Research Project
9043559
? DESCRIPTION (provided by applicant): Although respiratory syncytial virus (RSV) infection occurs in 60% of infants during the first year of life and 90% are infected one or more times by year 2, 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 2 deaths. The complication of ERD has contributed to the failure to develop a RSV vaccine for the past 50 years. No killed or subunit vaccines have been tested in naïve infants since the 1960s 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 epitope-based 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 24 residue site (F254-277). Our approach is to insert the F254-277 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 F254-277 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 F254-277 epitope. Our approach has been to use the Combinatorial Technology, developed for the WHcAg platform, to generate a library of 79 hybrid-VLPs displaying the F254-277 epitope to select several candidates. In this SBIR we will assess the feasibility of exploiting a panel of F254-277-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.
