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OfficeofthePrimeMinister’sChiefScienceAdvisorKaitohutohuMātangaPūtaiaoMatuakitePirimia
COVID-19vaccines:Summaryofcurrentstate-of-playPreparedunderurgency21May2020–updated16July2020
TheCOVID-19pandemichasspurredaglobalefforttofindavaccinetoprotectpeoplefromSARS-CoV-2infection.
Thissummaryhighlightsselectedcandidates,explainsthedifferenttypesofvaccinesbeinginvestigatedandoutlinessomeofthepotentialissuesandrisksthatmayariseduringtheclinicaltestingprocessandbeyond.
Keypoints• Thereareatleast22vaccinecandidatesregisteredinclinical(human)trials,outofatotal
ofatleast194invariousstagesofactivedevelopment.• Itistooearlytochooseaparticularfrontrunneraswelacksafetyandefficacyinformation
forthesecandidates.• Itisdifficulttopredictwhenavaccinewillbewidelyavailable.Thefastestturnaroundfrom
exploratoryresearchtovaccineapprovalwaspreviously4–5years(ebolavirusvaccine),althoughitislikelythatcurrenteffortswillbreakthisrecord.
• Thereareanumberofchallengesassociatedwithacceleratedvaccinedevelopment,includingensuringsafety,provingefficacyinarapidlychangingpandemiclandscape,andscalingupmanufacture.
• Thevaccinethatislicensedfirstwillnotnecessarilyconferfullorlong-lastingprotection.
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ContentsKeypoints..................................................................................................................................1
1. Typesofvaccines................................................................................................................4
1.1. Vaccinetrackers.................................................................................................................6
2. Timeline:Whenwillwehaveavaccine?..............................................................................7
3. Organisationsandprojectsofinterest.................................................................................9
3.1. CoalitionforEpidemicPreparednessInnovations(CEPI)...................................................9
3.2. Gavi,theVaccineAlliance..................................................................................................9
3.3. TheAccesstoCOVID-19Tools(ACT)Accelerator...............................................................9
3.4. OperationWarpSpeed(OWS).........................................................................................10
3.5. VaccinedevelopmentinAotearoaNewZealand.............................................................10
4. Potentialissues.................................................................................................................12
4.1. Provingvaccineefficacyonanacceleratedtimeline........................................................12
4.2. Immuneenhancement.....................................................................................................12
4.3. Vaccine-derivedoutbreaks...............................................................................................13
4.4. Mutationofthevirus........................................................................................................13
4.5. Durationofimmunity.......................................................................................................14
4.6. Immunesenescence.........................................................................................................14
4.7. Scalabilityandaccessibility...............................................................................................14
4.8. Vaccineuptake.................................................................................................................15
5. Selectedvaccinecandidates..............................................................................................16
5.1. Vaccinesinclinicalevaluation....................................................................................16
5.1.1. UniversityofOxfordandAstraZeneca..............................................................................16
5.1.2. CanSinoBiologicsandBeijingInstituteofBiotechnology................................................17
5.1.3. ModernaandNIAID..........................................................................................................17
5.1.4. InovioPharmaceuticals....................................................................................................18
5.1.5. SinovacBiotech................................................................................................................19
5.1.6. BioNTechandPfizer.........................................................................................................19
5.1.7. ShenzhenGeno-ImmuneMedicalInstitute(GIMI)..........................................................20
5.1.8. Sinopharm........................................................................................................................21
5.1.9. ImperialCollegeLondon(ICL)DepartmentofInfectiousDiseases..................................22
5.1.10.Novavax............................................................................................................................22
5.1.11.UniversityofQueensland.................................................................................................23
5.1.12.SymvivoCorporation,UniversityofBritishColumbiaandDalhousieUniversity.............23
5.1.13.CureVac............................................................................................................................24
5.1.14.Othervaccinecandidatesinclinicaltrials........................................................................24
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5.2. Selectedexamplesofvaccinesinpreclinicalstages....................................................25
5.2.1. Janssen/Johnson&Johnson.............................................................................................25
5.2.2. ArcturusTherapeuticsandDuke-NUS..............................................................................25
5.2.3. UniversityofPittsburghSchoolofMedicineandUPMC..................................................26
5.2.4. TheUniversityofHongKong............................................................................................26
5.2.5. InstiutPasteur,ThémisandtheUniversityofPittsburgh.................................................26
6. Repurposedvaccines:aninterimsolutionforfuturepandemics?......................................28
6.1. TheBCGvaccine...............................................................................................................28
7. Furtherreading.................................................................................................................29
8. Acknowledgements..............................................................................................................30
9. References............................................................................................................................30
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1. TypesofvaccinesVaccinesintroducethehumanimmunesystemtocertainproteinmoleculesfromthepathogenofinterest.Thiscontrolledexposureprovokesanimmuneresponsethatultimatelyleadstosomeperiodofimmunityfromthepathogen.Theimmuneresponseelicitedwouldideallyconsistofbothneutralisingantibodies(thatblockthevirusparticlefromenteringcells)andTcells,whichidentifyinfectedcellsandeliminatethem.
InthecaseofSARS-CoV-2,the‘spike’proteinisanidealtargetforvaccines.[1]Thisisbecausethespikeproteinisessentialforthevirustolatchontohumancells(viatheACE2receptor)andinfectthem.Itisthereforeconservedacrossdifferentstrains.Mostcurrentvaccineeffortstargetthespikeprotein.Somemighttargetthewholeprotein(alsoknownasanantigen)whileothersmayonlytargetspecificbitsofthespike.However,limitedinformationpubliclyavailablemeansthatanydifferencesbetweentargets,ortheprevalenceofothertargetsasidefromthespike,remainsunclear.[2]OtherantigensasidefromthespikeproteinareabletoinduceaTcellresponse.[3]
Figure1:Diagramofacoronavirusvirionwiththespikeproteinlabelled.CCBY3.0.[4]
Inadditiontothespikeprotein,somevaccinescontainanadjuvant:amoleculethatsignalstotheimmunesystemthatit’stimetojumpintoaction.Inparticular,subunitvaccinesoftenrequireanadjuvanttoinduceasufficientimmuneresponse.
Therearedifferentwaysofintroducingthe‘spike’protein(orothertarget)tothebody.Someofthesemethodsareexperimentalwhileothershaveaproventrackrecord.
Table1:Typesofvaccineplatforms
Virus
Live,attenuatedvirus
Aliveorganismwithitsvirulentpropertiesdisabled–usuallybybeingrepeatedlypassedthroughanimalorhumancellsuntilastrainisgeneratedwithmutationsthatmaketheviruslesspotent.Typicallyinvokelonger-lastingimmuneresponsesandresponsestoanumberofantigensbutmaynotbesuitableforimmunocompromisedindividuals.
Example:influenzavaccineadministeredbynasalspray;poliovirusvaccine.
Inactivatedvirus
Avaccinecontainingwholevirusesthathavebeenkilledthroughheatorchemicaltreatment.Productionrequireslargequantitiesofinfectiousvirusandcantakelongertoculturethanothervaccinetypes.Protectionusuallyweakerthanlivevirusvaccines,soboostershotsmaybeneeded.
Example:intramuscularinfluenzavaccine
Protein Subunit
Ratherthanintroducingawholeorganism,thistypeofvaccineonlyincludesafragmentorindividualproteinmolecule.Theseproteinmoleculesmaybecoveredwithdifferentsugarsto
Example:hepatitsBvaccine
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thoseonthenaturalvirusantigens,dependingonmethodofmanufacture,whichmayposechallengesforefficacy.Willprobablyrequireanadjuvantandmultipledoses.
Virus-likeparticle(VLP)
Essentiallyasubsetofsubunitvaccines,VLPsconsistofanantigenrepackagaedinaparticlethatresemblesavirus(usuallywithlotsofviralsurfaceproteins)butdoesnotcontainanygeneticmaterialandthereforecannotreplicate.Consideredsaferthanlive,attenuatedvirusvaccinesbutcanbedifficulttomanufacture.
Examples:HPVvaccine,hepatitisBvaccine
Viralvector
Non-replicatingviralvector
AharmlessvirusunrelatedtoSARS-CoV-2thatcontainsinstructionstocreatethespikeproteine.g.anadenovirusthathasbeenmodifiedsoitcannotreplicate.Pros:long-termstability,highlevelproteinexpression.Cons:manypeoplealreadyhavesomelevelofimmunitytocertainvectorssuchassomeadenoviruses.
Nolicencedvaccinesusingthismethod
Replicatingviralvector
Thesameconceptasanon-replicatingviralvector,howeverthevirusretainstheabilitytoreplicate.Thiscanenhancetheimmuneresponseasmorecellsareexposedtothespikeprotein.Pros:long-termstability,inducestrongimmuneresponse,highlevelproteinexpression
Example:ebolavirusvaccine.
