the future vaccine manufacturing hub: tools and technologies...imperial college london university of...
TRANSCRIPT
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TheFutureVaccineManufacturingHub:ToolsandtechnologiesMartinaMichelettim.micheletti@ucl.ac.ukDepartmentalofBiochemicalEngineeringUniversityCollegeLondon
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
PresentationOutline
• IntroductiontoVax-Hub,platformfundingandGrandChallengeresearchoverview
• Vaccinetechnologies
• Adenovirusmanufacturingplatformprocess
• VLPvaccines:Qualitybydesign
• Novelglycoconjugatevaccinestechnologies
• Nextsteps
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
TheGlobalVaccineActionPlan(GVAP)
In 2012, the World Health Assembly, representing 194 countries, endorsed the GVAP to ensure that no one missed out on a vital immunisation by 2020. To date, progress towards the GVAP targets is off track. In 2015, more than 19 million children missed out on basic immunisations.
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Themanufacturinglandscape–supplyisfailingdemand
VaccineaffordabilityandsupplyisoneofthekeyprioritiesidentifiedbytheWHOGlobalActionPlan
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
HubVisionandAim
Toadvancetechnologiesthatwillensurefuture,uninterruptedsupply.
Toensurethattheseadvancestranslateto
LMICmarketsandmanufacturers.
Abilitytosupportandrespondtoepidemicthreats.
TheHubsupportsanambitiousprogrammeofinnovativeresearchrelatedtothechallengesofdeveloping,scaling-upandmanufacturing
vaccinesofbenefittolowandmiddleincomecountries.
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Hub-Spokemodel
HubDirectors:ProfessorsSarahGilbertandMartinaMicheletti£7M,3years(April2018-March2021)TwoHubs:• UCLBiochemicalEngineering• TheJennerInstitute,UniversityofOxfordThreeUKSpokes:• ImperialCollegeLondon• UniversityofLeeds• LondonSchoolofHygieneandTropical
medicine
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Hubactivities
GCManufacturingResearchonthreemaindemonstration
technologies(viralvectors,conjugatesandVLPs)
Platform Operations Interaction Vouchers,
Training and Feasibility Studies
Hub Activities
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
PlatformOperations
InteractionvouchersCall8vouchersintotal,budgetofupto£10Kpervoucher(<6monthsduration)AvailabletoUsersgroupmembersonlyMustbringtogetheranytwoorganizations(includingacademia-industrypartnerships)FeasibilityprojectsCall(early2020)Minimumof6projects,£100Keach(<12monthsduration)
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
ManagementStructure
International Advisory
Board (IAB)
Hub Management Group
Co-Directors
User Group
UKVN
EPSRC
DoH
Grand Challenges Research
Platform Activities
Total£6.9million
89%
11%
GCResearch PlatformOps
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
GrandChallengeResearchOverview
GrandChallenge2:Enhancedoperationalandeconomictoolsforuninterrupted,lowcostsupply
GC1.3.2NextGenAnalytics
GC1.2.1Advancedaffordablemanufactureofviralvectors
GC1.2.1Advanced,affordablemanufacturingofViralVectors
GC1.3.1VLPAnalytics
GC1.1.2Newanddisruptiveconjugationtechnologies
NewToolsandTechnologies(GC1.1)
PlatformManufacturing(GC1.2)
Analytics(GC1.3)
Formulation(GC1.4)
Subunits/VLPs
Conjugates
ViralVectors
GC1.2.2Rapidlyscalablesystems
Techno-economicevaluation
GC1.4Thermo-stable
