Structural insights into the design of novel anti-influenza therapies

Abstract

A limited arsenal of therapies is available to tackle the emergence of a future influenza pandemic or even to effectively deal with the continual outbreaks of seasonal influenza. However, recent findings hold great promise for design of novel vaccines and therapeutics, including the possibility of more universal treatments. A major contribution to those advances comes from structural biology, in particular from the many studies on influenza hemagglutinin (HA), the major surface antigen. The HA primary function is to enable the virus to enter host cells, and structural work has revealed the various HA conformational forms generated during the entry process. Other studies have explored how human broadly neutralizing antibodies (bnAbs), designed proteins, peptides and small molecules, can inhibit and neutralize the virus. Here we review milestones in HA structural biology and how the recent insights from broadly neutralizing antibodies are leading to design of novel vaccines and therapeutics.

“Breathing” Hemagglutinin Reveals Cryptic Epitopes for Universal Influenza Vaccine Design

“…On the other hand, the HA ''stem'' is the least variable region on the HA surface from the primary sequences. For this reason, great efforts have been focused on the development of influenza vaccines that depend on protective epitopes in the stem domain (Wu and Wilson, 2018), but the vaccination strategies used to elicit these antibodies, for example by removing the head domain, have not yet translated into a universal vaccine.…”

Structural Basis of Pan-Ebolavirus Neutralization by an Antibody Targeting the Glycoprotein Fusion Loop

“…Our structures, however, provide a valuable tool for using structure-based design in silico to generate new starting models, such as those with increased affinity, that can be subsequently integrated into an in vitro evolution pipeline (Adolf-Bryfogle et al, 2018). Such efforts have shown promise for influenza mAbs, although it seems that increases in specificity result in diminished cross-reactivity (Wu et al, 2017; Wu and Wilson, 2017, 2018). Future work should be aimed at optimizing potent antibodies such as ADI-15878 for clinical development.…”

Vaccine innovations for emerging infectious diseases—a symposium report

“…Structurally, HA is a cylindrical homotrimer that consists of a head region and a stem region. Broadly neutralizing antibodies (bnAbs) elicited by both natural influenza infection and vaccination bind to both the head and stem regions . Wilson and others have solved the structures of several of these antibodies bound to HA from representatives of several major influenza strains, subtypes, and types.…”