Nucleicacid
RNA AvaccinemadeofviralRNAmoleculesthatdirecthumancellstoexpressthespikeprotein.Pros:speedofproduction,flexibility,cellmakesproteinwithcorrectsugarsattachedLimitations:RNAisinherentlyunstableandrequirescoldstoragepluscarefuldistributionmethods
Nolicencedvaccinesusethismethod
DNA
SimilartoRNAvaccines.AvaccinecomprisingDNAthatisincorporatedintohumancellsandinstructsthemtoexpresstheviralprotein,triggeringanimmuneresponse.Pros:speedofproduction,flexibility,cellmakesproteinwithcorrectsugarsattached
Nolicencedvaccinesusethismethod
Asof16July2020,thereareatleast194candidatevaccinesinvariousstagesofactivedevelopment.[5]Althoughthismayseemlikeahugenumberofoptions,theattritionrateforvaccinesisveryhigh.Themarketentryprobabilityfortheaveragevaccinecandidateisjust6%.[6]Anotherstudyfoundthatthe‘probabilityofsuccess’forinfectiousdiseasesclinicaltrialsisaround25%.[7]
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Figure2:chartbreakingdownthedifferentplatformsbeinginvestigatedforpotentialCOVID-19vaccines.ReproducedfromNature[8]
Figure3:Differentvaccinetypesandtheirprogressionalongthedevelopmenttimeline.Reproducedfromthe‘COVID-19vaccinedevelopmentpipeline’trackerpublishedbytheVaccineCentreattheLondonSchoolofHygieneandTropicalMedicine.[9]
1.1. VaccinetrackersTheCOVID-19vaccinelandscapeisrapidlyevolving.Thefollowingresourcesaretrackingthenumberofvaccinecandidatesindevelopmentandtheirprogressionthroughtheclinicaltrialpipeline.
• WorldHealthOrganization–DraftlandscapeofCOVID-19vaccinecandidates• MilkenInstitute–COVID-19vaccineandtreatmenttracker• VaccineCentre,LondonSchoolofHygieneandTropicalMedicine–COVID-19vaccine
developmentpipeline• BioRender–COVID-19vaccineandtherapeuticstracker• StatNews–COVID-19drugsandvaccinestracker• TheNewYorkTimes–Coronavirusvaccinetracker• TheGuardian–Coronavirusvaccinetracker:Howclosearewetoavaccine?• TheScientist–COVID-19vaccinefrontrunners
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2. Timeline:Whenwillwehaveavaccine?Whilesomepharmaceuticalcompaniesareaimingforemergencyusedispensationoftheirvaccineswithinmonths,[10,11]theWorldHealthOrganization(WHO)cautionsthatthefullprocesswilllikelytakeatleast12-18months,ifnotlonger.[12]Theaveragevaccinetakesmorethantenyearstoprogressfrompreclinicaldevelopmenttomarket,[6]althoughtherecentexampleofanebolavirusvaccineturnaroundoffiveyearssignalsthattheprocesscanbeaccelerated.[13]
Typically,onceavaccinecandidateisidentified,itwillproceedthroughthefollowingsteps:
1. Pre-clinicaltrials–studiesinanimalmodels(geneticallymodifiedmice,butalsoferretsandnon-humanprimates[14])toprovideapreliminaryassessmentofsafetyandgenerationofanimmuneresponse/antibodies.
2. PhaseIclinicaltrials–firsttrialsinhumanswithusuallyafewdozenhealthyparticipants;primarilytoassesssafetyandsideeffects,andfigureouttheoptimaldose.
3. PhaseIIclinicaltrials–severalhundredparticipants;assessesefficacyandcontinuestomonitorsafetyandsideeffects.
4. PhaseIIIclinicaltrials–ideallythousandstotensofthousandsofparticipantswiththediseaseofinterest;assesseseffectivenessandvalueinclinicalpractice.
5. Regulatoryapproval–bodiessuchastheFoodandDrugAdministration(FDA)andEuropeanMedicinesAgency(EMA)reviewthetrialresultsandotherinformationaboutthevaccinetodeterminewhetherthevaccinecangotomarket
6. Scaled-upmanufacture–dosesofthevaccinemustbeproducedatscaleanddistributed.Differentvaccinetypesrequiredifferentmanufacturinginfrastructure.
TheCoalitionforEpidemicPreparednessInnovations(CEPI)hasproposeda“pandemicparadigm”thatallowsforacceleratedvaccinedevelopment.[15]
Figure4:Differencebetweenthetraditionalvaccinedevelopmentparadigmandanaccelerated“pandemicparadigm”asproposedbyCEPI.[15]
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TheUSNationalInstitutesofHealth(NIH)isspearheadingacollaborativeprogramcalledAcceleratingCOVID-19TherapeuticInterventionsandVaccines(ACTIV).[16]Thisbringstogetherpublicandprivatestakeholderstoadvancethevaccinedevelopmenttimelineinacoordinatedmanner(Figure2).
Figure5:theACTIVmodelforSARS-CoV-2vaccinedevelopment.[16]
Beyondmodels,thisusefulinteractivefromTheNewYorkTimesexploresspecificwayswecouldpotentiallyacceleratethetimeline.[17]Theseinclude:
• AssumingwealreadyunderstandthecoronavirusbyrelyingonworkfromstudyingtherelatedSARSandMERScoronaviruses.
• Undertakingdifferentphasesinparallel.• Usingemergencyprovisionstovaccinateat-riskpopulations(e.g.healthcareworkers)
earlier.• Anticipatingwhichcandidatesarelikelytobesuccessfulandbeginmanufacturingearlyto
speedupproductionprocess.• Fast-trackingregulatoryapprovals.
These‘shortcuts’areassociatedwithvaryinglevelsofrisk,furtherexploredinsection3‘Potentialissues’.
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3. Organisationsandprojectsofinterest3.1. CoalitionforEpidemicPreparednessInnovations(CEPI)
CEPIisaglobalorganisationthatfinancesandcoordinatesthedevelopmentofvaccinesagainstinfectiousdiseases.CEPIissupportingthedevelopmentoftenvaccinecandidatesforCOVID-19whichcoveravarietyofplatforms(seetable2below,andsectionfive,‘Selectedvaccinecandidates’).CEPIestimatethatitwilltakeUS$2billiontobringavaccinetowidespreaduse.[18]Inadditiontothevaccinecandidateslisted,CEPIispartneringwithpharmaceuticalcompaniesGlaxoSmithKlineandDynavaxtomaketheirproprietaryadjuvantsavailabletovaccinedevelopers.
Table2:COVID-19vaccinesindevelopmentsupportedbyCEPI.Vaccinename Developer(s) Vaccineplatform CurrentstageAZD1222 UniversityofOxford,
AstraZenecanon-replicatingviralvector
phaseI/II/IIIclinicaltrials
PhaseIII
mRNA-1273 Moderna,NIAID nucleicacid,RNA phaseI/IIclinicaltrials
PhaseII
COVAC1 ImperialCollegeLondon
nucleicacid,self-amplifyingRNA(saRNA)
phaseI/IIclinicaltrials
INO-4800 InovioPharmaceuticals
nucleicacid(DNAplasmid)
phaseI/IIclinicaltrials
CVnCoV CureVac nucleicacid,RNA phaseIclinicaltrials
PhaseI
NZX-CoV2373 Novavax proteinsubunit phaseIclinicaltrials
SCB-2019 CloverBiopharmaceuticals
proteinsubunit phaseIclinicaltrials
Molecularclamp UniversityofQueensland,CSL
proteinsubunit pre-clinicaltesting
pre-clinical
unnamed UniversityofHongKong
live,attenuatedvirus
pre-clinicaltesting
MV-SARS-CoV-2 InstitutPasteur,Merck,UniversityofPittsburgh
replicatingviral(measles)vector
pre-clinicaltesting
3.2. Gavi,theVaccineAllianceGaviisaninternationalorganisationthatbringstogetherthepublicandprivatesectorstoenhanceequitableaccesstovaccinesworldwide.[19]Inparticular,theyboostaccesstonewandunder-usedvaccinesforvulnerablechildreninlow-incomecountries.
3.3. TheAccesstoCOVID-19Tools(ACT)AcceleratorTheACTAcceleratorisacollaborativeinitiativeledbyWHO,aimingtospeeduptheglobalpandemicresponsebysupportingresearch,developmentandequitableaccesstotests,treatmentsandvaccines.[20]
TheACTAcceleratorhasfourpillars:diagnostics,treatments,vaccinesandhealthsystems.ThevaccinespillarisspearheadedbyWHO,GaviandCEPI.Theyrecentlyannouncedan$18.1billionplancalledCOVAXtopurchasetwobilliondosesofvaccinetodistributetohigh-riskpopulationsworldwide.[21]CountrieswillbeabletobuysharesintheCOVAXFacility,allowingthemtoaccessthenineCEPIvaccinecandidates(oranyothervaccinestheconsortiumchoosestopurchase).This
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approachwaschosenbecausewedonotyetknowwhichvaccinecandidateswillbesuccessfulinclinicaltrials;itisawayofnotputtingallofacountry’sfundsintoasinglevaccinethatmightfail.