formulationsystems
GC1.1.1Microscaleprocess
development
GC1.1.2Novelconjugatetechnologies
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
HubExpertise-UCL
IndustrialBiotechnologye.g.chemicalsandpharmaceuticals
MacromolecularMedicinese.g.antibodiesandvaccines
CellandGeneTherapiese.g.cellsand
engineeredtissues
HighThroughputBioprocessDesignandScale-up
SyntheticBiology(Protein,VectorandCellEngineering)
DecisionalTools(DataMining,ProcessandEconomicModelling,LCA)
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
HubExpertise-UCL
IndustrialBiotechnologye.g.chemicalsandpharmaceuticals
MacromolecularMedicinese.g.antibodiesandvaccines
CellandGeneTherapiese.g.cellsand
engineeredtissues
HighThroughputBioprocessDesignandScale-up
SyntheticBiology(Protein,VectorandCellEngineering)
DecisionalTools(DataMining,ProcessandEconomicModelling,LCA)
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Toolsforbioprocessdesignandscaling
Experimentalstudyofflowdynamics,mixingandsuspensiondynamics
§ Laboratoryscalebioreactors(rocked,shakenandstirred)§ Single-useandconventionaltechnologies(Ambr250,SartoriusCultibag,
MilliporeCellReady,DasBox)§ Impactofenvironmentfordifferentcelltypesandproducts§ Robustscalingequationsandmethodologies
MiniaturisationanddevelopmentofScale-DownTools
§ Quasi-perfusionmicroscalemethodologies§ 250mlperfusionbioreactor§ Microscaletangentialflowfiltrationdevice§ Integrationofmimicswithinautomatedplatformstospeedup
bioprocessdevelopment
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
UltraScale-Down(USD)Technologies:Manufacturinginsightinthelab
Continuous centrifugation Chromatography Formulation/Fill-
finish
Fermentation Depth filtration Membrane filtration
Opportunitywithnewtechnologiestolinkwholebioprocesssequence
USDTechnologies
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
HubExpertise–UniversityofOxford
TheJennerInstituteUniquemissiontodevelopinnovativevaccinesagainstmajorglobaldiseaseandfocusontranslationalresearch(rapidearlystagedevelopmentandassessmentofnewvaccinesinclinicaltrials)ClinicalBiomanufacturingFacility(CBF)TheUniversityofOxfordGMPfacility–MHRAAuthorisationforviralvectoredvaccinesandATMPs–providingalinkbetweenacademicresearchandclinicaldrugdevelopment
DesignandtestingofviralvectoredandVLPvaccinesTransitionfromresearchtoGMPGMPmanufactureofviralvectors,VLPandrecombinantproteinsAssaydevelopmentforreleaseandin-processtestingFormulationofdrugproductClinicalvaccinedevelopment(UKandoverseas)
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AdenovirusManufacturingPlatform
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
ProcessrequirementsforPhaseI
Small≥100doses
SimpleLimitedstaff,oneteammakesallproductsLimitedcapitalequipmentLimitedcapacitytovalidatenewequipment/processesTransferabletoLMICmanufacturers
RobustTransferableacrossmultipleproducts
Qualitymeetingregulatoryrequirements
Aneffectiveadenovirusmanufacturingapproachislikelytobeapplicabletovaccinesagainstmultiplepathogens:EmergingoutbreakpathogensVeterinaryAntibody&Tcells
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Adenovirusbiology
• Non-envelopeddsDNAvirus,90nm
• Non-replicatingduetoE1(andE3)genedeletion
• HEK293orPERC6cellssupplyE1intrans• Antigen-encodingtransgeneunderstrong
constitutivemammalianpromoter• Antigenisnotastructuralpartofthevirionà
