pulmonary mucosal bcg vaccination shows protection of...
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PulmonarymucosalBCGvaccinationshowsprotectionofinfectioninanovelrepeatedultra-low
dosechallengemodelinrhesusmacaques.FrankVerreck
5thGlobalForumonTBVaccines[OA-04]21February2018,NewDelhi
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Biomedical Primate Research Centre Committed to health researchand alternatives
UsingMacaqueSpeciesinTBVaccineResearch
tosupportpreclinicalvaccinedevelopmentbyefficacytesting
toinvestigatemechanismsofdiseaseandprotectiveinfection
exploratory rsrch
applied rsrch
Macacamulattarhesus
Macacafasciculariscynomolgus
vaccine R&D
biomarker R&D
translation
back-translation& verification
• naturallysusceptibletoMtb• greatfacevalidityofTBinmanyaspects
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Today'sPresentation
• onoptimizingmodelconditionsforvaccineefficacyevaluationinrhesusmacaquesultimatelydemonstratingthefeasibilityofRepeatedUltra-LowDose(RULD)infectionasusefulmodellingcondition
• oninvestigatingmechanismsofdiseaseandofprotectiveimmunity,towardscorrelates/biomarkersfindinglocalpolyfunctionalIL17+CD4cellsandspecificimmunoglobulinsasdistinctivemarkersofprotection
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Standardising NHPTBStudiesforVaccineResearch
hostRhesus(Macacamulatta)M.tuberculosischallengestrainErdmanK01(harmonisationstrain,fromBEIResources,USA)byendobronchialinstillationBCGvaccinestandardhumandoseofstrainMoscow(a.k.a.Sophia),whileinearlierstudiesusingDanish1331
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SingleHighDose(500CFU)MtbChallenge
time-to-humane-endpoint (survival)highdose
Modusofreadout
ModusofInfection
12monthsfollow-up,groupsizeN=12Verreck etal(unpublished)
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SingleHighDose(500CFU)MtbChallenge
time-to-humane-endpoint (survival)highdose
Modusofreadout
ModusofInfection
advanced diseasehighdose
✓
12weeksfollow-up,groupsizeN=6Verreck etal(PLoSOne)2009
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IsHighDoseChallengeinRhesusTooStringentforTBVaccineEvaluation?
time-to-humane-endpoint (survival)highdose
Modusofreadout
ModusofInfection
advanced diseasehighdose
✓• 100%infection takeinnv.ctrls• rapid onset toprogressiveTB(≤12wks)• powerto demonstrate reductionofTB
(relative to nv.ctrls) with group size N=6only
BUT• unable to demonstrate
statistically significantimprovement overBCG;findingpositiveindicatorsonly
✓
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PulmonaryBCGprotectswherestandardBCGfails
time-to-humane-endpoint (survival)highdose
Modusofreadout
ModusofInfection
advanced diseasehighdose
✓
✓
cohortA
Corroboratingandextendingbeyondearlierstudiesshowingthesuperiorityofi.v.>pulm>i.dBCGadministrationinNHPBarclayetal(1970)AmJRev;
Barclayetal(1973)IAIVerreck etal(2017)
Tuberculosis
cohortB
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Working towards "low"dose infection modelling
time-to-humane-endpoint (survival)highdose
advanced diseasehighdose
milddiseaselowdose
infection(and/ormilddisease)
repeatedlowdose
infection(a/omilddisease)
naturaltransmission
Modusofreadout
ModusofInfection
✓
✓
✓
?