3.4. OperationWarpSpeed(OWS)AUS-basedoperation,OperationWarpSpeedaimstosecure300milliondosesofasafe,effectiveCOVID-19vaccineforAmericansbyJanuary2021.[22]ItisapartnershipbetweengovernmentandindustryledbytheUSDepartmentofHealthandHumanServices.
OWShasbeenidentifyingpromisingvaccinecandidatesandsupportingthemwithsignificantfundingforclinicaltrialsinanimalsandhumans,aswellasinvestinginmanufacturinganddistributioncapabilities.However,manyOWSactivitiesanddecisionsremainopaque.[23]Fromaninitialpoolof125candidates,anNIHexpertgroupundertookascientificreviewof50vaccinecandidatesforOWS,whichhasnotbeenmadepublic.[23]Thislistwasnarroweddownto14frontrunners,andthetaskforceplannedafurtherwinnowingtoaroundsevencandidatesforadavancementtoclinicaltrials.[22]
Table3:COVID-19vaccinesindevelopmentsupportedbyOWS.Vaccinename Developer(s) Vaccine
platformCurrentstage AmountofOWS
funding(US$)AZD1222 Universityof
Oxford,AstraZeneca
non-replicatingviralvector
phaseI/II/IIIclinicaltrials
$1.2billion[24] PhaseIII
Ad26.COV2-S Janssen(Johnson&Johnson)
non-replicatingviralvector
phaseI/IIclinicaltrials
$456million[25] PhaseII
mRNA-1273 Moderna,NIAID
nucleicacid,RNA
phaseI/IIclinicaltrials
$483million[26]
INO-4800 Inovio nucleicacid(DNAplasmid)
phaseI/IIclinicaltrials
unknown–fundedfornon-humanprimatechallengestudy[27]
BNT-162 Pfizer,BioNTech
nucleicacid,RNA
phaseI/IIclinicaltrials
DeclinedtoacceptOWSfunding[28]
NVX-CoV2373 Novavax proteinsubunit
phaseIclinicaltrials
$1.6billion[29] PhaseI
VAAST Vaxart non-replicatingviralvector
preclinicaltesting
unknown–fundedfornon-humanprimatechallengestudy[28]
pre-clinical
unnamed Merck,Sharpe&Dohme
replicatingviralvector
preclinicaltesting
$38million[30]
3.5. VaccinedevelopmentinAotearoaNewZealandTheNewZealandGovernmenthasallocated$37milliontoaCOVID-19vaccinestrategy.[31]ThiscomesaftersomeNewZealandscientistscalledfortheGovernmenttoinvestinanonshorevaccineprogrammeduetopotentialaccessibilityissues[32]andaletterintheNewZealandMedicalJournalco-signedby120scientistssupportingthisapproach.[33]
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ThestrategyaimstosecureasafeandeffectiveCOVID-19vaccineinsufficientquantitiesforAotearoaNewZealand.Itincludes$10millionforonshorevaccineresearchand$5millionforonshorevaccineproductioncapability.Upto$15millionwillgotowardsinternationalresearchcollaborationsmanagedbyCEPI,andafurther$7millionin“officialdevelopmentassistance”isearmarkedforGavi,theVaccineAlliance,tosupportvaccinedistributionindevelopingcountries.
AtaskforcecomprisingMBIE,theMinistryofHealth,Medsafe,Pharmac,andtheMinistryofForeignAffairsandTradeisoverseeingimplementationofthestrategy.
Proposalsfortheprogrammeincludeevaluationofvaccinesdevelopedinternationallyandaplanforvaccineroll-out.Suggestionsalsoincludeestablishingvaccinedevelopmentprogrammesin-countryalongsidevaccineproductioncapability.However,aproactively-releasedCabinetpapernotesthat“ItisunlikelythatawhollyindigenousNewZealandvaccinewillprovideourquickestandmostreliableroutetoasupplyofvaccine.”[34]
Considerationisalsobeinggiventoworkingonatrans-TasmaninitiativewhichwouldharnessexpertiseacrossAustraliaandAotearoaNewZealandandpossiblymitigatetherisksofbeinglowestpriorityforfuturesupply.FurtherinformationonAustralianvaccinedevelopmenteffortscanbefoundintheRapidResearchInformationForum’spaper,‘ThemostpromisingvaccinesforCOVID-19’.[35]Meaningfulparticipationininternationalvaccinedevelopmenteffortswillbeimportantforsecuringaccesstovaccineswhentheybecomeavailable.
InadditiontotheCOVID-19vaccinestrategy,MBIEhasestablishedaCOVID-19InnovationAccelerationFund.[36]
ThereareongoingresearchprojectsattheUniversityofAucklandandtheUniversityofOtagotounderstandimmunityandembarkonthefirststepstowardsavaccine(inatraditionaldevelopmentparadigm).[37]
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4. Potentialissues4.1. Provingvaccineefficacyonanacceleratedtimeline
Asdiscussedinsectiontwo(‘Timeline’),provingthatavaccineworksisusuallyachievedthroughaseriesofcomprehensiveclinicaltrials.Thesetypicallyinvolvethousandstotensofthousandsofparticipantswhoreceiveeitherthevaccineoraplacebo,andarethenmonitoredtoseewhobecomesinfected.Thisisatime-consumingprocess.
Furthermore,acquiringthenumbersnecessaryforprovingefficacywillbedifficult–especiallyatatimeofsocialdistancingandfallingcasenumbers.Evenifthepandemicisstillinfull-swing,wedon’tknowwheretheepicentrewillbeinseveralmonthswhenthefirstvaccinecandidatesarereadytomoveintotheselarge-scalephaseIIItrials.
Thesedifficultiescouldbeaddressedbyadifferentapproach:somehaveproposeda‘humanchallenge’studyasaquicker–butpotentiallyriskier–alternative.[38]Thiswouldinvolvedeliberatelyexposingvaccinatedparticipantstotheviruswhichmayreducethedevelopmenttimelinebyseveralmonths.However,participantswouldrisksufferingseverediseaseorperhapsevendeathinsuchastudy.Whilethismethodisnotbeingactivelypursuedatthistime,agrassrootsmovementcalled‘1DaySooner’hasattracted1500willingvolunteers.[39]Further,supportisbuildingfortheapproachamongUSlawmakers,whohavewrittentotheUSDepartmentofHealthandHumanServicesandFoodandDrugAdministration(FDA)supportingtheidea.[40]
4.2. ImmuneenhancementCoronavirusestypicallyinfecttheupperrespiratorytract,apartofthebodythatisdifficultfortheimmunesystemtoaccess.[41]Ifavirusisn’tactivatingastrongimmuneresponse,aneffectivevaccineishardtodevelop.Insomecases,avaccinecangenerateanimmuneresponsethatgoesawry,targetingthewrongcells.
Thishasbeenobservedinpreviousvaccinecandidatesforrelatedcoronaviruses(e.g.SARS,MERS):anadversereactionknownasimmuneenhancement.Inthesecases,humansoranimalswhohavebeenvaccinateddevelopedmoreseverediseasethanthosewhohadnotbeenvaccinated.[42]Thisimmuneenhancementcanoccurviatwoknownmechanisms:
• Antibody-dependentenhancement(ADE),wherethevirusco-optsantibodiestoenhanceinfectionandvirusentryintocells.[43]
• Cell-basedenhancement,whichiswhenafaultyT-cellresponsetriggersallergicinflammation.
ExpertscontinuetodebatewhethereitherofthesepathwayscouldbeanissueforSARS-CoV-2vaccines.ThereisalsospeculationthatADEandotherimmunereactionsgoneawrymayplayaroleintheseverityofCOVID-19cases.[44]AlthoughmostpeoplewhocatchCOVID-19sufferonlyamild-moderateillness,insomeindividualstheillnesswillprogressinseverity.Intheseinstances,itispossiblethatADEmayberesponsiblefortheworsenedcondition.[42]
BothADEandtherogueT-cellresponseplayedapartinthefailureofavaccineforrespiratorysyncytialvirus(RSV)inthe1960s.[45]Duringclinicaltrials,severalvaccinatedchildrenfellseriouslyillwithRSVandtwotoddlersdied.Toavoidanysimilar‘immuneenhancement’disasters,itisessentialthatrigoroussafetyevaluationsarenotbypassedintherushtodevelopavaccine.
