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

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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

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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

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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

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Vaccine Development: most advanced candidates

Sanofi Pasteur – toxoid vaccine (based on toxin A and B)

13PreparedfortheWHO`SProduct

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

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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?

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•  AddiFonal/alternaFvecandidates•  InclusionofBinarytoxins•  InclusionofaddiFonaltoxinBneutralisingepitopes

ToxinB

1N C

Tian2012Vaccine30:4249-58.Leuzzi2013InfectImmun81:2851-60Manard-Smith2014Vaccine32:700-5

Weaknessincurrentapproach•  Vaccineslimittoxinmediatedsymptoms•  Noimpactontransmission

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•  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

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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

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