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Title: Human respiratory syncytial virus F protein-induced immunosuppression : structures, mechanisms and novel vaccines
Author: Quinn , Caroline Frances
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality in humans. It repeatedly infects throughout life, suggesting induction of poor memory immune responses. The RSV F protein is a highly conserved antigen that was studied extensively as a vaccine both in animal models and clinical trials but has so far failed in humans. Interestingly. evidence suggested that RSV F blocks proliferation of PHA-stimulated human PBMCs in a contact-dependent and species-specific manner. Specifically, HRSV F preferentially inhibited human PBLs, while bovine RSV F preferentially inhibited bovine PBLs. We aligned multiple strains of human and bovine RSV to identify 8 species-specific residues. We hypothesized that replacing the 8 HRSV F residues with their bovine counterparts would not alter the antigenic or immunogenic structure of HRSV F, while removing the capacity of HRSV F to block human PBL proliferation. Using site-directed mutagenesis, we generated a recombinant HRSV F protein (rHRSV Fmut8) comprising the 8 bovine residues. rHRSV Fmut8 was shown to retain reactivity when tested with a panel of RSV F-specific MAbs, confirming that the antigenic structure was preserved. We subsequently generated and characterised a recombinant Sendai virus efficiently expressing our mutated HRSV F (rSeV/RSV Fmut8), found to be functional and antigenically intact. S.eV (mwine PIVI) was chosen as a vector, as it is immunogenic but non-pathogenic in humans, has vaccine potential against human parainfluenza virus type I (HPrv 1) and can be easily manipulated by reverse genetics. Following intra-nasal administration to BALB/c mice, rSeV/RSV Fmut8 induced protective immunity against RSV challenge. Human PBMC proliferation block experiments revealed that HRSV efficiently blocks inhibition, in which RSV F plays a role. If confirmed, abrogation of the human PBL proliferation block combined with its protective efficacy in vivo, suggests that rSeV/RSV Fmut8 will constitute a very interesting and novel RSV vaccine candidate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available