Abstract

InfluenzaAvirus(IAV)isamajorcauseofseriousrespiratoryillnessandhasbeenresponsibleforsignificant morbidityandmortalityinhumansworldwide.Thevirusleadstoapproximately200,000hospitalizationsand 36,000deathsannuallyintheU.S.duringnon-pandemicyears.Giventhediseaseseverity,theassociated economiccostsandtherecentappearanceofnovelIAVstrainsand/orvariants,thereisanurgentneedto developnovelandefficacious?universal?vaccinestocombatthissignificantglobalpublichealththreat.Current IAVvaccinesarelimitedbytheneedtoaccountforviralantigendrift/shift,theslowmanufacturingprocess,low tomoderateefficacyrates,andtheinabilitytoinducelungresidentmemoryTandBcellsthatoccurduring naturalIAVinfections.Themostefficaciousuniversalvaccinemayneedtotargetconservedepitopeswithin boththeheadandthestemregionsoftheIAVhemagglutinin(HA)andincludeconservedproteinsthatdriveT cellimmunity.Immunizationsthatgeneratelocaltissue-residentmemoryTandBmemorycellsandsystemic immunityofferthegreatestprotectionagainstfutureIAVencounters.Thus,ourlong-termgoalistodevelopa universalIAVvaccinethatwillinducebroadlyneutralizingantibodies(bnAb)anddurable,IAV-specific,lung- residentTandBcellimmunity,protectagainstgroup1and2IAVstrains,andnotrequireacoldchain.Tothis end,wehavediscoveredanovelimmunogenbasedonequinerecombinantHA3(rHA3)thatelicitsAbin multiplespeciesandprotectsacrossinfluenzagroupsbytargetingboththeHAheadandstemregions.We havealsodevelopedtwopromisingpolymericnanovaccineplatformsthathavebeenshowntoincreaseAb titer,improveTcellimmunity,andprolongantigenreleaseaftervaccination.Oneiscomprisedof biodegradablepolyanhydridenanoparticlesandtheotherisbasedonpentablockcopolymermicelles.Wehave shownthatbothplatformsinducedprotectiveimmunitywithreducedviralloaduponvaccination.TheIAV nanovaccineshowedpromisingefficacyinprotectionagainsthomologousandheterologousIAVinfectionsand inducedTandBcellresponsesinthelungs.Thisproposalwillusethecombinedexpertiseofourteamto determineifananovaccineapproachwillinducebothbnAbanddurable,lung-residentTandBcellimmunity andleadtouniversalprotectionusingthefollowingspecificaims:1)synthesizeandcharacterizerHA3 nanovaccines;?2)establishthesafetyandtoxicologicalprofileofrHA3nanovaccineinmiceandferrets;?3) determinerHA3nanovaccineformulation(s)thatwillelicitthemostappropriateandsustainedresponsetoIAV followingasingle-dosevaccination;?4)designmultivalentrHA3nanovaccinesthatincreasebnAbandCMIto diversestrainsofIAV;?and5)developGLP-compliantprocessforsynthesisofidentifiedleaduniversal nanovaccineandevaluateitsshelflifeindeliverydevices.Theproposedstudieswithtightlyboundmilestones anddecisionpointswillleadtoafinalproductthatwillmeetNIAID?scharacterizationofaprotectiveuniversal IAVvaccineandprovideimportantfirststepsfortranslatingourfindingstohumanclinicaltrials.

Public Health Relevance

ThediseaseseveritycausedbyinfluenzaAvirus(IAV),theassociatedeconomiccostsandtherecent appearanceofnovelIAVstrainsand/orvariantsunderscoreanurgentneedtodevelopnovelandefficacious ?universal?IAVvaccines.CurrentIAVvaccinesarelimitedbytheneedtoaccountforviralantigendrift/shift,the slowmanufacturingprocess,lowtomoderateefficacyrates,andtheinabilitytoinducelungresidentmemoryT andBcellsthatoccurduringnaturalIAVinfections.ThisprojectwilldevelopauniversalIAVvaccinethatwill inducebroadlyneutralizingantibodiesanddurable,IAV-specific,lung-residentTandBcellimmunity,protect againstgroup1and2IAVstrains,andnotrequirearefrigerationcoldchain.Theproposedstudieswillleadto afinalproductthatwillmeetNIAID?scharacterizationofaprotectiveuniversalIAVvaccineandprovide importantfirststepsfortranslatingourfindingstohumanclinicaltrials.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI141196-03
Application #
10079019
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Gordon, Jennifer L
Project Start
2019-01-24
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
Iowa State University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011