InpreviouseffortstodevelopaSARSvaccine,researchersfoundthatimmuneenhancementoccurredwhenthewholespikeproteinwasusedasatarget.Butwhentheyswitchedtackandbasedtheirvaccineonjustasmallpartofthespike–thebitthatattachestohumancells–theimmune
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enhancementdidnotoccur.[42]Inotherstudies,thelivevirusresultedincomplicationsincludinglungdamageinmice[46]andliverdamageinferrets[47],whileaninactivatedvirusvaccineledtoimmuneenhancementinnon-humanprimates.[48]
4.3. Vaccine-derivedoutbreaksVaccinesthatuselive,attenuatedviruscannotbegiventoimmunocompromisedindividualsduetotheriskofcausingillness.Further,thistypeofvaccinehasthepotentialtoseedoutbreaksinthecommunity–arareoccurrence,butonethathasbeendocumented.Forexample,thepoliovaccineinoculatesarecipientwithlive,attenuatedvirusthatreplicatesforatimeintheintestine,generatingantibodies.[49]Infectiveviruscanbeexcreted,andinareaswithpoorsanitation,thiscanbepassedontootherindividuals.Thiscanbehelpfulasaformof“passiveimmunisation”.However,thelongerthesevaccine-derivedvirusescirculateina(usuallyunderimmunised)community,themoremutationstheyaccumulate,sometimesleadingtooutbreaksofparalysingpoliovirus.Vaccine-derivedpoliovirusisresponsibleformorethan50recentpoliooutbreaksinWestAfrica.[50]
OnlythreecurrentCOVID-19vaccinecandidatesareusingalive,attenuatedvirus.Allthreeareinpre-clinicaldevelopment,accordingtotheVaccineCentreattheLondonSchoolofHygieneandTropicalMedicine.[9]Therefore,thelikelihoodofalive,attenuatedvirusvaccinereachingmarketislow,andthustheriskofvaccine-derivedoutbreaksisalsolow.
4.4. MutationofthevirusAstheSARS-CoV-2virusspreads,itnaturallyaccumulatesmutationsleadingtoanincreasingdiversityofgeneticsequences.Oneanalysissuggeststhatthereareatleastthreedistinctgenomicvariantsofthevirusfoundworldwide,distinguishedbyparticularaminoacidchanges.[51]Itispossible,althoughcurrentlyconsideredunlikely,thatthevirusmaymutatetosuchanextentthatanyvaccinedevelopedisrenderedineffective.Suchmutation,knownasantigenicdrift,isonereasonwhyanewinfluenzavaccineisneededeveryyear.[52]Antigenicdriftcomprisesaminorchangeinthegeneticsequenceofthevirus.Sometimes,thesechangesresultindifferencesontheinfluenzasurfaceproteins(antigens)whicharerecognisedbythebody’simmunesystem.Ifenoughchangesaccumulateovertime,anewstrainemergesthatisnotrecognisedbytheimmunesystem,andanewvaccineisrequired.[53]
TheantigenicdriftrateofSARS-CoV-2isslowandmutationsthathaveoccurredsofarhavenotmadethevirusmoredeadly.[54]Theseareperhapsgoodsignsforvaccinedevelopment.
Incontrast,antigenicshiftisamuchmoreabruptandsubstantialchangeresultingfromreassortmentofgenesegmentsbetweentwoseparatestrainsofthesamevirus.Antigenicshiftisthoughttoberesponsibleforthe2009H1N1swinefluepidemic.[55]However,SARS-CoV-2cannotundergoantigenicshiftascoronavirusesdonothaveasegmentedgenome.[56]
Twopreliminarystudies,notyetpeer-reviewed,haveidentifiedmutationsinthecriticalspikeproteinthatmediatesvirusentryintocellsandisthetargetofmanyvaccinecandidates.[57,58]TheauthorsofonestudyclaimtheobservedD614Gmutationenhancesthetransmissibilityofthevirus,[57]butthisinterpretationishotlycontested.[59]Continuedmonitoringofmutationsisessentialtoensureanypotentialvaccineremainseffective.Onereasonthespikeproteinhasbeentargetedinvaccinedevelopmentisthatamutationmajorenoughtopreventantibodiesraisedbyavaccinebindingtoitislikelytopreventitbindingtocellreceptorsandthereforenolongerbeinginfective.
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4.5. DurationofimmunityItispossiblethatthefirstvaccinetoreachmarketmayonlyprovideimmunityforalimitedduration,orimmunityinonlyalowpercentageofvaccinerecipients.[60]Inthiscase,itcouldbeusedasaninterimsolutionuntilalonger-lastingvaccineisdevelopedandpassesclinicaltrials.AsstatedbyProfessorDanuelAltmann,animmunologyresearcheratImperialCollegeLondon,“Weneedtobearinmindthatwe’rehuntingherefor‘goodenough’protection,notcomplete‘sterilisingimmunity’whichmightbehardtoachieve.”[61]
Immunityisasomewhatmurkyissue.ForSARS-CoV-2,therearesomereportsofrecoveredpatientsbeingreinfected.[62]Itispossible,however,thatthesepatientssimplyreturnedafalsenegativetestinthemidstofongoinginfection.Ratherthancatchingthevirusagain,theviralloadmayhavedroppedbelowthesensitivityofthetestasitfluctuatestowardsthetail-endoftheinfection.OnestudyfoundthatpatientscontinuedtoshedviralRNA,butnotinfectiouswholevirusparticles,betweensevenand20daysfromtheonsetofsymptoms.[63]
Inarecentstudy,rhesusmacaquemonkeyswereinfectedwiththeSARS-CoV-2virusanddevelopedsymptomssimilartothoseobservedinhumans.[64]Oncetheinitialinfectionhadcleared,themonkeyswerere-infected.Theydisplayedanimmuneresponseandasignificantreductioninviralload,indicatingthattheyhaddevelopedprotectiveimmunityagainstre-infection.However,durabilityofimmunityremainsunclear,withpreviousobservationsthatantibodyresponsesinducedbycoronavirusinfectioninhumansmaywaneovertimeinsomecases.[65]Indeed,arecentstudy(notyetpeer-reviewed)testedsamplesfrom23,000healthworkersinWuhanwhowereexposedtoinfectedpatients.[66]Fourpercenthadthetypicallylong-lastingIgGantibodiesasofApril,butitisestimatedthatupto25%ofthiscohortmayhavecontractedCOVID-19.Theauthorssuggestthatthosewithmildorasymptomaticcasesmaynotdevelopprotectiveantibodies.Evenamongthosewhodo,theprotectionmaynotlastlong.
Itispossiblethatnolonglastingvaccinewillbedevelopedandregularboostershotswillberequired.
4.6. ImmunesenescenceMostseverecasesofCOVID-19occurinindividualsaged50yearsormore.[65]Protectingthissegmentofthepopulationwithimmunisationisthereforeofparticularinterest.However,olderpeopletypicallydon’trespondaswelltovaccinesduetoageingoftheimmunesystem,knownasimmunesenescence.Thisphenomenonisseenwiththeinfluenzavaccine,whereolderindividualsmayrequireaformulationwithdifferentantigensoradjuvantstoelicitprotection.[67]
Evenifvaccinationinolderpeopleisineffective,theywillstillbenefitindirectlyfromuptakeofthevaccineamongyoungerpeoplethatpreventswidespreadtransmission.
4.7. ScalabilityandaccessibilityTheabilitytoscaleupproductionofavaccineisakeyissue,withdifferentvaccineplatformsmorescalablethanothers.Forexample,itistheoreticallypossibletoproducelargeamountsofvaccinebasedonthemRNAplatform,butestablishedplatforms,suchasliveattenuatedvaccines,alreadyhaveexistinginfrastructurethatcaneasilybeusedtomanufacturevastquantities.
Johnson&Johnson(J&J)believetheycanproduce300milliondosesoftheirAd26vaccineina2000-litrevesselonanannualbasis.Theycurrentlyhaveonevesselwithanothercomingonlinebytheendoftheyear.However,theyestimatetheywillneedatleastonebilliondosesavailabletoavoida“vaccinewar”.[10]Similarly,GermancompanyCureVaccurrentlyestimatesitwouldbeabletomanufacture400milliondosesofitsRNAvaccinecandidateperyear.[68]BioNTechandPfizersay
15
theycanproducemillionsofdosesoftheirRNAvaccinethisyear,withscale-uptohundredsofmillionspossiblefrom2021.[69]
Thesenumbersarestilltoosmalltomeetexpectedworldwidedemand.Withafixednumberofvaccinedosesavailable,theissuethenbecomesoneofaccessibility:whogetsthevaccinefirst?WHOisworkingtoaddressthisissuethroughtheirCovaxfacility.Currentbest-caseestimatessuggestCovaxcouldprovideafewhundredmilliondosesofvaccinebyDecember2020,scalinguptotwobillionbytheendof2021.[70]At-riskpopulationsmaybeprioritised,includinghealthcareworkersandcountriesorterritoriessufferinghighcasualtiesatthetimeavaccineisavailable.
However,hoardingbyindividualwealthycountriesmayeventuate,aswasseenduringthe2009H1N1influenzaepidemicwhenAustraliawasamongthefirsttomanufactureavaccine,butdelayedexportingtoprovidethevaccinetoitsowncitizensfirst.[68]Similarpracticeshavealreadybeenobservedinthecurrentpandemic–forexample,theUSbuyingtheentireglobalsupplyofremdesivir.[71]ACabinetpaperproactivelyreleasedontheCOVID-19vaccinestrategysaysthatthishistorysuggests“thattherewillbestrongincentivesonmanufacturingcountriestorestricttheexportofvaccinesuntiltheyhaveensuredsufficientsupplyfortheirownneeds”.[34]
InAotearoaNewZealand,caremustbetakentoensureanyvaccineisavailableequitably.Thismayinvolveprioritisingat-riskpeople,suchasthoseagedover65,pregnantwomen,andpeoplewithcertainchronicillnesses–ashasbeendonewiththeinfluenzavaccinethisyear.[72]Accesswillalsomeanensuringgeographicalspreadofvaccinestocksacrossthecountryandmayinvolvemoreproactivetargetingofat-riskpopulationsincludingMāori,Pasifika,andruralcommunities.Costshouldalsobeconsideredasthismaybeabarriertovaccinationforsome.
