Advancingthemanufactureanddeploymentofcosteffectivevaccines

EPSRCFutureVaccineManufacturingResearchHub

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunitiesforinteraction,partnershipsandproposals

• Discussion

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunitiesforinteraction,partnershipsandproposals

• Discussion

• ThenewFutureVaccineManufacturingResearchHubatImperialCollegeLondon,hasbeenestablishedwith£10million(GBP)offundingfromtheUKDepartmentforHealth,administeredbyEPSRC.

• IncorporatesresearchgroupsacrossImperialCollegeexperiencesinvaccineR&D,processengineeringandmanufacturing

• LinkedtoadditionalUKspokeswithexperienceinformulation,computationalmodelling,processdevelopmentandvaccineQA/QC(NIBSC)

• Establisheddevelopingcountryvaccinemanufacturerspokes,initiallyinIndia,Vietnam,Bangladesh,UgandaandChina

• Lookingtoexpandcollaborationwithadditionalpartners.

FutureVaccineManufacturingResearchHubIntroductiontotheHub

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunitiesforinteraction,partnershipsandproposals

• Discussion

• Wewilladoptanintegratedapproachthatwillbuildonnewdevelopmentsinlifesciences,immunologyandengineeringtoaddresstwokeychallenges

• Howtodesignproductionsystemsthatcanproducetensofthousandsofnewdoseswithinweeksofanewthreatbeingidentified

• Howtoimprovethewayvaccinesaremanufactured,stabilisedandstoredsothatexistingandnewdiseasescanbepreventedeffectively,andcostsreduced

FutureVaccineManufacturingResearchHubAimsandobjectives

Goal:advancingthemanufactureanddeploymentofcosteffectivevaccines

Responsivetothetreatofemergingandre-emerginginfections

7billionin2012

Respondingtodevelopingworldvaccineneeds

Identifyinggapsintechnologytransfer

• ResearchandDevelopmentcapacitytosupporttechnologytransfer,developnovelvaccines,workaroundexistingIP

• Vaccinespecificmodelling– manufacture,distribution,markets• Businesscase/sustainabilitytosupportadoption,adapttochangingmarkets,respondtosupplyanddemand

• Know-how– workforce(training,expertise,retention)• Know-howinemergingtechnology(whentoadoptordrop)• Know-howinprocessoptimisation• QA/QCandregulatoryaffairsfornewtechnologiesandultimatelypre-qualification

Opportunity:leap-frogexistinginvestmentsbyexploitingemergingplatforms

Technologyowner:rightsandknow-how

(IndustrializedPharma)

Bilateraltechnologytransfer

Jointventures,acquisitionsorwhollyownedsubsidiaries(oneorfewpartners)

PatentLapse

ManufacturersManufacturers

Manufacturers

Manufacturers

Manufacturers Manufacturers

NewmodelforTechnologyTransferAdvancedTechnologyHub

• Spokes• Spokes

• Spokes• Spokes

Know-howSharedIPInnovators

TechnicalAdvisorsQA/QC

ModellersDevelopers

FormulatorsManufacturers

ManufacturersManufacturers

Manufacturers

Manufacturers

Manufacturers Manufacturers

Engineeringdeliverablesatmultiplelevels• RepliconRNAvaccines• Enhancedyeastexpressionplatforms• Insectcell-baculovirus expressionsystem(IC- BEVS)• GeneralizedModulesforMembraneAntigens(GMMA)• Formulationforheatstabilisation• Processoptimisationofmanufacturingplatforms• Vaccinespecificmodellinganddecisionaltools• R&Dtrainingandsupport• QA&QCsupportandtraining

Risk

Inno

vatio

n

Levelofd

isrup

tion

R&D Pilot Full production

Fill & Finish

Upstream transfer(seed with know-how)Seed with technology platformPilot stage transfer

Fill and Finish transfer

Enhanced formulation

R&D technical support & trainingQC/QA technical supportPrequalificationProcess optimisation

Self developmentDevelopment with Hub supportTransfer of specific technology

Modelling

Developingappropriatepartnership

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunities• Discussion

1.ProvisionofQA/QCsupportandtraining• DevelopmentofQAassaysfornovelmanufacturingplatforms • Provisionofvaccinepotencyassaysforviralandbacterialvaccines • Developmentofvalidatedassaysandreferencematerialsforemerginginfections

• AdviceonmanufacturingQAandregulatoryapprovalunderpinningprequalification

NationalInstituteforBiologicalStandardsandControls

2.Provisionofvaccinespecificmodellinganddecisionaltools

§ Objectives:§ operationalefficiencyforcostreduction§ rapidresponseofexistingassets§ end-to-endsystemdesign

§ Wholeprocessanalysisandoptimisationtoaddressbottlenecks§ InLifeSciences:hostcellsystemorvectoroptimisationforimprovedproductivity/quality

§ InEngineering:downstreamseparations,formulationandpackaging

§ Establishedcomputationalplatformformodellingandoptimisingvaccinemanufacturingprocessestoreducecosts

Multi-scalemodellingcapabilities

Plant operations

Currentcapabilitieswithinthehub§ Wehaveestablishedacomputationalplatformformodellingandoptimisingvaccinemanufacturingprocessestoreducecosts

§ Applywholeprocessoptimisation,systemdesignandprocessintensificationtoimproveoperationalflexibilityandefficiency

§ Processintensificationhasgreatpromiseforcostreductionandimprovementofresponsivenessinvaccinemanufacturing

§ Optimiseusingprocessmapping,bottleneckidentificationandprocessintensification,buildingonworkinbiologicsmanufacturing.

