An Epitope-Focused Pediatric RSV Vaccine

DESCRIPTION provided by applicant Although respiratory syncytial virus RSV infection occurs in of infants during the first year of life and are infected one or more times by year representing the greatest risk for hospitalization for infants no vaccine or therapeutic treatment exists for this unmet medical need The first clinically tested vaccine a formalin inactivated RSV FI RSV preparation not only did not protect infants and young children but seriously enhanced respiratory disease ERD in a majority of children and resulted in deaths The complication of ERD has contributed to the failure to develop a RSV vaccine for the past years No killed or subunit vaccines have been tested in na ve infants since the s and live attenuated RSV vaccines have other attendant risks i e insufficient attenuation for the immature pulmonary and immune systems of infants and reversion to wildtype Our approach to this problem is to focus on producing an andquot epitope basedandquot vaccine that elicits the one anti RSV specificity that is known to protect against severe disease and is known not to enhance disease A monoclonal antibody Mab palivizumab specific for a site A domain on the fusion F protein neutralizes RSV and prophylactically acts against severe disease and is licensed to be prescribed for high risk infants The palivizumab specific antibody epitope has been well defined within a residue site F Our approach is to insert the F epitope onto a well characterized virus like particle VLP i e the WHcAg In other words we propose to elicit palivizumab like neutralizing antibodies by active immunization as opposed to the expensive and laborious method of passive Mab transfer This goal has proven to be challenging because the F epitope is conformational and the inserted epitope must approximate the antigenic structure that is present on the intact virus However we have succeeded in the design and production of several RSV WHcAg VLPs that bind palivizumab elicit high titer neutralizing antibodies and efficiently protect mice against RSV challenge Our success may be partly attributable to the fact that the immunodominant portion of our VLP carrier has a helix loop helix structure similar to that of the F epitope Our approach has been to use the Combinatorial Technology developed for the WHcAg platform to generate a library of hybrid VLPs displaying the F epitope to select several candidates In this SBIR we will assess the feasibility of exploiting a panel of F displaying VLPs to produce an epitope focused RSV vaccine with increased diversity for the palivizumab epitope In a final pivotal experiment we will perform a cotton rat immunization RSV challenge study to assess the potential of this approach to overcome ERD PUBLIC HEALTH RELEVANCE Narrative Human respiratory syncytial virus RSV is the leading worldwide agent of serious pediatric respiratory tract disease No vaccine or therapeutic treatment exists for this unmet medical need This project describes the development of a RSV vaccine candidate that has been demonstrated to protect rodents against a RSV challenge