4.8. VaccineuptakeEvenifavaccineisavailable,asufficientproportionofthepopulationmustbevaccinatedinordertosubstantiallyreducetransmission.ArecentpollconductedbyStickybeakonbehalfofTheSpinoffasked605respondents:“IfandwhenaCOVID-19vaccinebecomesavailable,willyouaimtogetvaccinated?”[73]Sixty-fivepercentofrespondentssaid“yes”,while20%said“unsure”and16%said“no”.Theseresultsconformwithexpectations,accordingtoProfessorPeterMcIntyre,amemberoftheWHOStrategicAdvisoryGroupofExperts(SAGE)andresearcherattheUniversityofOtago.BothMcIntyreandDrCarolineMcElnay,theMinistryofHealth’sdirectorofpublichealth,estimatethataround60–70%uptakewillberequiredtoachieveherdimmunityanddampenthespread.
16
5. SelectedvaccinecandidatesItistooearlytosaywhichofthevaccinesindevelopmentwillbesuccessful.TheRRIFpaper‘ThemostpromisingvaccinesforCOVID-19’saysthat,“…wedonotyetknowenoughregardingthesafetyorefficacyofeachcandidate,orglobalcapabilitytomanufacturethematlargescaleunderGoodManufacturingPracticeconditions”.[35]
5.1. VaccinesinclinicalevaluationAsof16July,thereareatleast22vaccinesregisteredinclinical(human)trials.
5.1.1. UniversityofOxfordandAstraZeneca
TheUniversityofOxford,withthesupportofCEPIandAstraZeneca,havedevelopedanadenovirus-basedvaccinenamedAZD1222(formerlyChAdOx1).ThevaccineusesanattenuatedchimpanzeeadenovirusasavectorwhichdisplaystheSARS-CoV-2spikeproteinonitssurface.
Currentstage:twophaseI/IIclinicaltrialsconcurrentwithtwophaseII/IIItrials.
• TheearliestphaseI/IItrialbeganon23April2020with1090participantsintheUK.Itaimstodeterminetheefficacy,safetyandimmunogenicityofAZD1222inhealthyadultsaged18to55.Thesingle-blinded,randomisedstudyhasdifferentgroupsreceivingdifferentsequencesofdosesplusboosterdosesoversixmonths.[74]
• AnotherphaseI/IIstudyhascommencedinSouthAfricaasof24June2020.Thedouble-blinded,randomisedandplacebo-controlledstudyisinvestigatingsafety,efficacyandimmunogenicityintwocohorts:adultswithoutHIV,andadultslivingwithHIV.[75]
• AphaseII/IIIstudyintheUKbeganon28May2020involvingupto10,260healthyvolunteersacrosssixstudygroups.[76]
• AphaseIIItrialinBrazilbeganon20June2020andwillenrol5000volunteers.[77]• ThereisanongoingphaseIclinicaltrialinSaudiArabiausingthesameadenovirusvectorto
targettherelatedcoronavirusthatcausesMiddleEastRespiratorySyndrome(MERS).[78]
Results:
• Apreprint(notyetpeer-reviewed)describingresultsfromtestinginrhesusmacaquemonkeysrevealednoevidenceofimmune-enhanceddiseasefollowingchallengeinvaccinatedanimals.[79]Vaccinationinducedanimmuneresponseandreducedviralloadbutdidnotcompletelyprotecttheanimalsfrominfectionandsymptoms.TheseresultspromptedProfessorEleanorRiley,animmunologyresearcherattheUniversityofEdinburgh,tostate,“Ifsimilarresultswereobtainedinhumans,thevaccinewouldlikelyprovidepartialprotectionagainstdiseaseinthevaccinerecipientbutwouldbeunlikelytoreducetransmissioninthewidercommunity.”[80]
• Anotherpreprintdescribesresultsoftestinginpigs,withtwodosesofthevaccinegeneratingagreaterneutralisingantibodyresponsethanasingledose.[81]
Future:PreliminaryresultsfromtheclinicaltrialsareexpectedinAugust/September2020.[82]
TheAstraZenecaCEOhasstatedthatthevaccineisexpectedtoprovideprotectionforaboutoneyear.[82]Itisunclearwhetherrecipientswouldthenreceiveaboosterdose,switchtoadifferentvaccine,orsimplyrelyontreatmentsifsubsequentinfectionweretooccur.
Name:
AZD1222
Type:
Non-replicatingviralvector
Currentstage:
PhaseI/II/III
17
AstraZenecahasatleasttendealswithcountriestosupplyitsvaccine,consideredbyWHOtobeafrontrunner.[83]MorethanonebilliondosesofAZD1222havebeenorderedbyEurope,Britain,theUSandGavi,theVaccineAlliance.[84]ThirtymillionofthesewillbemadeavailableinBritainbySeptember2020.[84]TheSerumInstituteofIndiaisproducingonebilliondoses,with400millionexpectedtobeavailablebytheendof2020,mostlyforlow-andmiddle-incomecountries.OnedoseoftheAZD1222vaccinecostsaboutthesameasacupofcoffee.[84]
5.1.2. CanSinoBiologicsandBeijingInstituteofBiotechnology
SupportedbyChina’sAcademyofMilitaryMedicalSciences,CanSinoBiologics(CanSinoBIO)havefast-trackeddevelopmentofavaccineknownasAd5-nCoV.Thisvaccineusesanon-replicatingadenovirusvector–aplatformthathasbeenusedtoproduceanebolavirusvaccine,Ad5-EBOV,whichisapprovedforclinicaluseinChina.[85]
Currentstage:temporary,year-longapprovalforuseamongChinesemilitarypersonnel.
RecruitmentforphaseIIclinicaltrialsunderway,asCanSinoBIOforgesaheadbasedonpreliminarysafetydatafromphaseItrialswhichbeganmid-March.[86]ThephaseIIstudywillenrol500participantstoreceivelowormediumvaccinedosesoraplacebo.Theywillbemonitoredforsixmonthstoassessreactionsandantibodyproduction.
Results:
• ResultsofaphaseItrial,reportedinTheLancet,weremixed.[87]Onehundredandeightarticipantsreceivedinjectionsatlow,middleorhighdoses.Althoughno“serious”sideeffectswereobserved,nearlyhalfoftheparticipantsexperiencingfever,fatigueormusclepain.Theimmunogenicitystatswerealso“lukewarm”[88]witharoundhalfoftherecipientsinthelow-andmiddle-dosegroupsdevelopingneutralisingantibodies.Thisrosetoaround75%inthehigh-dosegroup,butwasaccompaniedbyanincreaseinadversesideeffects.
• ResultsfromaphaseIItrialof508peoplewerereportedly“muchbetter”thanphaseIbuthavenotbeenreleasedpublicly.
• Preclinicalanimalstudiesshoweda“goodsafetyprofile”.[89]
Future:ResultsofphaseI/IIexpectedapproximatelysixmonthsfromnow.PhaseIIItrialswith40,000participantsareexpectedtobeginsoonasCanSinoBIOisintalkswithRussia,Brazil,ChileandSaudiArabia.[90]AcollaborationwithCanadatotestthevaccinetherewaspreviouslyannouncedinMay.[91]
5.1.3. ModernaandNIAID
Name:
Ad5-NCoV
Type:
Non-replicatingviralvector
Currentstage:
PhaseI/IIApprovedformilitaryuse
Name:
mRNA-1273Type:
Nucleicacid(RNA)
Currentstage:
PhaseI/II
18
Anothercandidatetoenterhumantrialsatrecordpace,Moderna’smRNA-1273candidateisalsosupportedbytheNationalInstituteofAllergyandInfectiousDiseases(NIAID)andCEPI.Thevaccine,injectedintothearm,consistsofasmallpieceofmessengerRNA(mRNA)wrappedupinlipidssoitcanenteracell.
Currentstage:phaseIclinicaltrialstoassesssafetyandimmunogenicitybegan16March2020inSeattle,US.TrialruninconjunctionwiththeNIAIDandinvolves45healthyadultsreceivingtwodosesofthevaccine28daysapart.[92]Thistrialisongoing.
