Abstract

Respiratorysyncytialvirus(RSV)isaleadingcauseofsevereacutelowerrespiratorytractinfectionininfants andchildrenworldwide.BovineRSV(BRSV)iscloselyrelatedtohumanRSVandasignificantcauseof morbidityinyoungcattle.BRSVinfectionincalvesdisplaysmanystrikingsimilaritiestoHRSVinfectionin humans,andcattleareanoutbredpopulationthatisnaturallysusceptibletoBRSVinfection.Therefore,BRSV infectionincalvesrepresentsanexcellentmodelforstudyingRSVinfectionandantiviralimmunityinchildren. RSVispoorlyimmunogenicandthishasbeenacomplicatingfactorinthedevelopmentofasafeandeffective RSVvaccine.Polyanhydridenanovaccineshaveshowngreatpromiseasadjuvantsandvaccinedelivery vehiclesinrodentmodelsduetotheirabilitytopromoteenhancedimmunogenicitythroughboththerouteof administrationandtheabilitytoprovidesustainedantigenexposure.InapreviouslyfundedNIHgrant,the polyanhydridenanovaccineplatformwasusedtodevelopanefficacious,mucosalnanovaccinethat incorporatedthepost-fusionFandGproteinsfromBRSV.NeonatalcalvesvaccinatedwiththeBRSV-F/G nanovaccinedevelopvirus-specificcellularandhumoralimmuneresponsesinthemucosa,anddemonstrate significantreductionsinviralburdenanddisease-associatedpathology.Theoverallobjectiveofthisapplication istoimproveupontheestablishedefficacyofthepolyanhydridenanoparticleplatformforuseagainstRSV infectionintheneonate,andtofurthercharacterizethemucosalimmuneresponsesthatcorrelatewith resistancetoRSVinfection.TheexperimentsinAim1buildupontheestablishedefficacyofthepost-fusion F/Gnanovaccinewiththeincorporationofadditionaltolllikereceptoragonistsandmodificationstothe mucosal/parenteralinoculationregimen.TheexperimentsinAim2willdeterminetheefficacyofamucosal nanovaccinethatincorporatesthepre-fusionFandGproteinsfromBRSV,aswellascharacterizethe antibodyresponsetowardsthepre-fusionandpost-fusionFproteinintherespiratorytractofneonatalcalves. TheexperimentsinAim3willdeterminethedurationofimmunityinducedbypolyanhydridenanoparticle vaccination,whiledeterminingthemucosalimmuneresponsesthatcorrelatewithlong-termresistancetoRSV infectioninthecalf.MuchofourknowledgeofRSVinfectionandimmunitystemsfromstudiesinrodentsand adultanimals;?however,theexperimentsproposedherewillstudyanaturalhost-pathogeninteractionandwill examinetheresponseintheneonate,thesamepopulationcommonlyaffectedbysevereRSVdisease.We anticipatethatthesestudieswillhaveapositiveimpactbyidentifyingasafeandefficaciousvaccineforusein childrenandanimals,andbydeterminingtheimmuneresponsesthatarenecessaryforlong-termresistance againstRSVinfectionintheyoung.

Public Health Relevance

Respiratorysyncytialvirus(RSV)isaleadingcauseofsevereacutelowerrespiratorytractinfectionininfants andchildrenworldwide.SevereRSVinfectionasachildisalsoasignificantriskfactorfordevelopmentof wheezingandallergicairwaydiseaselaterinlife.ThisprojectusestheneonatalcalfmodelofbovineRSV infection.Theobjectiveoftheproposedstudiesistodevelopanefficacious,mucosal,nanoparticlevaccinefor useagainstRSVinfectioninneonates;?andtoidentifycellularandhumoralmucosalimmuneresponsesthat correlatewithresistancetoRSVinfection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD095880-01A1
Application #
9794218
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kapogiannis, Bill
Project Start
2019-09-12
Project End
2023-07-31
Budget Start
2019-09-12
Budget End
2020-07-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011