Development of Nasal Spray Vaccines

DevelopmentofNasalSprayVaccines

Nasalsprayvaccinesareapromisingrouteofvaccinationandofferuniqueadvantages, especiallyinthepreventionofinfectiousdiseasestransmittedviatherespiratorytract Comparedtoinjectablevaccines,nasalsprayvaccinesalsohavetheadvantageofbeing lessinvasiveandeasiertostoreanddistribute

Thenasalsprayvaccineforinfluenzahasbeenusedstablyformorethanadecade,and thefirstnasalsprayCOVID-19vaccinehasbeenapprovedforemergencyuseinChina andIndiaHere,wefocusontheinfluencingfactorsandcurrentstatusofthenasalspray vaccinedevelopment

PhysiologicalStructureandImmunogenicityof theNasalCavity

Thenasalcavityreferstotheinteriorofthenoseorthestructurethatopensexteriorlyat thenostrils.Itistheentrancetotheinhaledairandisthefirstofaseriesofstructuresthat makeuptherespiratorysystemThenasalcavityiscompletelylinedbythenasalmucosa, oneoftheanatomicalstructuresthatformthephysicalbarriertothebody'simmune systemThesebarriersprovidemechanicalprotectionagainsttheinvasionofinfectious andallergicpathogens.

Vaccinesarealsoforeignantigens,andthenasalcavityactivatesimmunemechanisms whenexposedtoforeignantigens(vaccines)Uponenteringthenasalcavity,theantigen istrappedonthemucosalepitheliumandthemicrofoldcells(Mcells)ofthelymphoid follicularepitheliumthenabsorbtheantigenparticlesSubsequently,theantigenismoved tothebasalendofthecellandpassedontoantigen-presentingcells(APCs),suchas

dendriticcells(DCs)andmacrophagesThereafter,DCcellsmigratethroughafferent lymphaticvesselstonearbydraininglymphnodeswhereantigenispresentedtonaiveT andBcellsviatheMHC-IIcomplex

Nasal-associatedlymphoidtissues(NALTs)areanimportantcomponentofmucosal immunityintherespiratorytractnALTshaveahighdistributionofMcellsandarethe mainsiteofuptakeofmacromoleculardrugsandparticlesinthenasalcavity,aswellas themainsiteofantigendeliveryinthenasalimmuneresponseNALTshave antigen-specificeffectorBandTcellsthatdifferentiateintoplasmacellsthatproduce aggregatedIgAandIgGandeventuallydifferentiateintosIgA,triggeringanimmune responsethatinterceptsantigensandpathogensMucosalimmunityalsohasaunique setofmechanismsforco-immunitythatinducesanimmuneresponseindistalmucosa, suchasthedigestiveandgenitaltractmucosa,butusuallytheintestinalimmunity activatedbynasalsprayvaccinesislesseffective.

Similartonasaladministration,nasalsprayvaccinesneedtoovercomemultiple constraints,suchastheeffectofnasalmucosalciliaclearance,theproblemofshort residencetimeinthenasalcavity,andtheobstructionofantigensbythemucusand epitheliallayersofthenasalmucosalsiteThesolutionoftheseproblemsoftenalso requirestheassistanceofimmuneadjuvantsandpenetrationenhancers

KeyTechnicalFactorsintheDevelopmentof NasalSprayVaccines

Mostofthecurrentlymarketednasalvaccinesareliveattenuatedinfluenzavirusvaccines Wenowpresentseveralkeyfactorsthatshouldbeconsideredwhenresearchingand developingnasalsprayvaccines,mainlyfromtheperspectiveoftheimmuneprocess

1.FirstStepofDrugDelivery-DosageFormsandDelivery Equipment

SuccessfulnasaldeliveryfirstrequiresthecooperationofasuitabledeviceAlthoughthe nasalcavityhasalargemucosalsurfacearea,intranasaldeliveryofvaccinesislimitedby nasalanatomyandaerodynamics,wheredrugswithlargeparticlesizesareusually depositedintheanteriornoseandconsequentlyexpelledorwipedoff,whilesmallparticle sizes(ie,<10μm)maybypassthenoseandenterthelungsThus,asuitabledeviceis neededtodispersetheintranasalvaccineformulationintoappropriateparticlesizesfor deliverytotheposteriorregionofthenose,andachievingabalanceofparticlesizesis criticaltoincreasingantigenexposuretothenasalmucosaFluMistvaccinescurrentlyis deliveredusingtheAccuSpraynasaldeliverysystemInaddition,MADNasalfrom Teleflex,ViaNasefromKurve,PuffHalerfromAktiv-Dry,andSoloventfromBDalloffer nasalmucosalnebulizationsolutions