§ Deliverable:Demonstrationofbenefitsofintegratedapproachonprimaryproductionsystems

Downstreamseparationstypicallyincursignificantcostsandin-processtimes

Exemplarpurificationconcepts§ “processtelescoping”wherebyseveralunitoperationsarecombinedintoone(e.g.expandedbedaffinityadsorptioncombiningsolidsremoval,captureandprimarypurification)

§ continuousoperation(e.g.movingtocontinuouschromatographyusingsimulatedmovingbedtechnology).

§ Ourkeyactivitieswillinvolvehighthroughputexperiments,modelsandbigdataanalytics.

§ Deliverable:Demonstrationofnewvaccineseparationdesignconceptsatlabscale

Design

Modeling

OptimizationControl

Experiments

• Study dynamics• Thorough

system understanding

• Dynamic • High-fidelity• Testing platform

• Optimal operating conditions

• Optimal performance

• Monitoring• Optimal

performance guaranteed

• Only the necessary

• Minimizelabor time& cost

• Re-designcurrent state-of-the-art

Computationalmodelsforwholesystemsanalysis

§ Multi-scalemodellingofbiologicalprocessesthroughtounitoperationandwholevaluechainswillbeusedforsystemanalysis,designandmanufacturingoperationoptimisation

§ Howdoparameterscharacterisingsingleunitperformancee.g.titre,purity,recovery,formulationrecipeinfluencewholesystemmetricse.g.costperdose,leadtimes?

3.Processoptimisationofemergingmanufacturingplatforms:Industrialisation,demonstration,deployment

WS4-8

Processconcepts

ManufacturingEngineeringDesignOptimisation

10platformdesigns(“blueprints”)

6physicaldemonstratorsatLMICsitesScaleupandindustrialisationanalysis;Valuechainmodellingandeconomicanalysis,decisionmakingtoolsBuildsonexistingexperienceinoptimisingindustrialprocesses

4.Formulationforheatstabilisation• Advancedfreeze-dryingformulationsandprocessesforvaccinestabilisation≥6months

• Generationofhighlythermally-stableliquidvaccineformulations• (biocompatibleionicliquids,40°Cfor12months)

• Novelvaccinedeliveryformulationsprovidingdosesparingandenhancedimmunogenicity

• Widerexploitationofdisposablepouchsystemfororalvaccinedelivery

2 ˚C to 8 ˚C 2 ˚C to 8 ˚C 2 ˚C to 8 ˚C 2 ˚C to 8 ˚C

Manufacture Land Transport Aviation Transport Storage Administration

Centralisedversusdecentralisedmanufacture

Staff/trainingQMSEquipmentConsumablesQA/QCtesting

SeedtechnologytoanynumberofLMICfacilitiescapableofcGMP,fill/finishlabelling

CentralHub

Atoolboxoftechnologies,training,methodologies,andmaterialdesignedtomeetcommonneedsamongemergingvaccinemanufacturers

UptomillionsofdosesNational/regionalNeglecteddiseasesRapidresponsetoemerging

andlocalinfectionsHighflexibility

Singlemanufacturingplant

EconomiesofscaleandvolumeHundredsofmillionsofdosesStandardised QC/QAApplicabletocomplexmanufacture(pneumococcalconjugatevaccine)GlobaldistributionHighupfrontcapitalcostsHighpersonnelcostsLowflexibility

Enhanceddelivery:formulation,route,supplychain…

RNA

RNA

RNA

RNA

RNA

RNA

RNA

RNA

Identifyingcoreplatformsforfurtherexploitation

ExploitationofthemultiBac Platform

Baculovirus expressionvectorsystem(BEVS)

Engineeringenhancedyeastbasedexpressionplatforms

AnumberofindividualstrainmodificationshavebeenidentifiedWeaimtocombinethesetocreatea“super-strain”andre-engineerhumanglycosylationEnsurebioprocessoptimisation

SecretoryPathwayEngineering:• UpregulateUPR• ExpandERsize• ‘bgs’modifications

GeneralizedModulesforMembraneAntigens(GMMA)

F.Micoli|GMMAtechnology

25

Eleonora Meloni &Taddei Anna Rita C.I.M.E. Institute, Università della Tuscia

Break links

Induce blebbing

GMMA(gemma: Italian for bud or jewel)

X X X

X X X

– Genetic modifications trick bacteria into shedding outer membranes

– GMMA are released yielding pure source of outer membrane– Similar size to virus-like particles– Contain PAMPs: naturally adjuvanting– Multiple antigens are presented in their natural

environment and conformation

GSKVaccinesInstituteforGlobalHealth(GVGH)