vaccinesusingasingleAdserotypearestructurallythesame,regardlessofAg
• Antigenisexpressedinculture:canaltergrowthcharacteristics,selectionpressureforgeneticinstability
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Chimpanzeeadenovirusvectors(‘ChAds’)
• Minimalpre-existinganti-vectorimmunityinhumanpopulation
• Multipleserotypes
• Differenthexon/fibercapsidproteins
• IssueofcompatibilitywithHEK293Ad5-
derivedE1:• Manufacturingcanbeenhancedbynon-structural
genemanipulation
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Smallscaleadenovirusproductionprocess
Cells
3.Culture&infection
4.Lysis&DNAremoval5.Clarification
6.TFF17.AEX8.TFF2
Upstream
process(USP)
DSP
Tet-repressingHEK293
3LstirredbioreactorsTween20&benzonase,in
bioreactor
MerckC0SPdepthfilter
SpectrumLabs300kDahollowfibre
2.Startingmaterial 1-3Lshakeflask1.Cellseedtrain Shakeflasks
MerckPellicon2300kDa
MustangQmembrane
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Vaccinesusedfor‘testcases’
ChAdOx2RabG(rabiesvaccine)
ChAdOx1RVFVGnGc(RiftValleyFevervaccine)
ChAd63ME-TRAP(malariavaccine)
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Vaccinesusedfor‘testcases’
0
5×1010
1×1011
1.5×1011
2×1011
2.5×1011
24 42 46 72 960
5×1010
1×1011
1.5×1011
2×1011
24 42 46 72 96
0
2×108
4×108
6×108
8×108
24 42 46 72 96
0
50
100
24 42 46 72 96
0
1×109
2×109
3×109
24 42 46 72 96
0
50
100
150
24 42 46 72 96
ChAdOx2 ChAdOx1ChAd63
Viru
s pa
rtic
le ti
ter
(VP/
mL
of c
ultu
re)
Infe
ctiv
ity ti
ter
(IU/m
L of
cul
ture
)Vi
able
cel
l den
sity
(% o
f sta
rtin
g va
lue)
0
2×108
4×108
6×108
8×108
24 42 46 72 96
0
2×1010
4×1010
6×1010
8×1010
24 42 46 72 96
0
50
100
150
24 42 46 72 96
Time after infection (hours)MOI3MOI10
Fedosyuketal,Vaccine2019
InAg-repressingHEKs,infectionatMOI3,harvestat~42hgivesgoodyieldsofallthreeviruses
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
3Lstirredtankbioreactor• Goodresultswithtwodifferentvessels
• Yieldc.1x105VPpercell
• Simple<48hrbatchprocess• Cellexpansioninshakeflasks
0 2 0 4 03 5
3 6
3 7
3 8
E la p s e d t im e (h rs )
Te
mp
era
ture
(°C
)
0 1 0 2 0 3 0 4 00
2 0
4 0
6 0
8 0
1 0 0
0
2
4
6
8
1 0
E la p s e d t im e (h rs )
DO
(%
)
Air flo
w ra
te (m
l/min
)
0 1 0 2 0 3 0 4 07 .0
7 .1
7 .2
7 .3
7 .4
0
1
2
3
4
5
E la p s e d t im e (h rs )
pH
CO
2 F
low
(ml/m
in) &
Ba
se
ad
ditio
n (p
um
p m
inu
tes
)
InfectionFeed InfectionFeed InfectionFeed
Fedosyuketal,Vaccine,2019
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Separationofadenoviralproductvariant
Total Virus Particles Lowry Protein Assay Dynamic Light Scattering SPR UV Measurement Full Particles Genome Quantitation Assay (GQA) Reverse-Phase HPLC Assay CsCl Gradient Analysis (% full)UV Absorbance Assay (UV-SDS) Infectious Particles TCID50 Q-PCR Based Potency Assay Antigen Expressing Particles Western blot In vitro Antigen Expression Assay
TotalVirusParticle
InfectiousParticle
EmptyParticleFullParticle
Non-InfectiousParticle
AntigenExpressingParticle
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VLPVaccines:QualitybyDesign
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
VLPVaccines:UnderstandingVLPassemblyandqualityattributes
DesignandProductionofhighqualityFoot-and-MouthDisease(FMD)virus-likeparticles(VLP)
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
VLPVaccines:Design(I)
Pull-down
E. coli P. pastoris
a.
Ex vivo assembly
b.
