亚开行-新冠肺炎疫苗生产竞赛：新兴疫苗技术（英）

THERACETOMANUFACTURECOVID-19VACCINES

EMERGINGVACCINETECHNOLOGIES

NOVEMBER2023

ASIANDEVELOPMENTBANK

THERACETOMANUFACTURE

COVID-19VACCINES

EMERGINGVACCINETECHNOLOGIES

NOVEMBER2023

ASIANDEVELOPMENTBANK

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DOI:

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Notes:

Inthispublication,“$”referstoUnitedStatesdollars.

ADBrecognizes“America”astheUnitedStatesand“China”asthePeople’sRepublicofChina.

ThisstudywaspreparedbytheTherapeuticGoodsAdministration(TGA)fortheAsianDevelopmentBank(ADB).

Theinformationprovidedisadviceonlyforthepurposesofinvestmentandprocurementdecision-makinginemergingvaccinetechnologyforinfectiousdiseases(includingCOVID-19).Itrepresentsasummaryofliterature-basedanalysisandscientificevaluation.Someofthedataandopinionspresentedinthisdocumentarederivedfrominformation

providedbytherelevantcompaniesandhavenotalwaysbeensubjecttoindependentvalidation.Thisinformationisnotanauthorization,warranty,orguaranteeofanytherapeuticgood.TheAustralianGovernmentisnotresponsible

fornegligenceorotherwiseinanyinjury,loss,ordamagehoweverarisingfromtheuseof,orrelianceon,the

informationprovided.

Suggestedcitation:

P.Papathanasiou,P.Osewe,M.Apostol,andB.Coghlan,eds.2023.TheRacetoManufactureCOVID-19Vaccines—EmergingVaccineTechnologies.Manila:ADB.

CoverdesignbyClaudetteRodrigo.

Contents

TablesandFigureiv

Abbreviationsv

I.Introduction1

II.OverviewofVaccinePlatforms2

III.VaccineBriefs3

A.ArcturusTherapeutics(UnitedStates)3

B.BaiyaPhytopharm(Thailand)5

C.BeijingWantaiBiologicalPharmacyEnterpriseCo.Ltd.(People’sRepublicofChina)7

D.BiologicalE.Limited(India)9

E.CanSinoBiologics,Inc.(People’sRepublicofChina)10

F.Codagenix(UnitedStates)13

G.HDTBio(UnitedStates)15

H.MedigenVaccineBiologicsCorp(Taipei,China)17

I.NanogenPharmaceuticalBiotechnology(VietNam)19

J.ProvidenceTherapeutics(Canada)20

K.RaphaelLabs(Ireland)22

L.Sanofi(France)24

M.Shionogi(Japan)25

N.Valneva(France)26

O.Vaxxas(Australia)29

P.Vaxxinity(UnitedStates)29

Appendix:

NovelExpressionSystemsforVaccineDevelopment32

References34

TablesandFigure

Tables

1ListofVaccinesandProductsbyManufacturer1

2VaccinePipelineforArcturusTherapeutics4

3ArcturusTherapeutics’Partnerships5

4VaccinePipelineforBaiyaPhytopharm7

5VaccinePipelineforBeijingWantai9

6VaccinePipelineforCanSino12

7VaccinePipelineforCodagenix14

8VaccinePipelineforHDTBio16

9VaccinePipelineforMedigenVaccineBiologicsCorp.19

10VaccinePipelineforProvidenceTherapeutics21

11ScaleupofmRNAVaccineManufacturingCapacityforProvidenceTherapeutics22

12GapsinMeasurestoPreventRespiratoryInfections23

13VaccinePipelineforValneva27

14VaccinePipelineforVaxxinity31

A1NewExpressionSystemsforDevelopingVaccines32

Figure

TypesofViralVaccines2

Abbreviations

ADB

–

AsianDevelopmentBank

DMC

–

developingmembercountry

COVID-19

–

coronavirusdisease

DNA

–

deoxyribonucleicacid

EUA

–

emergencyuseauthorization

EUL

–

emergencyuselisting

GMP

–

goodmanufacturingpractice

LMICs

–

low-andmiddle-incomecountries

MHRA

–

MedicinesandHealthcareProductsRegulatoryAgency(UnitedKingdom)