AphaseIItrialhascompletedrecruitmentfor600participantsintwocohorts:healthyadultsaged18-55,andadultsagedover55.[93]
Results:
• ModernahasreleasedapreliminaryreportdetailingresultsfromitsphaseItrial.Thevaccineinducedanti-SARS-CoV-2immuneresponsesinallparticipants,anddespitesomeadverseeventsbeingrecorded,therewerenotrial-limitingsafetyconcernsidentified.[94]
• Fourpeopleinthestudyof45experienced“Grade3”adverseevents.Oneofthesewasalow-doserecipientwhodevelopedrashattheinjectionsite;theotherthreereceivedthehighestdoseandhadreactions“thatinvolvedtheirwholebodies.”[95]
• ThevaccinewasnottestedinanimalspriortophaseIbeginning.
Future:phaseIIIstudyinvolving30,000participantshasbeendelayedaschangesaremadetothetrialprotocol,butthetrialisstillexpectedtocommenceon27July.[96]ThevaccinecouldbeavailableintheUSunderemergencyuseauthorisationinlate2020dependingonresultsandregulations.[97]
5.1.4. InovioPharmaceuticals
WiththesupportofCEPI,InoviohasdevelopedaDNA-basedvaccinecandidatecalledINO-4800.
Currentstage:pre-clinicaltrialsinAustralia/elsewhereconcurrentwithphaseI/IIatrialsintheUS.
• TheAustralianpre-clinicaltrialsinvolveachallengestudyusingferretswhileInoviotoldNaturethatchallengestudiesarealsounderwayinmonkeys.[98]
• ThephaseItrialinvolves40adultsinPhiladelphia,PennsylvaniaandKansasCity,Missourireceivingtwodosesofvaccinefourweeksapart.[99]Thefirstdosewasadministeredon6April2020.[100]
• ThephaseI/IIastudy,tobeundertakeninSouthKorea,isnotyetrecruiting.[101]INO-4800willbeadministeredviainjectionfollowedbyelectroporation.ThestudyaimstoevaluatethesafetyandimmunogenicityofINO-4800.
Results:
• Inovioissuedapressreleasedclaiming“positive”interimresultsfromthephaseItrial.[102]However,theydidnotincludeinformationonhowmanypatientsproducedneutralisingantibodies–keytounderstandingwhetherthevaccineactuallyworks.
Name:
INO-4800
Type:
Nucleicacid(DNAplasmid)
Currentstage:
PhaseI/II
19
• Resultsfrommiceandguineapigswererecentlyreported,withthevaccineelicitingbothantibodiesandaT-cellresponse.[103]
• AnInovio-developedMERSDNAvaccinecandidateunderwentPhaseItesting,yieldinghighlevelsofantibodies.[104]
Future:Inovioexpectstohaveonemilliondosesavailablebytheendof2020forongoingtrialsandpossibleemergencyuse.[100]Theyplantoproceedwithlargertrialslaterthisyear.
5.1.5. SinovacBiotech
Beijing-basedcompanySinovachaverapidlyprogressedtheirvaccinecandidate‘CoronaVac’(previouslyPiCoVacc)throughclinicaltrials.Whiletheinactivatedvirusplatformisconsidered“oldschool”,itisavaccinetypethatmanylow-middleincomecountrieswillhavetheabilitytomanufacture.[105]
Currentstage:PhaseI/IItrialsongoing;phaseIIIduetostartimminently.ThephaseI/IIclinicaltrials(randomised,double-blinded,placebo-controlled)involve744healthyadults(144phaseI,600phaseII)inJiangsu,China.[106]Thetrialsbeganinmid-Aprilandaimtoevaluatethesafetyandimmunogenicityofthevaccine.
Results:
• PreliminaryresultsfromthephaseIIstudyindicatedthatCoronaVacissafeandinducesneutralisingantibodiesinmorethan90%ofrecipients14dayspost-vaccination.[107]Detailedresultswillbepublishedinacademicpeer-reviewedliterature.
• Studiesinmice,ratsandnon-humanprimatesfoundthatthevaccineinducedneutralisingantibodies.[108]Differentdosesweretested,withthehighestdoseprovidingcompleteprotectionagainstSARS-CoV-2inmacaquemonkeys.
Future:ThephaseIIItrialisduetostartinJuly.Thedouble-blind,placebo-controlledstudywillassessthesafetyandefficacyofthevaccineacrossmorethan8800healthcareprofessionalsinBrazil.[109]
5.1.6. BioNTechandPfizer
ThiscollaborationbetweenUS-basedPfizerandGermany-basedBioNTechinvolvessimultaneoustestingoffourRNAvaccinecandidates,eachwithadifferentmRNAformatandtargetantigen.TheyarereferredtoasBNT162a1,b1,b2andc2.
Currentstage:fourcandidatevaccinesinrandomised,placebo-controlledphaseI/IItrials.[110]Theparalleltrialsbeganon29April2020andconsistofthreestages.Inthefirststage,theaimistoidentifythebestvaccinecandidate,appropriatedoseandscheduleofadministrationifmultiple
Name:
CoronaVacType:
Inactivatedvirus
Currentstage:
PhaseI/II/III
Name:
BNT162Type:
Nucleicacid(RNA)
Currentstage:
PhaseI/II
20
dosesarewarranted.Stagestwoandthreewillcompriseexpandedparticipantcohorts(givingaprojectedtotalof7,600)toassesssafety,immunogenicityandpotentialefficacy.Thestudywillbesplitintodifferentagecohortsincludingone18–55years,18–85years,and65–85yearsacrossmultiplelocationsintheUSandGermany.
Results:interimresultsfortheBNT162b1variantwerereleasedonpreprintservermedRXiv.[111]Twnety-fourparticipantsreceivedtwoinjectionsthreeweeksapart,either10μgor30μg(athird,higherdoseof100μgwasonlyadministeredonceaftercausingpainattheinjectionsite).After28days,participantshaddevelopedhigherlevelsofSARS-CoV-2antibodiesthanthoseobservedininfectedpatients.Seventy-fivepercentofthe24participantsdevelopedashortfeverfollowingtheseconddose.
Future:
• BothcompaniesareanticipatingpositiveresultsandareinvestinginscalingupmanufacturinginfrastructureintheUS,BelgiumandGermany.[69]Theyaimtoproducemillionsofvaccinedosesbytheendof2020,increasingtohundredsofmillionsin2021.
• OnthebackofanFDAfast-tracklabel,thecompaniesarenowplanningforaJulystartdateforaphaseIIb/IIItrialthatcouldenrolupto30,000subjects.[112]
5.1.7. ShenzhenGeno-ImmuneMedicalInstitute(GIMI)
AninstitutefoundedbytheShenzhengovernmentinChina,theGIMIcurrentlyhastwovaccinecandidatesinclinicaltrials.
LV-SMENP-DCisavaccineusingalentiviralvector.Lentivirusesareasubsetofretroviruses,withthemostwell-knownexamplebeingthehumanimmunodeficiencyvirus(HIV).Theyhavelongbeeninvestigatedasvectorsforgenetherapy,andmorerecentlyvaccines,duetotheirabilitytoefficientlydelivergeneticmaterialintocells,whichisthenincorporatedintothehostgenome.[113]However,theyhavenotcrossedintowidespreadclinicaluse.Useoflentivirusesorotherretroviralvectorscanleadtorandominsertionofgeneticsequencesinhostcells,potentiallyleadingtocancerdevelopment,asdocumentedinsomestudies.[113]TheLV-SMENP-DCvaccineusesalentiviralvectortodeliver“minigenes”encodingtheSARS-CoV-2spikeprotein,aswellasimmunemodulatorygenesthatactivateT-cellsandmodifydendritic(antigen-presenting)cells.OnehundredCOVID-19patientswillreceiveinjectionsandIVinfusionsofthevaccinepluscytotoxicT-cells(CTLs)inthephaseI/IItrialthataimstoassessthevaccine’ssafetyandefficacy.Thetrialbeganon24March2020.[114]
COVID-19/aAPCisavaccineplatformusingartificialantigen-presentingcells(aAPCs).TheaAPCsaremadespecifictoSARS-CoV-2byapplyingalentiviralvector(seeabove)containingviralminigenesandimmunemodulatorygenes.TheaAPCsareinactivatedbeforebeingadministeredtoparticipants
Name:
LV-SMENP-DCType:
Replicatingviralvector
Currentstage:
PhaseI/II
Name:
COVID-19/aAPCType:
Virus-likeparticle(VLP)
Currentstage:
PhaseI
21
viaarminjectioninthisphaseItrial.Thetrial,whichbeganon1gm5February,isenrolling100healthyorCOVID-19-positiveindividualstoassesstheefficacyandsafetyofthevaccine.[115]
5.1.8. Sinopharm
Thestate-backedChinesecompanySinopharmisdevelopingtwovaccinecandidatesbasedon‘oldschool’methodologyofwhole,inactivatedvirusparticles.BotharecurrentlyinphaseI/IIclinicaltrials.BBIBP-CorVisbeingdevelopedoutoftheBeijingInstituteofBiologicalProducts,whileanunnamedcandidateisbeingdevelopedattheWuhanInstitueofBiologicalProducts.
