Induction of neutralising antibodies against conserved rhinovirus capsid protein VP4 depends on presenting VP4 in a virus-like conformation

Abstract

Infection with rhinovirus (RV) is associated with significant morbidity and hospitalisation in people with chronic lung disease. At present there is no approved RV vaccine or antiviral. There are approximately 180 RV serotypes, classified into 3 species (RVA, RVB, RVC). 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. A more feasible strategy is to direct the immune response towards conserved but less dominant epitopes. The capsid protein VP4 is highly conserved within each RV genotype and some antibodies that target VP4 are neutralising. This makes VP4 vulnerable to antibodies and a promising vaccine target. Here we investigate the ability of RV VP4 N-terminal peptides presented on different display systems to initiate a neutralising immune response in mice. We compared three different-sized VP4 peptides (spanning residues, 1-15, 1-30 and 1-45) displayed on two different display systems-SpyCatcher Virus-like particles (VLPs) or Keyhole Limpet Hemocyanin (KLH). Overlapping regions of VP4 were antigenically different when presented on different platforms and in peptides with different length. The conformation of the 1-15 region of VP4 was critical for inducing antibodies that were both neutralising and able to bind 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 will 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. Impact statementRhinovirus (RV) is a highly prevalent respiratory virus that is a frequent cause of common cold symptoms. For people with chronic lung diseases such as asthma, infection can cause significant worsening of disease, leading to increased suffering and hospitalisation. There are currently no vaccines or anti-viral drugs that target RV infections. Development of a RV vaccine would be hugely beneficial to suffers of chronic lung diseases. Attempts to develop a broadly protective RV vaccine have been hindered by the presence of over 180 serotypes which have little or no natural cross-reactivity. Previous studies have identified the highly conserved VP4 epitope as a potential target for broadly protective vaccines. However, there has been little progress in evaluating its effectiveness as a vaccine candidate. In this study we assessed the ability of different RV VP4 immunogens to induce neutralising antibodies in mice. We demonstrated that antigenic conformation of VP4 varies greatly between immunogens and presentation of the first 15 N-terminal residues in a virus-like conformation is important for generating neutralising antibodies. This knowledge could help to maximise the production of neutralising VP4-specific antibodies in future studies which could ultimately lead to a universal RV vaccine.