mRNA

–

messengerribonucleicacid

nAb

–

neutralizingantibody

RBD

–

receptorbindingdomain

RSV

–

respiratorysyncytialvirus

S-2P

–

recombinantspikeprotein

TGA

–

TherapeuticGoodsAdministration

USFDA

–

UnitedStatesFoodandDrugAdministration

WEIGHTSANDMEASURES

g

l

ml

–

–

–

gram

liter

milliliter

I.Introduction

Theglobaloutbreakofthecoronavirusdisease(COVID-19)in2020wasthedriverforAustralia’sTherapeuticGoodsAdministration(TGA)toconducthorizonscanningfornewvaccinesandnewvaccineproduction

technologies.

Thispapersummarizesaselectionoftheproductsandtechnologiesidentifiedduringthishorizonscanningto

informnationalCOVID-19responsesofAsianDevelopmentBank(ADB)developingmembercountries(DMCs),aswellastoinforminitiativestostrengthenvaccinemanufacturinginAsiaandthePacific.Forexample,DMCs

mayusethisinformationtoassistwithinvestmentdecisionsrelatedtovaccineprocurementandmanufacturing.

The16companiesincludedinthispaperwereidentifiedbytheTGAasdevelopingemergingvaccine

technologies(Table1).AllcompaniessignedconfidentialdisclosureagreementswithTGAduring2021–2022toworkwithADBtoassistDMCsinAsiaandthePacific.Somecompaniesareemployingestablishedtechnologicalplatformsadaptedtonewpathogenslikethesevereacuterespiratorysyndromecoronavirus2(SARS-CoV-2),thecausativeagentofCOVID-19,whileothersaredevelopingnoveltechnologies.

Table1:ListofVaccinesandProductsbyManufacturer

Company

Vaccine/ProductType

VaccineSubtype

ArcturusTherapeutics

Componentviral

Ribonucelicacid

BaiyaPhytopharm

Componentviral

Proteinsubunit

BeijingWantaiBiologicalPharmacyEnterprise

Componentviral

Nonreplicatingviralvector

BiologicalE.Limited

Componentviral

Proteinsubunit

CanSinoBiologics,Inc.

Componentviral

Nonreplicatingviralvector

Codagenix

Wholevirus

Live-attenuated

HDTBio

Componentviral

Ribonucelicacid

MedigenVaccineBiologicsCorp

Componentviral

Proteinsubunit

NanogenPharmaceuticalBiotechnology

Componentviral

Proteinsubunit

ProvidenceTherapeutics

Componentviral

Ribonucelicacid

RaphaelLabs

Prophylacticspray

Sanofi

Componentviral

Proteinsubunit

Shionogi

Componentviral

Proteinsubunit

Valneva

Wholevirus

Inactivated

Vaxxas

Skinpatch

Vaxxinity

Componentviral

Proteinsubunit

Source:AsianDevelopmentBank.

III.VaccineBriefs

Eachofthe16manufacturersummarieshereincludes,whererelevant,thefollowingcontent:

(i)backgroundinformationaboutthemanufacturer;

(ii)adescriptionofthevaccineplatformsand/ortechnologiesemployedbythemanufacturer;

(iii)detailsofCOVID-19vaccine(s)developed;

(iv)detailsofvaccinepipeline;and

(v)existingpartnershipsandapproachtoworkingwithADB’sDMCsorlow-andmiddle-incomecountries(LMICs).

A.ArcturusTherapeutics(UnitedStates)

1.Background

ArcturusTherapeuticsisalate-stageclinicalmessengerribonucleicacid(mRNA)and

deoxyribonucleicacid(DNA)medicinesandvaccinescompany.Itwasfoundedin2013andisbasedintheUnitedStates(US).Thecompanyhassetitssightsonproducingvaccinesforcommunicablediseasesandtherapeuticsforrarerespiratorydiseases.

