Traditional and new influenza vaccines

Abstract

The challenges in successful vaccination against influenza using conventional approaches lie in their variable efficacy in different age populations, the antigenic variability of the circulating virus, and the production and manufacturing limitations to ensure safe, timely, and adequate supply of vaccine. The conventional influenza vaccine platform is based on stimulating immunity against the major neutralizing antibody target, hemagglutinin (HA), by virus attenuation or inactivation. Improvements to this conventional system have focused primarily on improving production and immunogenicity. Cell culture, reverse genetics, and baculovirus expression technology allow for safe and scalable production, while adjuvants, dose variation, and alternate routes of delivery aim to improve vaccine immunogenicity. Fundamentally different approaches that are currently under development hope to signal new generations of influenza vaccines. Such approaches target nonvariable regions of antigenic proteins, with the idea of stimulating cross-protective antibodies and thus creating a "universal" influenza vaccine. While such approaches have obvious benefits, there are many hurdles yet to clear. Here, we discuss the process and challenges of the current influenza vaccine platform as well as new approaches that are being investigated based on the same antigenic target and newer technologies based on different antigenic targets.

Fig 1

Timeline of major events in influenza vaccine development. Influenza pandemics and major H5N1 outbreaks are indicated in red, while major breakthroughs in influenza vaccine development are highlighted in blue. Superscript numbers indicate references. *, see the FDA website (http://www.fda.gov/); ∧, see the European Medicines Agency website (http://www.ema.europa.eu); #, see the CDC website (http://www.cdc.gov/vaccines/acip/index.html).

Fig 2

(A) Crystal structure of the hemagglutinin (HA) trimer. Shown in this figure is a group 1 HA (H1 subtype) (Protein Data Bank [PDB] accession number 3LGZ), and only one monomer is colored for clarity. The receptor-binding domain (yellow spheres) and the antigenic sites (for H1N1, Sa [blue], Sb [cyan], Cb [magenta[, Ca2 [white[, and Ca1 [orange]) are all located within the globular head of the protein. The stalk region, consisting of long alpha-helix loops (in red) and the fusion peptide, is more conserved across the different subtypes and plays an important role in the fusion process during virus uncoating. Epitopes/regions in the stalk region that induce broadly cross-reactive antibodies to group 1 (circled in blue) and both group 1 and 2 (circled in red) have been identified (as indicated). (B) A group 2 HA monomer (H3 subtype) (modified from data reported under PDB accession number 3DSY), with the group-reactive epitope highlighted in magenta. References are indicated in parentheses.