Virus-like Particle Vaccines Containing RSV Fusion Protein Cleavage Mutations Are Immunogenic and Protective in Cotton Rats With a Prime Dose
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An effective respiratory syncytial virus (RSV) vaccine should elicit neutralizing Abs and confer protection without causing vaccine-enhanced disease. Virus-like particle (VLP) is a safe vaccine platform that can display multivalent Ags similar to a virus and induce potent neutralizing Abs without adjuvant. We investigated the impact of mutations in the furin cleavage site, fusion (F) peptide, and change in the transmembrane (TM) domain of RSV F protein in VLPs on inducing RSV neutralizing Abs and efficacy in a cotton rat model. Palivizumab-binding antigenic site II epitope was preferentially exposed by combination mutations in the furin cleavage sites and F peptide together with a change in the TM domain. A single dose of mutant F protein VLP containing these combination mutations effectively induced IgG Ab responses to post-F and pre-F proteins, neutralizing activities, and protection without apparent lung histopathology. The VLP also induced the highest level of INF-γ, indicating the Th1-skewed immune response against the virus infection. A single dose of RSV F mutant exposing an antigenic site II on VLP vaccine could induce RSV-neutralizing Abs, conferring protection without causing vaccine-enhanced disease in cotton rats.
Abstract
An effective respiratory syncytial virus (RSV) vaccine should elicit neutralizing Abs and confer protection without causing vaccine-enhanced disease. Virus-like particle (VLP) is a safe vaccine platform that can display multivalent Ags similar to a virus and induce potent neutralizing Abs without adjuvant. We investigated the impact of mutations in the furin cleavage site, fusion (F) peptide, and change in the transmembrane (TM) domain of RSV F protein in VLPs on inducing RSV neutralizing Abs and efficacy in a cotton rat model. Palivizumab-binding antigenic site II epitope was preferentially exposed by combination mutations in the furin cleavage sites and F peptide together with a change in the TM domain. A single dose of mutant F protein VLP containing these combination mutations effectively induced IgG Ab responses to post-F and pre-F proteins, neutralizing activities, and protection without apparent lung histopathology. The VLP also induced the highest level of INF-γ, indicating the Th1-skewed immune response against the virus infection. A single dose of RSV F mutant exposing an antigenic site II on VLP vaccine could induce RSV-neutralizing Abs, conferring protection without causing vaccine-enhanced disease in cotton rats.