Codon optimised precursor for E. coli and P. pastoris
method 1 method 2
E. coli P. pastoris
H
H
H
H
H
H
…
…
…
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
VLPVaccines:Cloning/Expression(II)
3C pLysSpRha-3CL127P
pET3a-P1-2A
BL21(DE3)
= T7 promoter
= Rha promoter
= rbs
= T7 terminator
=Vp0 =Vp3 =Vp1 =2A
* non-specificbinding
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
VLPVaccines:Cloning/Expression(II)
* non-specificbinding
His6
+ c.
His6
+ a.
His6
+ b.
= T7 promoter = rbs = T7 terminator
=Vp0 =Vp3 =Vp1
BL21(DE3) 37°C
cont
rol
a. b. c.
100
50 37
150 M
18°C
αTypO-FMDV
75
a. b. c. - + - + - + - + - + - +
*
BL21 CodonPlus(DE3)-RIL
100
50 37
20
150
25
75
αTypO-FMDV
37°C
a. b. c. M
18°C
a. b. c. - + - + - + - + - + - +
*
*
25 20
Vp1his6~ 25 kDa Vp3his6 ~ 27 kDa Vp0his6 ~ 35 kDa
+
cont
rol
+
cont
rol
+
cont
rol
+
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
VLPVaccines:PlatformApproachesforDenguevaccine
390millionsinfectionsperyearAsymptomatictosevereacutefebriledisease
• Controlmeasurestargetingmosquitovectorshaveverylimitedeffectiveness
• Vaccinationisanimportantpartofanintegrateddenguepreventionandcontrolstrategy
• Onelicenseddengue,Dengvaxia®(CYD-TDV)andonlyeffectiveinseropositiveindividuals
Developmentofacost-effectiveplatformforthedeliveryofamulticompetentDengue
vaccine
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
ProposedPlatform
Upstreamproduction
VaccinePrototypePurification
VaccinePrototypeQualityAssessment
VectorDesignandStrainSelection
TobeperformedatBiofarma(Indonesia)
Development of a representative upstream dengue vaccine, VLP form,productionplatforminPichiaPastoriso Studyingoptimalstrategyinmedium,feeding,inductiontechnologiesand
VLPeffectiverecoveryo Developmentofrobustanalyticsforproductcharacterisationandquality
evaluation
Developmentofastrategyforscale-upandtechnologytransfer
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Preliminaryresults
GrowthprofileofPichiapastorisexpressingthedenguevaccinevector(DENVprM/E).Significantimprovementswereachievedinbiomassyieldbyfermentationprotocoloptimisation.However,higherdensitiesaredesiredtoachievedesiredtiters.
PurificationandpreliminarycharacterizationofrecombinantprM/Edengueserotypeusinganion-exchangechromatography(AEC)andhydrophobicinteractionchromatography(HIC).
0
50
100
150
200
250
0 50 100 150 200
Optic
al d
ensit
y
Time (h)
HostImprovement
0.0
25.0
50.0
75.0
100.0
Conc.(µg/mL)
Volume(mL)
Mass (mg) Purity (%)
Rela
tive
valu
es
Goal
Virus-LikeParticle(VLP)prM/Edengueserotype1(A),2(B),3(C)and4(D)usingtransmissionelectronmicroscopy(TEM).Theparticlediametersvariedbetween29-35nmdependingontheserotypeandaresmallerthanthenaturalvirus(40-50nm).