2.VaccinePlatformandTechnologies

(i)LUNARDeliverySystem

LUNARisaproprietarylipid-mediatednucleicaciddeliverysystemdevelopedbyArcturus

thataimstoimprovethedelivery,tolerance,andsafetyofnucleicacid-basedmedicines(Muckeretal.2020).TheLUNARsystemencapsulatesanddeliverstherapeuticnucleicacidstospecificcellsbyendocytosis

(Ramaswamyetal.2017;Perez-Garciaetal.2022;Diaz-Trellesetal.2022):particlesfusetothemembraneofthecellandthenbringthemRNAorDNAinsidethecell.Thiscorrectsthegeneticdefectandallowsthecelltoproducehealthyproteins.

Thelipidsdonotaccumulateinsidethecellallowingforrepeateddosing.UseofLUNARmayrequireasmaller

amountofactivepharmaceuticalingredientfortherapeuticeffects,potentiallyreducingtheriskofadverseevents.LUNARcanbeadministeredbymultipleroutes—intravenous,intramuscular,inhaled,nebulized,subretinal,and

intravitreal—andcandelivermixturesofdifferentmRNAsasasingledrugproduct.ThelipidshavebeentailoredtobehighlyefficientatencapsulatingmRNAandDNA,whichalsoreducesmanufacturingcosts.

4TheRacetoManufactureCOVID-19Vaccines

(ii)STARRDeliverySystem

TheSTARRdeliverysystemspecificallycombinesLUNARwithself-replicatingRNA(srRNA).Thiscanbeusedforprophylacticvaccinesthatstimulateantigenexpressionwithinhostcells,leadingtolong-termprotective

immunityagainstselectedinfections.Inaddition,srRNA-basedvaccinesrequirelowerdosesthannon-srRNA-basedvaccines,andproductionisfastandsimple(Lundstrometal.2021).

3.COVID-19Vaccine

TheCOVID-19vaccineboostercandidate,ARCT-154,wasdevelopedusingtheSTARR

technologyandmayofferadvantagesincludinglow-dose(5micrograms),lyophilized

formulation,acceptablevaccineefficacy,durability,andsafetyprofile,aswellasrapidglobalscale-up,andimprovedsupplychainanddistribution.Thevaccinealsodoesnotuseany

adjuvantsorviralvectors.

4.VaccinePipeline

ArcturusisdevelopingnumerousmRNAvaccinecandidatestopreventCOVID-19(Alwisetal.2021)andinfluenzainfections.

ThecompanyisalsodevelopinganmRNAmedicineforornithinetranscarbamylase(OTC)deficiency,themostcommonureacycledisorderinhumans(Yuetal.2022).OTCdeficiencycausesammoniatobuildupinthe

blood.Withoutalivertransplantation,currentlytheonlycureforOTCdeficiency,thehighlevelsofammoniacanleadtoneurologicaldamage,coma,anddeath.

Inaddition,ArcturusiscollaboratingwiththeCysticFibrosisFoundationintheUStodevelopanmRNA

medicine(Peietal.2022).Overtime,cysticfibrosisleadstoirreversibledamagetotherespiratorytractandgut.Whiletreatmentshaveimproved,peoplewithcysticfibrosisstilltypicallydieintheirmid-40s(Table2).

Table2:VaccinePipelineforArcturusTherapeutics

VaccineName

IndicationGroup

DevelopmentStage

Discovery

Preclinical

Phase1

Phase2

Phase3

Registration

LUNAR-COV19

ARCT-154asBoosterVaccine

COVID-19

LUNAR-COV19

ARCT-154asPrimaryVaccine

COVID-19

LUNARFLU

Influenza

LUNAR-OTC

ARCT-810

OTC

Deficiency

LUNAR-CF

ARCT-032

Cystric

Fibrosis

COVID-19=coronavirusdisease,OTC=over-the-counter.

Source:Arcturus.