12monthsfollow-up,groupsizeN=12
12weeksfollow-up,groupsizeN=6
10to25CFUNHPTBResearchCommunityofCTVD
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FindingthelowestamenabledoseforRLDinfectionacomparativeinfectiondose-escalationstudyinrhesusversuscynomolgus
challenge(0.5(CFU(
immune((monitoring(
+ve(
yes$
no$
challenge(2.5(CFU(
immune((monitoring(
+ve(
yes$
no$
challenge(12.5(CFU(
immune((monitoring(
+ve(
yes$
no$
challenge(62.5(CFU(
immune((monitoring(
+ve(
yes$
endpoint(evalua<on(@(wk(6+(
endpoint(evalua<on(@(wk(12+(
if$N≥5,$then$for$N=½n$
endpoint(evalua<on(@(wk(6+(
endpoint(evalua<on(@(wk(12+(
if$N≥5,$then$for$N=½n$
endpoint(evalua<on(@(wk(6+(
endpoint(evalua<on(@(wk(12+(
if$N≥5,$then$for$N=½n$
endpoint(evalua<on(@(wk(6+(
endpoint(evalua<on(@(wk(12+(
if$N≥5,$then$for$N=½n$
0 4 8 12
0
25
50
75
100
Study Weeks (post-primary infection)
%
Time to IGRA conversion
CynoRhesus
0.2 CFU 1.3 CFU 7 CFU
K.Dijkman etal.(inpreparation)VisitposterPD-10,ondiseasesusceptibilityandimmuneprofilesofrhesusversuscyno
KarinDijkman,Ph.D student
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Repeated Ultra-LowDose (RULD)Infectious Challengean alternative study designinrhesus (N=8pergroup)toward readout ofPoI
K.Dijkman etal.(inpreparation)
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IGRAresponsedynamics overtimeby specific IFNg ELISPOT
PPDstimulated ESAT6-CFP10stimulated
K.Dijkman etal.(inpreparation)
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Mucosal BCGshowssignificantly delayedIGRAconversion,aPoIsignal
K.Dijkman etal.(inpreparation)
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Mucosal BCGsignificantly reduces pathology
K.Dijkman etal.(inpreparation)
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Mucosal BCGsignificantly reduces bacterialload
K.Dijkman etal.(inpreparation)
pathology
bacteriology
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CD4Tcells inBALby multi-labelflow-cytometry,8weekspost-vaccination
mucosal BCGinduces highest cyk levelsandan exclusive IL17signal
IFNg TNFa IL-2 IL-17A
NVIFNg
BCGIFNg
MUCIFNg
0
2
4
6
20
40
60
80
% c
yto
kin
e p
ost
ive
0.000155
0.0006220.00109
NVTNFa
BCGTNFa
MUCTNFa
0
2
4
6
20
40
60
80%
cyt
oki
ne
po
stiv
e0.000155
0.0006220.00171
NVIL-2
BCGIL-2
MUCIL-2
0
2
4
6
20
40
60
80
% c
yto
kin
e p
ost
ive
0.000155
0.0003110.000622
NVIL-17A
BCGIL-17A
MUCIL-17A
0
2
4
6
20
40
60
80
% c
yto
kin
e p
ost
ive
0.000155
0.0001550.0595
*** *** *** ********* ****** ****** ***
K.Dijkman etal.(inpreparation)
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mucosal BCGexcl.induces alocal poly-functionalTh17response
K.Dijkman etal.(inpreparation)
wk8post-vaccination
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mucosal BCGinducesspecific localIgGandIgA
K.Dijkman etal.(inpreparation)
BALflu
id
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SummarizingConclusionsRULDchallengeisafeasiblestrategyforenhancedvaccineefficacyreadoutinrhesustowardPoIandPoDsignals
showingmoresubtleTBinfectionanddiseasephenotypes
PulmonarymucosalBCGvaccinationinNHP(again)issuperioroverstandardintradermal BCGadministration
bydelayedIGRAconversionandsignificantreduction ofpathologyandbacterialload(noCFUdetectablein2outof8)
Local,Ag-specific,multi-functional IL17+CD4+Tcellsand IgG&IgA appearascorrelatesofprotectiveimmunity
LocalmucosalvaccinationperseandperhapspulmonaryBCGadministrationinparticular,providesagreatperspectiveforimprovedBCGvaccinationorBCGre-vaccinationtofightTB
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AcknowledgementsBPRC,TBResearch&Immunology
KarinDijkman
RichardVervenneClaudiaSombroekSamHofmanCharelBoot
M.A.KhayumKristaHaanstraMichelVierboom
BPRC,AnimalScience DepartmentPathology TeamClincal LabAnimalCARE TeamVetCARE Team
LUMC,LeidenTomOttenhoffc.s.