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NovelGlycoconjugatesTechnologies
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
RelevanceofGlycoconjugateVaccines
GlycoconjugatesfavourT-cellsdependentresponse(memory)Polysaccharides-basedvaccines(Glycanonly)TcellsindependentimmuneresponseExamplesofsuccessfulhumanglycoconjugate:
1. Haemophilusinfluenzae2. Neisseriameningitidis(excepttypeB)3. Streptococcuspneumoniae(someserotypes)
BertiandAdamoChemSoc.Rev.2018
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
ProteinGlycanCouplingTechnology(PGCT)forlowcostglycoconjugatevaccines
• PGCTischeap,safeandflexibleindesign
• Itcanbeappliedtoimproveexistingvaccines(pneumococcol)
• ordevelopnewones(Francisella)
• Orenternewmarkets(veterinary)
PGCTreview:Kay,CuccuiandWren,npjVaccines2019
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
DevelopmentofavaccineagainstS.pneumoniaStreptococcuspneumoniae:• Gram+,alpha-haemolyticdiplococcus,
commensalandrespiratorypathogen• Over95differentserotypes
• Causespneumonia,meningitis,conjunctivitis,bacteraemiaandotitismedia
• Estimatedthatglobally0.5millionchildrenunderfivedieofpneumococcaldiseaseeachyear(mostlyindevelopingcountries)
• Efficaciousvaccines(eg.PCV13)areavailable,butexpensiveandoftenunaffordablefordevelopingcountries
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Strategiesforglycoconjugatevaccineproduction
Chemicalorenzymaticconjugation
• Requiresseparatepurificationoftheglycanandcarrierprotein
• Strainusedforglycanpurificationmaybeunsafe
• Multi-stepheterogeneouspreparation• Expensiveandtimeconsuming
Biologicalconjugation• EngineeredsafelaboratoryE.colistrain• Singlepurificationstepofthe
glycoconjugate• Homogeneousprep• Manufacturingexpectedtobecheaper
andlesstimeconsuming
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Designandongoingwork
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
VaccinesindevelopmentKay,CuccuiandWren,npjVaccinesreview2019
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
AutomatedMicroscaleProcessdevelopment
Conditionsforscreening:
• Mediacomposition• DO,pH,temperature• Harvesttimes/cultureduration• E.colistrain• Carrierproteinandenzymealternatives
AIM:Toscaleoriginal20mLcultureto2mL
Operating conditions at themicroscale baseduponengineeringfundamentals.
• Sca l ing based upon match ing m ix ingcharacteristicsatbothscales
• Scalingbaseduponmatchingtheoxygentransfercoefficient,kLa
24conditionsinparallel
Highthroughputcharacterisation(e.g.ELISA)
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Nextsteps
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
BenefitsforHubUsers
Accesstointernationally-leadingacademicsandtopresearcherswithexpertiseinprocessdevelopment,vaccinology,analyticaldevelopment,GMPmanufacturinganddecisionaltoolsAbilitytosteertheresearchagendaoverthenext2years,alignedtoyourorganization’sprioritiesandthehubvisionandremitEarlyaccesstoHuboutputs(newmethodologiesandtechnologies)viatheCollaborationAgreementParticipationinvouchersorfeasibilitystudiestoevaluateHuboutputsusingyoursystemsandprocessesLeveragefundingforgreaterimpactviaindustry-ledInnovateUKprojectsOpportunityforwidercollaborationviatheEngineeringDoctorate(EngD)studentshipsAccesstohighlyskilledgraduatingdoctorateandresearchers
Driving the research agenda
Access to funding, outputs and skillset
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
PlatformOperations
InteractionvouchersCall8vouchersintotal,budgetofupto£10Kpervoucher(<6monthsduration)AvailabletoUsersgroupmembersonlyMustbringtogetheranytwoorganizations(includingacademia-industrypartnerships)FeasibilityprojectsCall(early2020)Minimumof6projects,£100Keach(<12monthsduration)
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
UpcomingeventsVax-HubUsersGroupmeeting–8thNovemberVouchersInteractionSubmissiondeadline–4th
NovemberFormoreinformationandnews
BiochemicalEngineeringDepartmentWebsite@VaxHub
ForhowtobecomeamemberPleasecontactDrNavGill([email protected])
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University College London The Jenner Institute London School of Hygiene & Tropical Medicine Imperial College London University of Leeds
Acknowledgements/Thankyou
AdenovirusplatformmanufacturingDrSandyDouglasProfessorSarahGilbertDrFatemehVahidDastjerdiVLPVaccinesDrSaraPlacemente,DrSteffiFrankDrSalomeDeSaMalaghaes,ProfEliKeshavarz-MooreGlycoconjugatesDrMartaMauri,ProfBrendanWrenDrJasminSamaras