VaccineBriefs5

5.Partnershipsand/orApproachtoWorkingwithLow-andMiddle-IncomeCountries

Arcturushaspartneredwithseveralindustryleaderstobolsteritspreclinicaldrugdevelopmentpipeline.

Externaldevelopmentpartners(Table3)includeCureVacAG;JanssenPharmaceuticals,Inc.(Johnson&

Johnson);SyntheticGenomicsInc.;TakedaPharmaceuticalCompanyLimited;andUltragenyxPharmaceuticalInc.TreatmentsforarangeofgastrointestinaldisordershavebeendevelopedincludingglycogenstoragediseasetypeIII,HepatitisBvirusinfection,andnonalcoholicsteatohepatitis(NASH).

Table3:ArcturusTherapeutics’Partnerships

Program

Partner

Indication

Stage

LUNAR-GSDIII

UltragenyxPharmaceuticalInc.

GlycogenStorageDiseaseTypeIII

Phase1/2

LUNAR-RARE

UltragenyxPharmaceuticalInc.

N/A

Preclinical

LUNAR-HBV

Johnson&Johnson

HBV

Preclinical

LUNAR-NASH

TakedaPharmaceuticalCompanyLimited

NASH

Preclinical

HBV=HepatitisBvirus,NASH=nonalcoholicsteatohepatitis.

Source:Arcturus.

In2020,ArcturusandDuke-NUSMedicalSchoolusedtheSTARRtechnologytoproduceaCOVID-19vaccinefortheSingaporeEconomicDevelopmentBoard.In2021,ArcturusannouncedanagreementwithVingroup,

thelargestconglomerateinVietNam,focusingontechnology,healthcare,industry,realestatedevelopment,retail,andhospitality.ThisagreementaimstobuildamanufacturingplantinVietNamforCOVID-19vaccinesfordomesticuse.Undertheagreement,VinbiotechwillbuildthemanufacturingfacilitywhileArcturuswill

provideaccesstoproprietarytechnologiesandprocessestomanufactureCOVID-19vaccines.Thelicense

andtechnologytransferappliestodrugproductmanufacturing.OtherglobalmanufacturingpartnersincludeAldevron(US),Catalent(US),Recipharm(Germany),PolymunScientific(Austria),andARCALIS(Japan).

InNovember2022,Arcturussignedamajorlicensingdeal(Reuters2022)withAustralianvaccinemanufacturerCSL,whichgivesCSL’svaccinearm,CSLSeqirus,an(i)exclusivelicensetoArcturus’snext-generationmRNA

technologyformedicalproductsforrespiratorydiseases,includingCOVID-19andinfluenza;and(ii)nonexclusiverightstodevelopvaccinesandtherapeuticsthatcanaddressmultiplediseasesofpandemicpotential.

B.BaiyaPhytopharm(Thailand)

1.Background

Foundedin2018asastartupcompanywithintheChulalongkornUniversityFacultyof

PharmaceuticalSciencesinBangkok,Thailand,BaiyaPhytopharm’svaccinetechnologyaspirestoreplacebiotech’sfermenterofanimalcellswithplant-basedbiologics(Shanmugarajetal.2021).

Thecompanyclaimsthisplatformmaydramaticallyacceleratebiopharmaceuticalmanufacturing—productsmaybeproducedinweeks—andreducecostsforresearchanddevelopment(R&D).

6TheRacetoManufactureCOVID-19Vaccines

BaiyaPhytopharmhasacurrentgoodmanufacturingpractice(GMP)facilityof1,200squaremetersinBangkok,licensedformanufacturingclinicaltrialproductsbytheFoodandDrugAdministrationofThailand.Thecompanyclaimsthisfacilitycanproduceclinicalmaterialsofplant-producedproteintosupplyupto60millionvaccine

dosesyearly.BaiyaPhytopharm’ssuiteofproductshelpsmoveThailandtowardsustainabilityinhealthcareandvaccineproductionandfurtherdevelopsthenation’spharmaceuticalindustry.

