clostridium difficile · clostridium difficile dr gill douce university of glasgow 1 prepared for...
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Clostridium difficile
Dr Gill Douce University of Glasgow
1
PreparedfortheWHO`SProductDevelopmentVaccineAdvisoryCommi?ee,
June2016
The organism
2 PreparedfortheWHO`SProduct
DevelopmentVaccineAdvisoryCommi?ee,June2016
• GramposiFve,obligateanaerobe
Mildtoseverediarrhoealdisease/otherinflammatorycomplicaFons
Asmall%ofstrainscarryathirdtoxin–Binarytoxin
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 3
RiskFactors• Increasingage• Lengthofhospitalstay• AnFbioFcuse• Co-morbidiFes
Impactofdisease• US-500,000infecFons*• 29,000deaths*• Increasein30daypaFent
mortality*LessaN.EngJMed2015372:825-34
EconomicburdenLOS:primary9.5days1recurrent20daysCost:primary$16,930recurrent$36,683Drugs:primary$60secondary$140Shah:JournalofhospitalinfecFon2016
• RecurrentinfecFonDiseaseBurden
Changingepidemiology
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 4
IncreasedratesofinfecFonintheUK
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Heetal2013NatureGeneFcs45:109-113
• About25%ofCDIsinUSareduetoCD027
CurrentintervenFons• Prudent antibiotic prescribing
– Avoid 4C antibiotics in vulnerable population • Fluoroquinolones • Clindamycin • Co-amoxy-clav, • 3rd generation cephalosporins
– Narrow spectrum antibiotics • Fidixamicin
• Enhanced infection control – Hand washing/disinfection – Environmental decontamination – Isolation/cohort nursing
• Faecal transplantation – Re-establish microbiome diversity
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 6
Theunmetneed
• No prophylactic treatment available • Treatments effective
– Withdrawal can initiate recurrent infection • Changes in Transmission
– Increased acquisition in community • disease reported in younger population
• Global Surveillance – Early warning for emergence of virulent types
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TargetgroupsforvaccinaFon
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Leffler,DA,Lamont,JTN.EnglJMed2015372:1539-1548
Vaccine Development: Background• CorrelaFonbetweentoxinneutralisinganFbodyinhumanserumand
diseaseprotecFon– AgainsttoxinA–acutediarrhoea– AgainsttoxinB–severe,relapsingdisease
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 9Lyerly1990CurrMicrobiol21:29-32
• Toxinsasvaccines-Complexityandsizeofprotein/difficulttoproduce
308KDa
270KDa
Animal models of disease • SyrianGoldenHamster
– Modelofacutetoxinmediateddisease• Diarrhoea• Pathology• Fatal• PreclinicaltesFng
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CorrelatesofProtecFon–ToxinNeutralisingAcFvity(TNA)
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Toxinmediateddamage
CombininganF-serumfromvaccinatedpaFentswithtoxin–capacitytolimittoxinmediateddamagecanbequanFfied 0.1 1 10 100 1000 10000 100000
0
20
40
60
80
100High level ofneutralisingactivity
Low level ofneutralisingactivity
Dilution of antisera
% o
f cell
s sho
wing
cell r
ound
ing
VaccineCandidateSelecFoncriteria
• Strong neutralising activity • Prevention of fatal disease/symptoms/
pathology in hamsters • Protection against multiple C. diificile
types including epidemic hypervirulent 027 strains
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 12
Vaccine Development: most advanced candidates
Sanofi Pasteur – toxoid vaccine (based on toxin A and B)
