Induction of neutralising antibodies against conserved rhinovirus capsid protein VP4 is dependent on presentation of VP4 peptide immunogens in a virus-like conformation.

Infection with rhinovirus (RV) is a frequent cause of the common cold and is also associated with more significant morbidity, including hospitalisation, in people with chronic lung disease. At present, there is no licensed RV vaccine or antiviral. There are over 150 RV strains classified into 3 species (RV-A, RV-B, RV-C), and approximately 100 of these have been characterised as distinct serotypes. There is no cross-protection between serotypes because of high diversity in immunodominant antigenic sites. This makes it impractical to create a broadly protective vaccine using traditional methods, involving whole capsids. An alternative strategy is to direct the immune response towards conserved but less dominant epitopes. The capsid protein VP4 is highly conserved within each RV species, and antibodies that target the N-terminal region of VP4 have previously been shown to be neutralising. Here, we investigate the immunogenicity of three RV N-terminal VP4 peptides of different sizes (spanning residues 1-15, 1-30, and 1-45) presented on SpyCatcher virus-like particles (VLPs). Neutralising antibodies were only induced against the shortest peptide. The neutralising epitope contained within the first 15 amino acids was antigenically and structurally different in the context of longer peptides. This indicates the conformation of the 1-15 region of VP4 is critical for inducing antibodies that neutralise by binding VP4 in the context of the virus particle. Therefore, correctly displayed VP4 peptides can recapitulate virus-like antigenicity. These findings improve our understanding of VP4 antigenicity and may inform the design of future RV vaccines. This work could also impact the design of other peptide vaccines, since a variable antigenic conformation is a common characteristic of pathogen-derived peptide targets.