Currentstage:
• AccordingtotheChineseClinicalTrialRegistry,phaseI/IItrialsareongoingforBBIBP-CorV,with480participantsinphaseIand1648inphaseII.[116]
• TheunnamedvaccinehasreporterdlyenteredphaseIIItrialsintheUnitedArabEmirates.[117]
• Therearereportsthatemployeesatsomelargestate-runcompaniesinChinahavebeenofferedeitherofthetwovaccinespriortooverseastravel.[118]
Results:
• SomepreliminaryresultsreleasedbySinopharmfortheunnamedvaccineindicateittriggersa‘high’neutralisingantibodyresponse,althoughspecificdatahasnotbeensharedpublicly.[119]Noseriousadversereactionswereobserved.AllvolunteersinthephaseI/IItrialhavereceivedtwoinjectionsofthevaccine.Theparticipantsweresplitintoplacebo,low,middleandhighdosagegroupsandreceivedtheinjectionseither14,21or28daysapart.Themiddle-strengthdose28daysapartappearedmostpromising,accordingtoSinoparm.
• InearlyJune,SinopharmpublishedpositiveresultsforBBIBP-CorVinCellfromanimalstudiesinmice,rats,rabbits,guineapigsandtwodifferentmonkeyspecies.[120]ThevaccineinducedneutralisingSARS-CoV-2antibodiesanddidnotspuranyseriousadversereactions.Thevaccinealsoprotectedrhesusmacaquemonkeyswhowere‘challenged’withthevirusanddidnottriggerantibody-dependentenhancement.
Future:AnewmanufacturingfacilityhasbeenconstructedinBeijingalongsideasisterfacilityunderconstructioninWuhan.Together,thetwofacilitieswillhavecapacitytoproduce200milliondoses.
Name:
BBIBP-CorVType:
Inactivatedvirus
Currentstage:
PhaseI/II
Name:
[unnamed]Type:
Inactivatedvirus
Currentstage:
PhaseI/II
22
5.1.9. ImperialCollegeLondon(ICL)DepartmentofInfectiousDiseases
AnRNA-basedvaccinecandidatecalledCOVAC1withfundingsupportfromCEPI.Thevaccineconsistsofself-amplifyingRNA(saRNA)whichisinjectedintramuscularly.TheICLteamreceivedfundingfromCEPIinDecember2018todeveloptheirsaRNAplatformforgeneraluseagainstinfectiousdiseases.[121]
Currentstage:phaseI/IIclinicaltrials.Morethan300participantshavebeenscreenedfortheUK-basedtrials,andICLiscontinuingtorecruitforthestudy.[122]Thefirstphaseofthetrialisexpectedtolasttwomonths.[123]
Results:
• TheICLteamconductedpreclinicalsafetytestinginanimalmodelspriortostartingthetrialsinhumans,with“promising”results.[124]
• Within14daysofreceivingthegeneticsequenceofthevirusinJanuary2020,theteamhaddevelopedavaccinecandidate.[125]
Future:planstoproceedwithphaseII/IIItrialstoassessefficacywith6000participantsbeginninginOctober.[122]
5.1.10. Novavax
NamedNVX-CoV2373andsupportedbybothCEPIandOperationWarpSpeed,thiscandidatewasidentifiedfromarangeofconstructs.Thevaccineconsistsofnanoparticlescarryingmodifiedspikeproteinantigens,aswellasasaponin-basedadjuvantcalledMatrixM.Novavaxhasneverbroughtaproducttomarketbefore.
Currentstage:phaseIclinicaltrialsongoing.[126]Thetrialisrandomised,observer-blindedandplacebo-controlledin131participants.ItaimstoassessthesafetyandimmunogenicityoftheNVX-CoV2373vaccinebothwithandwithouttheMatrixMadjuvant.
Results:Pre-clinicaltrialshaveyieldedneutralisingantibodiesinanimalmodels.[127]
Future:
• PreliminaryresultsareexpectedinJuly2020.ThestudywillproceedtophaseIIifphaseIresultsarepromising.PhaseIIIefficacytrialsareplannedforlaterin2020andinterimresultsareexpectedbytheendof2020also.[128]
• Novavaxhasa$60millioncontractwiththeUSDepartmentofDefensetodeliver10milliondosestoAmericantroops.[128]
• ThroughOperationWarpSpeed,Novavaxhasadealtodeliver100milliondosestotheUSbythebeginningof2021.[128]
Name:
COVAC1Type:
Nucleicacid(RNA)
Currentstage:
PhaseI/II
Name:
NVX-CoV2373Type:
Proteinsubunit
Currentstage:
PhaseI
23
5.1.11. UniversityofQueensland
TheUniversityofQueensland(UQ)hasreceivedsupportfromCEPIandtheQueenslandGovernmenttodevelopa“molecularclamp”proteinsubunitvaccine–anexperimentalplatformthatcouldberepurposedforotherpathogentargets.The“molecularclamp”holdstheviralantigeninthecorrectconformation.UQispartneringwithCSLLtdtousetheiradjuvanttechnologyandasatrustedmanufacturershouldclinicaltrialsbesuccessful.[129]
Currentstage:phaseIclinicaltrialsinBrisbane,Australiawith120participantsaged18to55.Thestudywasplacebo-controlledandfirstdoseswereadministeredon13July2020.[130]
Results:preclinicaltestingshowedinductionofneutralisingantibodiesanddemonstratedbaselinesafety.[130]
Future:
• PreliminarydatafromthephaseItrialisexpectedinaboutthreemonths’time.[131]• Ifresultsarepositive,UQwillproceedtolargertrials.• Themolecularclamptechnologyisageneral-purposetechniquethatmaybeappliedto
otherpathogens.
5.1.12. SymvivoCorporation,UniversityofBritishColumbiaandDalhousieUniversity
SymvivoisadaptingitsbacTRLplatformforSARS-CoV-2.[132]ThisconsistsofabacterialcellcontainingplasmidDNAthatencodesantigensandneutralisingnanobodies.Thevaccineisingested(liketakingprobioticcapsules)andthebacteriabindtogutepithelialcells.ThisdeliverstheplasmidDNAinamannersimilartoanaturalinfection.ThevaccinecurrentlybeingtestediscalledbacTRL-Spike,withthevirus’spikeproteinservingastheantigentarget.TherearetwofurtherbacTRLformulationsforSARS-CoV-2undergoinginvestigation.
Currentstage:84participantsaged18–45inarandomised,placebo-controlledanddouble-blindphaseItrial.[133]TheCanada-basedstudyaimstoevaluatesafetyandimmunogenicity.
Future:studyisexpectedtostartinJuly.
Name:
bacTRL-Spike
Type:
DNA,bacterialmedium
Currentstage:
PhaseI
Name:
MolecularclampType:
Proteinsubunit
Currentstage:
PhaseI
24
5.1.13. CureVac
ThisRNAvaccinecandidate,dubbedCVnCoV,isbeingdevelopedbyCureVacwithfundingsupportfromCEPI.ItusesmessengerRNA(mRNA),whichhasalreadybeenusedbyCureVactodeveloparabiesvaccinethatgeneratesimmunity.[134]
Currentstage:aplacebo-controlledphaseIclinicaltrialin168participantsinGermanyandBelgium.[135]Thestudywillevaluatesafety,appropriatedose,adversereactionsandimmuneresponsesgenerated.
Results:preclinicaltestingfoundthatalowdoseofCVnCoVgeneratednautralisingantibodies.[136]
Future:DependingontheoutcomesofthephaseItrial,largerphaseIItrialswillbegininthelaterhalfof2020.[136]
5.1.14. OthervaccinecandidatesinclinicaltrialsTable4:Othervaccinecandidatesinclinicaltrialsasof15July
Vaccinename Vaccinetype Developedby Currentstage ReferenceAG0301-COVID19
Nucleicacid(DNA) AnGesInc. PhaseI/II [137]
V-SARS Inactivatedvirus Immunitor PhaseI/II [138]
AV-COVID-19Virus-like
particle(VLP)/modifiedAPC
AivitaBiomedicalLtd PhaseI/II [139]
[unnamed] Inactivatedvirus ChineseAcademyofMedicalSciences PhaseI/II [140]
Gam-COVID-Vac Non-replicatingviralvector
GamaleyaResearchInstitute PhaseI/II [141,142]
AlloStim Livingcell ImmunvativeTherapiesLtd PhaseI/II [143]
GX-19 Nucleicacid(DNA) GenexineInc PhaseI/II [144]
[unnamed] Virus-likeparticle(VLP) MedicagoInc PhaseI [145]
SCB-2019 Proteinsubunit CloverBiopharmaceuticals PhaseI [146]
COVAX-19 Proteinsubunit GeneCureBiotechnologies PhaseI [147,148]
Name:
CVnCoV
Type:
Nucleicacid(RNA)
Currentstage:
PhaseI
25
5.2. Selectedexamplesofvaccinesinpreclinicalstages
5.2.1. Janssen/Johnson&Johnson
Janssen,aresearchdivisionofcorporationJohnson&Johnson(J&J),iscollaboratingwiththeUSGovernment’sBiomedicalAdvancedResearchandDevelopmentAuthority(BARDA)viaOperationWarpSpeed.EachorganisationiscommittingnearlyUS$500millioninfundingtotheeffort,foratotalofnearlyUS$1billion.[10]Thevaccinecandidatebeingfunded,namedAd26.COV2-S,usesanon-replicatingviralvectorplatform,specificallyanadenovirus.