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DevelopmentVaccineAdvisoryCommi?ee,June2016
Valneva/SKB – Recombinant fragment encode binding domains of both toxins
1 2366
Pfizer – genetically detoxified toxins expressed in non-toxic C. difficile
C
DXDtoAXA 27101CN
DHCtoDHA
Glucosyltransferase BindingDomain
2366
ToxinB
1
ToxinA Autoprotease Delivery/PoreFormingDomain
27101C
N C
N
ClinicalData
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 14
Vaccinetype Age Dose +/-Adjuvant
Schedule(days) OpFmalformulaFon
ReadoutTNA
Sanofi/Pasteur1
40-75 50-100ug +-
0,7,300,7,30,180
100uginAl(OH3)0,730
97%toxA64%toxB
Pfizer2 50-85 50,100,200ug
+-
1,28,180 100-200ugNoadjuvant
Aveincrease3foldtoxA4foldtoxB
Valneva3 18-65>65
20,75,200ug +-
0,7,210,7,21,56
75ugNoadjuvant1,7,21,56
4foldin70%totoxinAand80%totoxinB
1. ReportedPhaseIIDeBryn2016Vaccine34:2170-78.,iniFatedphaseIII2. ReportedPhaseISheldon2016Vaccine34:2082-91,completedphaseII3. ReportedPhaseIBezay201634:2585-92,completedphaseII
Most promising approaches • AllcandidatessuccessfulinphaseIIstudies
– Healthyadults(40-85)– Safe/welltolerated– Immunogenic/NeutralisingacFvity
• ObservaFons– Slightlylessefficaciouselderly(65+)versus40-65group– Lessrequirementforadjuvant(Pfizer/Valnevavaccines)– NoandFmingofvaccinaFons
• CorrelaFonofTNAtoProtecFon?
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 15
• AddiFonal/alternaFvecandidates• InclusionofBinarytoxins• InclusionofaddiFonaltoxinBneutralisingepitopes
ToxinB
1N C
Tian2012Vaccine30:4249-58.Leuzzi2013InfectImmun81:2851-60Manard-Smith2014Vaccine32:700-5
Weaknessincurrentapproach• Vaccineslimittoxinmediatedsymptoms• Noimpactontransmission
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 16
• Vaccinatedindividuals-remainasilentsourceofinfecFon?
• TargetanFgensreducecolonisaFonand/orsporulaFon
• PossiblecandidateanFgens• Cwp84,66,fli,slpA,sporeproteins
Assessment
• Current Vaccines in development – Potential to be effective against symptomatic
primary and recurrent CDI • Require confirmation efficacious in vulnerable
populations
• Further optimization work required – Inclusion of
• additional toxin neutralising epitopes and antigens to prevent transmission
– Spore proteins, S layer, cwp84, flagella
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PreparedfortheWHO`SProductDevelopmentVaccineAdvisoryCommi?ee,
June2016
PotenFalRoleforWHO• Improve
– Awareness and diagnosis of CDI worldwide • Encourage
– Adoption of National Surveillance within countries – Early warning of emergence of virulent types
• Reduceincidence– Setpolicy/guidelinestoreducFon/restricFonofanFbioFcuse
• Especiallyfluoroquinoloneuse–limitspreadofepidemic027strains• TargetvaccinaFon
– toappropriate/vulnerablepopulaFons• Encourage
– FurtherdevelopmentandopFmisaFontoensurevaccinesarebotheasytomanufactureandefficacious
PresentaFontoWHOVaccineAdvisory
Commi?ee,8-19thJune2016 18
• PassiveImmunisaFon• Merek–ivinfusionasadjuncttostandardanFbioFctreatment• BezlotoxumabinphaseIIIstudies(toxinB)
• Actoxumab(toxinA)-?ProphylacFc?
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• MicrobiomeReplacement• RebioFx-Standardisedmicrobiotasuspension/RestoraFontherapy
formicrobiome• Future
• CombinaFonofdefinedbacteriathatlimitsporegerminaFon
• AnFbioFcBindingResin• DaVolterra–charcoalbasedresin
• BindexcessanFbioFcsingut• Minimalchangestomicrobiome
Vaccination – not the only approach?
THANKYOU
PresentaFontoWHOVaccineAdvisoryCommi?ee,8-19thJune2016 20