2.VaccinePlatformandTechnologies

BaiyaPhytopharm’srecombinantproteinexpressionsystemusestheleavesofanAustralianheirloomtobaccoplant,Nicotianabenthamiana,astheplatformfortransientexpression.Thisplantissaidtoofferadvantagesoverotherplantexpressionsystems:easy,fast,low-cost,andproduceshighyieldsofrecombinantproteins.

3.COVID-19Vaccines

BaiyaPhytopharmhasexaminedtheuseoftheplant-producedreceptor-bindingdomain(RBD)oftheSARS-CoV-2virusasasubunitCOVID-19vaccine,BaiyaSARS-CoV-2Vax1.TheRBDwasjoinedwithanFcfragmentofhumanIgG1andtransientlyexpressedinNicotianabenthamianaby

agro-infiltration(Shanmugarajetal.2022).Inonestudy(Siriwattananonetal.2021),twointramuscularinjectionsoftheRBD-Fcprotein(usingalumasanadjuvant)wereadministeredinmice,monkeys,andrats3weeksapart

ondays0and21.Inoculationelicitedhighneutralizationtiters,reducedthelevelofvirusinthebrainandlungs,protectedalltheanimalsagainstchallengewithSARS-CoV-2,andinducedcell-mediatedandhumoralimmuneresponses,aswellasvaccine-specificT-cellresponses.

Theanimalsinthestudyremainedhealthy,andnopathologicalchangesrelatedtothevaccinewere

found.Further,thevaccinewastoleratedatthehighestconcentrationstested.Anotherstudyofmonkeys

(Khorattanakulchaietal.2022a)immunizedwiththreeintramusculardosesofthevaccinefoundthattheir

serainducedaneutralizingantibody(nAb)responseagainstfiveSARS-CoV-2variants(Alpha,Beta,Gamma,Delta,Omicron).TheDeltaandEpsilonRBD-Fc-basedvaccinesalsodisplayedcross-reactiveimmunogenicity

inmonkeys,raisingtheprospectthatthisplant-derivedvaccinecouldbeusedafterprimaryvaccination

toboostbroadlyneutralizingantibodies(Khorattanakulchaietal.2022b).Aseparatestudydemonstratedimmunogenicityinmice(Panapitakkuletal.2022).

Theseresultsshowpromisethattheplant-producedSARS-CoV-2RBDmaybeusedasaneffectiveCOVID-19vaccinecandidate.Humanclinicaltrialsareongoing.

BaiyaPhytopharmhasalsodevelopedahybridsubunitvaccinethatisintendedasamulti-straincoronavirus

vaccinebecauseitcaninduceimmunityagainstabroadrangeofCOVID-19variants.Thiscandidateiscurrentlybeingtestedinnonhumanprimatestudies.

4.VaccinePipeline

BaiyaPhytopharmisinvestigatingadditionalbiologicalcandidatesusingtheirplant-basedmodelasvaccinesagainstinfectiousdiseasesandasmedicinesforcancer.Thisincludesvaccinesfor

infectionslikeCOVID-19andrespiratorysyncytialvirus,aswellascancersofthelung,skin,gastrointestinalsystem,andbreast(Table4).

VaccineBriefs7

Table4:VaccinePipelineforBaiyaPhytopharm

VaccineName

IndicationGroup

DevelopmentStage

Discovery

Preclinical

Phase1

Phase2

Phase3

Commericial

BAIYA-SARs-CoV-Vax1

COVID-19

BAIYA-SARs-CoV-Vax1

COVID-19

RSVvaccine

RSV

Baiya-CA001

Cancer

Baiya-CA002

Cancer

Baiya-CA003

Cancer

Baiya-CA004

Osteoporosis

COVID-19=coronavirusdisease,RSV=respiratorysyncytialvirus.

Source:BaiyaPhytopharm.

C.BeijingWantaiBiologicalPharmacyEnterpriseCo.Ltd.(People’sRepublicofChina)

1.Background

BeijingWantai,establishedin1991inthePeople’sRepublicofChina(PRC),isamanufacturer

oftherapeuticgoods,includingvaccines,infectiousdiseasediagnosticreagents,andmedical

devices.Thecompany’ssubsidiary,Innovax,wasfoundedin2005todevelopvaccinestocombatinfectiousdiseases,includingHepatitisE,humanpapillomavirus(HPV),andCOVID-19.