Todate,allapprovednasalsprayvaccineshavebeeninliquidformbecauseofthehigh solubilityandpotencyofliquidvaccines.However,liquidformulationsarefluidandany liquidthatexceedsthenasalvolumewillbedrainedfromthenasalcavity,andonlyhighly solubleorlowdoseantigenscanbedeliveredintranasallyvialiquidformulationsThe applicationofdrypowderformulations,ontheotherhand,requiresaprolongedresidence timeinconjunctionwithmucoadhesivepolymerssuchasstarchandchitosantoimprove antigenavailabilitytothenasallymphatictissue

2.ProlongingTheResidenceTimeOfVaccine–Mucoadhesives

MucoadhesivesarecommonlyusedinthedevelopmentofnasalsprayvaccinesOnce themucoadhesiveagentinthevaccinecomesintocontactwiththemucusofthenasal epithelium,thepolymerhydrates,swellsandbindstothemucus,prolongingtheresidence timeofthevaccineinthenasalmucosaInaddition,mucoadhesivesalsotemporarilyslow mucusciliaclearanceanddonotinhibitantigenreleasefromthevaccineCommonly usedmucoadhesivepolymersincludeegchitosan,starch,etc

3.PromotingTransmembranePenetrationofVaccinesPermeationEnhancers

Thenasalepitheliallayeriscoveredbyalayerofmucus,andnasalspray vaccines/antigensneedtocompletethepenetrationofthemucuslayerandepithelialcells. Firstly,itisnecessarytopenetratethemucuslayerPolyethyleneglycol(PEG)canbe usedasamucuslayerpenetrationenhancer,whilemannitolcandilutethemucus Therefore,theuseofPEG,mannitolorothermucuspenetrationenhancersinthe formulationcanhelpimprovethepenetrationofvaccines/antigensintothemucuslayer.

Thetransportofantigenacrosstheepithelialcellbarrierisacriticalstepintheinductionof immunityAntigenscanpenetratetheepitheliallayerthroughcellsoracrosscells,and permeationenhancerssuchaschitosanandbacterialtoxinsareoftenusedinthisprocess toincreasethepermeabilityofantigenstothemucosaBothchitosanandbacterialtoxins candisruptepithelialjunctionsandenhanceparacellularmotilitySpecifically,chitosan promotestranscellularuptakeofantigensbyMcellsinthenasalmucosaandintestinal mucosa.Incontrast,enterotoxinsdisruptthemucosalepitheliumandenhanceantigen uptakebyDCcells,leadingtoupregulationofCXCR4andCCR7,therebyallowingDC cellstomigratetolymphnodes

4.ReducingPotentialIntracranialTransport–Nose-to-Brain TransportInhibitors

Animportantsafetyconcernregardingnasalsprayvaccinesisthepotentialfortransport ofvaccineantigensoradjuvantsfromtheolfactoryepitheliumtothecentralnervous system(CNS),althoughresearchersanalyzing460adverseeventsassociatedwith FluMistfoundonlyonecaseofencephalitisandlaboratoryconfirmationthatitwascaused byanenterovirusHowever,thenasalmucosaprovidesadirectentrypointbetweenthe externalenvironmentandthecentralnervoussystem(nose-to-brainpathway),and compoundscanenterthecerebrospinalfluidthroughthenervesassociatedwiththe olfactoryarea.Therefore,neurophilicityneedstobeevaluatedinnasalsprayvaccine development

5.EnhancingtheImmunogenicityofAntigens-Vaccine Adjuvants

AdjuvantsthattargetAPCantigensintheprocessofimmunizationcanbeusefulas immunostimulants.Commonlyusedimmuneadjuvantsareinsolublealuminumsaltsand TLRagonists