CAg Replicase

Rep

Ag Rep- Antigengene - Antigenprotein - Replicase gene - Replicase protein - CAP - Genomicpromoter

- Subgenomic promoter

Ag

Replicase Ag PolyAC Replicase Ag PolyAC

Replicase Ag PolyAC

Replicase Ag PolyAC

Replicase Ag PolyAC

Ag PolyAC

Ag PolyAC

Ag PolyAC

Ag PolyAC

Ag PolyAC

Ag

AgAg

Ag

Ag

Legend

AgAg

Ag PolyACAg PolyAC

B:Self-amplifyingRNA

A:mRNA

Self-amplifyingRNAbasedvaccines

Chillon'I'et#al.'Methods#in#Enzymology,'2016'''

Mul0ple'op0ons'for'purifica0on'can'be'

considered.''

Note:'5’'capping'and'polyadenyla0on'reac0ons''

performed'before'addi0on'of'Proteinase'K'

Chillon'I'et#al.'Methods#in#Enzymology,'2016'''

Mul0ple'op0ons'for'purifica0on'can'be'

considered.''

Note:'5’'capping'and'polyadenyla0on'reac0ons''

performed'before'addi0on'of'Proteinase'K'

Chillon'I'et#al.'Methods#in#Enzymology,'2016'''

Mul0ple'op0ons'for'purifica0on'can'be'

considered.''

Note:'5’'capping'and'polyadenyla0on'reac0ons''

performed'before'addi0on'of'Proteinase'K'

Chillon'I'et#al.'Methods#in#Enzymology,'2016'''

Mul0ple'op0ons'for'purifica0on'can'be'

considered.''

Note:'5’'capping'and'polyadenyla0on'reac0ons''

performed'before'addi0on'of'Proteinase'K'

Chillon'I'et#al.'Methods#in#Enzymology,'2016'''

Mul0ple'op0ons'for'purifica0on'can'be'

considered.''

Note:'5’'capping'and'polyadenyla0on'reac0ons''

performed'before'addi0on'of'Proteinase'K'

Chillon'I'et#al.'Methods#in#Enzymology,'2016'''

Mul0ple'op0ons'for'purifica0on'can'be'

considered.''

Note:'5’'capping'and'polyadenyla0on'reac0ons''

performed'before'addi0on'of'Proteinase'K'

Capping

RNAcapping

Fullysynthetic,smallfoot-print,low-costrapidmanufacture

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunitiesforinteraction,partnershipsandproposals

• Discussion

CurrentLMICpartnerships

• HillemanLaboratories,India• developmentofathermostablecombinedoralCholera-ETECvaccine

• DalianHissen,China• developmentofrobust,modularandintensifiedmanufacturingprocesscapableofenhancingandacceleratingyeastbasedproduction

• Incepta Pharmaceuticals,Bangladesh• productionofformulatedpilotvaccinesusingnoveltherostable stableformulationsanddemonstrationofthermalstabilityandthereforethelifetimeoftheformulation

• Vabiotech,Vietnam• EstablishmentofamodularplatformforIC-BEVSproductioninVietnam

• UVRI,Uganda• EstablishmentofamodularplatformforRNAproductioninUganda

AdvancedTechnologyHub

•Cambridge•Nottingham•Bristol• Cranfield

•HillemanLaboratories–India

•UVRI,Uganda

•GSK(GlobalHealth)•DalianHissen,China• InceptaPharmaceuticals,Bangladesh

•Vabiotech,Vietnam

•NIBSC•CPI,Darlington•NHSBTCBC,Bristol

Know-howSharedIPInnovators

TechnicalAdvisorsQA/QC

ModellersDevelopers

Formulators

Manufacturers

Manufacturers

Manufacturers

FutureVaccineManufacturingHub

DevelopingCountriesVaccineManufacturersNetwork GMMA

VLPs

IC-BEVS

Delivery

Yeast

Processinnovation

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunitiesforinteraction,partnershipsandproposals

• Discussion

Opportunitiesforinteractions&partnerships

• QA&QCsupportandtraining• R&Dtrainingandsupport• AccesstoVaccinespecificmodellinganddecisionaltools• Collaborationonprocessoptimisationofmanufacturingplatforms• Partnershipsonformulationforheatstabilisation• Partnershipsonvaccineplatformdevelopment• Leveragingofexistinginvestmenttoattractadditionalfunding

Proposals

• LMICR&Dandtechnologytransferflexiblefund(£400,000)• VaccineHubtopresent,togetherwithmembersatthepre-meetingsymposium

• DCVMNlikelytoserveasplatformforsmallgrants(applications/management/reporting)

• WillprovideconsultingexpertiseformemberstoadvancewithGMP,processoptimization,regulatorydossiers,PQ,investments,andpartnershipswiththeHub

FutureVaccineManufacturingResearchHub

• IntroductiontotheFVMRHub• Aimsandobjectives• Hubcapabilitiesandinitiatives• Currentpartners• Opportunitiesforinteraction,partnershipsandproposals

• Discussion

Thankyouforyourattention

Contact:r.shattock@ic.ac.uk