Abstract
Respiratory syncytial virus (RSV) causes severe lower respiratory tract illness in infants and young children. The significant morbidity and mortality rates associated with RSV infection make an effective RSV vaccine development a priority. Two neutralising antibody binding sites, Ø and II, located on the pre-fusion RSV F glycoprotein are prime candidates for epitope-focused vaccine design. We report on a vaccine strategy that utilises a lipid core peptide (LCP) delivery system with self-adjuvanting properties in conjunction with either the antigenic site Ø or II (B cell epitopes) along with PADRE as a T helper cell epitope. These LCP constructs adopted the desired helical conformation in solution and were recognised by their cognate antibodies D25 and Motavizumab, specific for site Ø and II on RSV F protein, respectively. The LCP constructs were capable of eliciting higher levels of antigen specific antibodies than those induced by antigens administered with complete Freund’s adjuvant, demonstrating the potent adjuvanting properties of LCP delivery. However, the antibodies induced failed to recognise native F protein or neutralise virus infectivity. These results provide a note of caution in assuming that peptide vaccines, successfully designed to structurally mimic minimal linear B cell epitopes, will necessarily elicit the desired immune response.
Highlights
Human respiratory syncytial virus (RSV) causes serious lung and airway infection such as pneumonia and bronchiolitis in infants and young children[1]
Two further constructs were generated (IILCP6 and IILCP7), which consisted of peptides (IIP4 and IIP5) fused to the lipid core peptide (LCP) system but with two extra copies of lipoamino acid coupled at the N-terminus of synthesised B cell epitope to adopt helix-loop-helix conformation
The use of a self-adjuvanting delivery system eliminates the requirement for vaccine formulation that incorporates an adjuvant such as complete Freund’s adjuvant (CFA) and can aid in the correct presentation of the incorporated epitope in the desired conformation[34, 36]
Summary
Human respiratory syncytial virus (RSV) causes serious lung and airway infection such as pneumonia and bronchiolitis in infants and young children[1]. While some subunit-based and live attenuated vaccines have shown promise in clinical trials[15], an alternative, minimalistic approach to subunit-based vaccines is epitope-focused vaccine design Such an approach focuses on only a single protective, neutralising epitope with the aim of eliciting known protective antibodies without inducing imbalanced T-cell responses. Due in part to its more recent discovery, site Ø has not yet been directly targeted by peptide-based vaccine design This epitope has been a major focus in the development of stabilised pre-fusion F vaccine constructs[21] and the virus neutralising effect of antibodies targeting this site has been shown to be significantly more potent than antibodies with comparable affinities to elsewhere within RSV F10, 22–24
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