm). The images were displayed with program PyMOL (www.pymol.org)