covid-19 vaccines: summary of current state-of-play · 6 figure 2: chart breaking down the...

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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)


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


$456million[25] PhaseII

mRNA-1273 Moderna,NIAID

nucleicacid,RNA


$483million[26]

INO-4800 Inovio nucleicacid(DNAplasmid)


unknown–fundedfornon-humanprimatechallengestudy[27]

BNT-162 Pfizer,BioNTech

nucleicacid,RNA


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:


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:


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:


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:


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:


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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