Improved RSV F Vaccine Candidates

Abstract Respiratory syncytial virusRSVa viral agent that causes severe respiratory illnessinfects a large percentage of infants and children worldwide by the age of threeEHeylen et alAccording to the CDCRSV is responsible for overhospitalizations andmillion outpatient visits among children younger thanyears as well ashospitalizations anddeaths among the elderly in the US aloneEKMilleret alAfter more thanyears of researchseveral RSV vaccine candidates are in the pipelinebut none have progressed through the final approval processA major target for vaccine development has been guided by the successful prophylactic use of a neutralizing monoclonal antibodypalivizumabSynergisRwhich is directed against the fusion glycoproteinF proteinThe treatment is expensivemust be given everymonths for maximum protectionand is currently limited to high risk young pediatric patientsEHeylen et alClinical studies with unmodified F protein stimulates some neutralizing antibodiesbut also non neutralizing antibodiesWe hypothesize that the non neutralizing antibodies interfere with the action of neutralizing antibodies and that their elimination may improve the protective immunity stimulated by rationally designed F variantsGuided by our previous work with HIVInfluenzaHRVand most recently with RSVwe analyzed structural and immunological data for the F protein RSV to identify and immune dampen nonneutralizing epitopesIn a preliminary studywe designed and produced a panel of immune refocused F antigens and showed that the most promising candidates retained binding to neutralizing antibodies while losing binding to non neutralizing antibodiesWe propose to examine these types of F variants in both preand post fusion conformations for improved protection in a cotton rat challenge study Narrative RSV infections are a leading cause of respiratory illness and bronchiolitis in infantsthe elderlyand the immunosuppressedProphylaxis in at risk infant populations is based on perfusion with the neutralizing monoclonal antibodySynagisto establish passive immunitySeveral vaccines are in the development pipeline including a number which are based on the F glycoproteinImmunization with some of the most advanced candidates have failed to meet clinical endpointsIt appears from structural studies that F proteinwhile a critical target for inducing Synagis like and other neutralizing antibodiesa large fraction of non neutralizing antibodies is made in humans infected with RSVWe hypothesize that these nonneutralizing antibodies interfere with the protective activities of neutralizing antibodiesWe propose technology to dampen the immunogenicity of the non neutralizing epitopes in both preand post fusion F antigens and assess their protective immunity in a cotton rat challenge study