Currentstage:Currentlyinpre-clinicaltrials.TheAd26vectorhasbeenusedasplatformforothervaccinecandidatesandiscurrentlyinvariousphasesofclinicaltrials.AnebolavirusvaccineusingtheAd26vectorwasrolledoutintheDemocraticRepublicoftheCongoinNovember2019.[149]
Future:JanssenhasacceleratedphaseI/IIatrialstoevaluatethesafetyandimmunogenicity,andnowplanstocommencetheseinmid-lateJuly2020.[150]Thetrialwillenrol1045healthyadultvolunteersintheUSandBelgium.JanssenisalsoindiscussionswiththeNIAIDtoacceleratephaseIIIefficacytrials(pendingphaseIresults).[151]
5.2.2. ArcturusTherapeuticsandDuke-NUS
ThiscollaborationbetweenanRNAmedicinescompanyandmedicalschoolisworkingonamessengerRNA(mRNA)-basedvaccineforSingapore.[152]ThevaccineusesArcturus’proprietarySTARR™technology(self-transcribingandreplicatingRNA)withalipid-mediatednanoparticledeliverysystemcalledLUNAR®todeliverRNAencodingtheSARS-CoV-2spikeprotein.[153]Thistechnologymeansthatthevaccinecanlikelybeadministeredinasingleshotatverylowdose.[154]
Currentstage:preclinicaldevelopment.
Results:
• PreclinicaldatafromstudiesinrodentmodelsreleasedthusfarshowsthatLUNAR-COV19triggersmultipleelementsoftheadaptiveimmuneresponse,includingneutralisingantibodiesandTcells.[155,156]
• TheSTARR™mRNAelicitedhigherlevelsofIgGantibodiesthanconventionalmRNAatequivalentdoses.[156]
Future:
• ArcturusexpectstobeginphaseIclinicaltrialsinSingapore“this[northernhemisphere]summer”.[157]Currentplansinvolveenrolmentofupto76healthyadultvolunteers(includingelderlyindividuals)whowillbefollowedforseveralmonthstoevaluateimmunogenicity.[154]
Name:
Ad26.COV2-S
Type:
Non-replicatingviralvector
Name:
LUNAR-COV19
Type:
Nucleicacid(RNA)
26
• ArcturushaveannouncedadealwithCatalentInc,basedinWisconsin,US,tosupporthumanclinicaltrialsandpotentialmanufactureandcommercialisationofLUNAR-COV19.[158]
5.2.3. UniversityofPittsburghSchoolofMedicineandUPMC
Inadditiontotheirroleinaconsortiumdevelopingameaslesvectorvaccine(seebelow),theUniversityofPittsburghisworkingonanotherapproach.ThiscandidateiscalledPittCoVaccandconsistsofaproteinsubunit(asectionofthespikeprotein)deliveredviaamicroneedlepatch(essentiallyabandaidwithtinyvaccine‘needles’madeofproteinandsugarthatdissolveintheskin).
Currentstage:Pre-clinicaltrials.
Results:ArecentstudyreportsthatvaccinatedmiceproducedantibodiesspecifictoSARS-CoV-2.[159]Thisrepresentsthefirstpeer-reviewedresearchintoaCOVID-19vaccinecandidate.[160]
Future:AwaitingapprovaltobeginphaseIclinicaltrialstoassesssafety.[161]
5.2.4. TheUniversityofHongKong
AvaccinecandidateindevelopmentattheUniversityofHongKong(HKU)withsupportfromCEPI,DelNS1-SARS-CoV2-RBDLAIVisbasedonanestablishedliveattenuatedinfluenzavirus(LAIV)platform.[162]TheinfluenzavectorhasakeyvirulentelementdeletedfromitsgenomeandismodifiedtoexpressaSARS-CoV-2-specificantigen.
Currentstage:pre-clinicaltrialsandproof-of-conceptstudiesinanimalmodels.
Future:ExpectedtoenterphaseIclinicaltrialsinJuly.[163]
5.2.5. InstiutPasteur,ThémisandtheUniversityofPittsburgh
ThisconsortiumiscollaboratingwiththesupportofCEPItorepurposetheirmeaslesvirusvector.ThecandidateiscalledMV-SARS-CoV-2andusesareplicatingviralvector:themeaslesvaccinevirus(MV).Thisplatformhaspreviouslybeenusedbytheconsortiumabovetodevelopandinvestigate
Name:
PittCoVaccType:
Proteinsubunit
Name:
SARS-CoV2-RBDLAIV
Type:
Live,attenuatedviralvector
Name:
MV-SARS-CoV-2
Type:
Replicatingviralvector
27
vaccinesforSARS,MERSandChikungunya.[164]NotethatThémishasnowbeenacquiredbyMSD/Merck&Co.[165]
Currentstage:pre-clinicaldevelopment.
Future:Althoughtechnicallyfurtherbehindonthedevelopmenttimeline,thiscandidateusesalicensedplatform(measlesvaccinevirus)withanestablishedsafetyandefficacyrecord.[166]Thismeansitwillpotentiallyclearhurdlesfaster.Inaddition,thistypeofvaccineiseasytoproduceinlargequantities.
28
6. Repurposedvaccines:aninterimsolutionforfuturepandemics?Severalclinicaltrialsareaimingtoassesswhethervaccinesforotherdiseasescouldinducenon-specificimmune-enhancingeffects[167],therebyreducingmorbidityfromCOVID-19.Theseinclude:
• TheBacilleCalmette-Guérin(BCG)vaccinetopreventtuberculosis[168]• Theoralpoliovaccine[169]• Themeasles,mumpsandrubella(MMR)vaccine[170]
6.1. TheBCGvaccineTrialsinAustraliaandtheNetherlandsareunderwaytoassesswhetherthebacilliCalmette-Guérin(BCG)vaccinecanreducetheseverityofCOVID-19symptoms.[168]TheBCGvaccinehasbeenusedasatuberculosisvaccinefornearlyonehundredyears.[171]Aroundtwobilliondoseshavebeenadministeredduringthistime,and130millionchildrenworldwidecontinuetoreceivethevaccineeveryyearincountrieswhereTBisstillprevalent.Ithasanexcellentsafetyprofileandsideeffectsarerare.
Beneficialoff-targeteffectsoftheBCGvaccinehaverecentlybeenrecognised,includinganimmune-boostingeffectwhichtrainstheinnateimmunesystem(thefrontlineresponse)torespondtoinfections.PreviousresearchhasfoundthatindividualswhoreceivetheBCGvaccinesufferfromfewerrespiratoryviralinfections,[172]andexperimentalinfectionstudiesshowthatthevaccinereducesthelevelofviruspresentinthebody.Anumberofpreprintsyettobepeer-reviewedclaimtohavefoundthatcountrieswithactiveBCGvaccinationregimesalsohavelowerinstancesofCOVID-19,[173,174]butotherscautionagainstover-interpretingsuchecologicalstudieswithmanyconfoundingfactors.[175]ArecentanalysisfromIsraeldidnotfindalinkbetweenBCGvaccinationstatusandprevalenceofCOVID-19.[176]Meanwhile,anepidemiologicalstudypublishedinPNASthatcontrolledformultipleconfoundingfactorsfound“severalsignificantassociationsbetweenBCGvaccinationandreduceCOVID-19deaths”.[177]
AlthoughtheongoingtrialsareendorsedbyWHO,theorganisationhasalsoreleasedascientificbriefstatingthattheydonotcurrentlyrecommendBCGvaccinationforthepreventionofCOVID-19.[178]InadditiontoWHO,thetrialhasalsoreceivedsupportfromtheBillandMelindaGatesFoundationwithadonationofAU$10million.[179]
ResearchersinAustraliaareinvestigatingwhethertheBCGvaccinecanbe‘rejigged’withantigensfromSARS-CoV-2tomakeitmorespecific.[180]TheyarecallingthisvaccineBCG:CoVacandsay“initialresultsarepromising”.
29
7. FurtherreadingThemostpromisingvaccinesforCOVID-19RapidResearchInformationForum
TheCOVID-19vaccinedevelopmentlandscapeNatureReviewsDrugDiscovery
ThevirusandthevaccineABCAustralia
COVID-19vaccinefrontrunnersTheScientist
COVID-19vaccinedevelopmentpipelineLondonSchoolofHygiene&TropicalMedicine
Coronavirusdisease(COVID-2019)R&DWHO
CouldBCG,a100-year-oldvaccinefortuberculosis,protectagainstcoronavirus?TheConversation
SARS-CoV-2vaccines:StatusreportImmunity
CochraneCOVID-19StudyRegisterCochrane
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