InsolublealuminumsaltsareclassicalFDA-approvedimmuneadjuvantsSeveral aluminumsaltsarecurrentlyusedinvaccinesapprovedintheUnitedStates,suchas Alhydrogel(aluminumhydroxide),Adju-Phos(aluminumphosphate),andamorphous aluminumphosphatesulfate(AAPS)Theimmunostimulatoryeffectsofaluminumsalts arisefromavarietyofmechanisms,includingslowingthespreadofantigenfromthesite ofadministration,increasinginflammatorycellaccumulation,activatingcomplement,and inducingthedifferentiationofmonocytesintoDCsaswellasuptakeofantigen,antigen delivery,andactivationofCD4+TcellsbyDCs

TLRagonistscanactasadjuvantsformucosalimmunity;specifically,TLRagonists functionaspathogen-associatedmolecularpatterns(PAMPs)andactbybindingto pathogenrecognitionreceptors(PRRs)onDCcellsCommonlyusedareTLR2/6agonists, TLR3agonists,TLR3agonists

CurrentDevelopmentStatusofNasalSpray Vaccine

1.ApprovedNasalSprayVaccines

FluMist®(MedImmune,LLC)isthefirstliveattenuatedinfluenzavirusintranasal vaccinethatwassuccessfullyapprovedandcommercializedintheUSandEurope(as Fluenz®)ItisavaccinethatissprayedintothenosetohelpprotectagainstinfluenzaIt canbeusedinpeople2through49yearsold

Nasovac-SisaliveattenuatednasalsprayvaccineproducedbytheSerumInstituteof IndiaforthepreventionofinfluenzaA(H1N1)

Themainnasalsprayvaccinescurrentlyundergoingclinicaltrialsincludeinfluenza vaccines(H5N1,H1N1,etc.),humanparainfluenza(types2and3),respiratorysyncytial virus(RSV),streptococcuspneumoniae,andmycobacteriumtuberculosisResearchis alsounderwayonnasalsprayvaccinesagainstgonorrheaandchlamydiausingantigens fromonespecificmucosalregiontoinitiatecommonmucosalimmunesystemproperties thatcaninduceresponsesindifferentmucosalregions.

2.SafetyandWeakImmunogenicityofNasalSprayVaccines

Intranasalinfluenzavaccinesaregenerallyconsideredsafeandeffective,buttherehave beenexamplesofwithdrawalsduetoassociatedadverseevents,withthewithdrawalof NasalgluproducedbyBernaBiotechin2001duetoinducedBell'spalsyThereisalso evidencethatliveattenuatedinfluenzavaccines(LAIVs)cancauseencephalitisthrough theolfactorynerveintothebrain(nasal-to-brainpathway)Althoughtheseare theoreticallysoundstudies,theyshouldnotbeignoredinpractice

Moreimportanttonote,however,istheimmunogenicityofnasalsprayvaccines.Although theabilityofthenasalsprayvaccinetoinducesystemicandmucosalimmunitywould theoreticallyleadtogreaterprotectiveimmunity,theefficacyofthenasalsprayvaccine wouldbelimitedbytheshortresidencetimeinthenoseandthemovementofenzymes, mucus,andnasalhairsinthenasalcavity.

Conclusion

Nasalsprayvaccinesoffermanyadvantagessuchaseaseofadministrationandthe potentialtoinducesystemicandmucosalimmunity,whichhasgreatpotentialespeciallyin today'sepidemicofrespiratoryinfectiousdiseases.However,nasalsprayvaccinesarea multidisciplinaryfieldthatintegratesformulation,device,andclinicalresearch,andthe challengesofdevelopinganewnasalsprayvaccinearenumerous

BiopharmaPEGisaleadingsupplierofhigh-qualityPEGderivativesWecan providePEGderivativesfromlabtolargescaleinGMPandnon-GMPgrade.PEG derivativesnotlistedinourcatalogcanbeprovidedbycustomsynthesis

References:

[1]AluA,ChenL,LeiH,etalIntranasalCOVID-19vaccines:Frombenchtobed[J] EBioMedicine,2022,76:103841

[2]LobainaMatoYNasalrouteforvaccineanddrugdelivery:Featuresandcurrent opportunities[J]Internationaljournalofpharmaceutics,2019,572:118813