2.VaccinePlatformandTechnologies

BeijingWantai’scorevaccineplatformusesDNArecombinanttechnologytoadoptan

establishedandrelativelylow-costEscherichiacoli(E.coli)expressionsystem.Thesystemwas

developedincollaborationwiththeNationalInstituteofDiagnosticsandVaccineDevelopmentinInfectiousDiseasesofXiamenUniversity.

3.COVID-19Vaccine

Alive-attenuatedinfluenzavirusvector-basedSARS-CoV-2vaccine,dNS1-RBDisdelivered

byintranasalspray.Thevaccineencodesacodon-optimizedreceptorbindingdomain(RBD)ofthespike(S)proteinoftheSARS-CoV-2virus.Withnonstructuralprotein1(NS1)ofinfluenza

virusdeleted,thevectormayelicitpotentandlong-lastingimmunity.PreclinicalstudiesofdNS1-RBDsuggestedthattheimmuneresponseinthelungwasmanytimesstrongerthantheperipheralbloodandthatthelungsof

hamsterswerelargelyprotectedaftersingle-dosevaccinationandboostervaccinationforthemostprominentvariants,includingOmicron(Zhuetal.2022a;J.Chenetal.2022).Thiswasdespitepoorhumoral,mucosal,

andT-cellimmuneresponses.Inaddition,dNS1-RBDalsoprovidedsimultaneouscross-protectionagainst

influenza(H1N1andH5N1viruses).Thevaccineisdeliveredbysyringe,withaspecialtipdesignedtoproduceamist.Resultssuggestthatthemodeofdeliveringthevaccineintothenose,mouth,andthroatmayinfluencetheeffectivenessofintranasalandinhaledvaccines.NasalvaccinesmimicthewaytheSARS-CoV-2virusinfects

humansandstimulateimmunityintheliningoftheupperairways.

8TheRacetoManufactureCOVID-19Vaccines

DatafromPhase3clinicaltrialscarriedoutinColombia,thePhilippines,SouthAfrica,andVietNamshowed

thattheabsoluteprotectiveefficacyofthevaccineagainstCOVID-19within3monthsofvaccinationwas55%inthosewhohadnothadanypreviousvaccines;thisincreasedto82%within6monthsofboostervaccination

inthepopulationwithvaccinationhistory.Theprotectiveefficacyinpeopleaged60yearsormorewassimilar

topeopleaged18–59years.ThevirussequencedfromtheendpointcasesshowedthatallconfirmedcaseswereOmicronstrains,includingBA.2(42%),BA.4(39%),andBA.5(18%).ThisfindingindicatedthatthevaccinehadproducedeffectiveprotectionagainstCOVID-19causedbyOmicroninfectionwithafavorablesafetyprofile.

In2022,dNS1-RBDintranasalvaccinereceivedemergencyuseauthorization(EUA)fromtheCenterforDrugEvaluationoftheNationalMedicalProductsAdministrationinthePRC.BeijingWantaiintendstomanufacture200milliondosesduringthefirsthalfof2023.

4.VaccinePipeline

Numerousvaccinesarecurrentlyindevelopmentandclinicaltrials(Table5),includingavaccineagainstrotavirus,a20-valentpneumococcalconjugatevaccine(PCV20),andalivevaricella

vaccine(W.Wangetal.2022).

BeijingWantaihasthreecommerciallyavailablevaccines:

(i)dNS1-RBD.dNS1-RBDisalive-attenuatedinfluenzavirusvector-basedSARS-CoV-2vaccinedeliveredbyintranasalspray.In2022,itreceivedEUAfromtheCenterforDrugEvaluationoftheNational

MedicalProductsAdministration.

(ii)Hecolin.HecolinisaHepatitisEvaccine(Zhuetal.2010;T.Wuetal.2