Developing Vaccines against Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV. The F and G glycoprotein of RSV are potentially important targets for protective antiviral immune responses. Here, recombinant replication-deficient adenovirus-based vaccines, rAd/3xG, expressing the soluble core domain of G glycoprotein (amino acids 131 to 230), engineered by codon optimization and tandem repetition for higher level expression, were constructed and evaluated for their potential as RSV vaccine in murine model. Strong serum IgG as well as mucosal IgA responses were induced by intranasal immunization of rAd/3xG. A single intranasal immunization of rAd/3xG vaccines provided potent protection against RSV challenge without vaccine-enhanced immunopathology. We also tested the efficacy of our vaccines against RSV field isolates from Korean pediatric patients and the data showed that our vaccine confers complete protection against RSV-A isolate challenge. We also show that sublingual or intranasal immunization of a procaryotically expressed and purified G protein fragment of amino acids from 131 to 230, designated Gcf, induces strong serum IgG and mucosal IgA responses. Interestingly, these antibody responses could be elicited by Gcf even in the absence of any adjuvant, indicating a novel selfadjuvanting property of our vaccine candidate. Gcf exhibited potent chemotactic activity in in vitro cell migration assay and cysteine residues are necessary for chemotactic activity and self-adjuvanticity of Gcf in vivo. Mucosal immunization with Gcf also provides protection against RSV challenge without any significant lung eosinophilia or vaccine-induced weight loss. Together, our data demonstrate that mucosal administration of our vaccine candidates elicit beneficial protective immunity and represent promising vaccine regimens preventing RSV infection.