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Virus spillover: EbolaJonathan.ball@nottingham.ac.uk@Jonathan Ball

Revelations 6:7-8I looked, and there before me was a pale horse! Its rider was named Death, and Hades was following close behind him. They were given power over a fourth of the earth to kill by sword, famine and plague, and by the wild beasts of the earth.

1st September 1976Yambuku Mission Hospital, Zaire

Mabalo Lokela, 44year old male schoolteacher,presents with unexplained haemorrhagic fever

One week later the mission hospital closed following the death of 11 of the 17 staff members

Peter Piots team identified the cause as a new Filovirus

EbolaNot wanting to stigmatise the village by naming the virus after it, they gave it the name of a nearby river:

Outbreak chronology1976, Zaire (DRC): 318 cases 280 deaths

Zaire EBOV

Outbreak chronology1976, Sudan: 284 cases 151 deathsSudan EBOV

Outbreak chronology1976, Porton Down, England: 1 case - recoveredSudan EBOV

Outbreak chronologyFurther small outbreaks were seen in Zaire and Sudan during the 1970s

Outbreak chronology1989-92, the Philippines, USA then Italy: 7 asymptomatic cases 0 deathsReston EBOV

Outbreak chronologyIn Africa, during the 1980s, no Ebola cases were reported. But the subsequent decades saw outbreaks in:

Outbreak chronologyTai Forest1 cases 0 deaths

Tai Forest EBOV

Outbreak chronologyGabon:1994, 52 cases 31 deaths1996, 60 cases 42 deaths2001, 65 cases 53 deaths

Zaire EBOV

Outbreak chronologyRepublic of the Congo:2001, 57 cases 43 deaths2002, 143 cases 128 deaths2003, 35 cases 29 deaths

Zaire EBOV

Outbreak chronologyUganda:2000, 425 cases 224 deathsSudan EBOV

2007, 149 cases 37 deathsBundibugyo EBOV

2011, 1 case 1 deaths2012, 6 cases 3 deaths

Outbreak chronologySudan and especially Zaire (DRC), the countries most affected during the early phases, continued to see outbreaks

Outbreak chronologySudan: 2004, 17 cases 7 deaths

Outbreak chronologyZaire (DRC): 1995, 315 cases - 250 deaths2007, 264 cases - 187 deaths2008, 32 cases 15 deaths

Zaire EBOV

2012, 36 cases 13 deathsBundibugyo EBOV

Outbreak chronologyAll outbreaks had been contained and case numbers kept well below 1,000.

Outbreak chronologyThat was until:

Year 2014 - West Africa

CountryCase definitionCumulative casesCumulative deathsGuineaConfirmed1647958Probable208208Suspected640All19191166LiberiaConfirmed2562*Probable1716*Suspected2600*All68782812**Sierra LeoneConfirmed4683978Probable79174Suspected82435All55861187Total143835165The largest outbreak ever recorded

Exponential growth

Patient zero - Guinea

What is EbolavirusVirus belonging to family FiloviridaeOther members are Marburgvirus and CuevavirusEbolavirus genus contains five species with four restricted to Africa and one S.E. AsiaZaire, Sudan, Bundibugo and Tai Forest (Africa) and Reston (Asia)Varies from non-pathogenic (Reston) to highly pathogenic (Zaire)Ebolavirus & reservoirs

EnzooisEpizoonosisZoonosis

?

Bausch D G et al. J Infect Dis. 2007;196:S142-S147 2007 by the Infectious Diseases Society of AmericaTransmission vehiclesVirus culture and reverse-transcription polymerase chain reaction (RT-PCR) results from 54 clinical samples collected from 26 patients with laboratory-confirmed Ebola hemorrhagic fever.Ebola transmission

Replication and the art of camouflage

Ebolavirus pathogenesis

Winning the fight in West AfricaTried and tested versus

Experimental and unknown

Therapeutic approachesInvestigational drugsAntiviralConvalescent seraMonoclonal antibody combinationsZmappReplication inhibitorssiRNA (Tekmira)Favipiravir (Fuji Films)

Symptom-targetingSeptic shockE.g. Statins

Therapeutic antibodies: ZMapp

PCR

Therapeutic antibodies: ZMapp

X Qiu et al. Nature 000, 1-7 (2014) doi:10.1038/nature13777 Days post-infectionDays post-infectionDays post-infection100% survival in experimental NHPsIn real-life humans 5/7 survived?Investigational drugsSupply issuesEspecially for biologics: Only a few treatments of ZmappUnknown safety profilesSome antiviral s trialled in other settings (e.g. Favipiravir for influenza) but Ebola differentCost (long-term)Ebolavirus vaccinesReplication-deficient viruses genetically modified to express Ebolavirus proteinVesicular Stomatitis VirusChimapanzee AdenovirusModified Vaccinia AnkaraZaire proteins or Zaire and SudanPhase I underway

Immunological goal is induction of effective antibody and CD8 T cell responses for both short and long term protectionThe Okairos vaccine is based on the surface glycoprotein GPViral Vectors encoding the Ebola GP

Chimpanzee Adeno 3(ChAd3)

MVA33105158227313464501502672GP2GP1Furin cleavage5546511676SPRBSGlycan CapMucinIFLTMSP: signal peptideRBS: receptor binding siteIFL: internal fusion loopTM: transmembrane anchorGuinea 2014 changes shown in redEbola Zaire GP DNA

(1010 vp)Survival (% protected)Vaccine EfficacyHuman rare serotype Ad35 and Ad26 fail to protect against Ebola challengeSelection of Alternative Adenovirus VectorsFor an Ebola VaccineStrategy to Identify a Lead Ebola Vaccine Candidate

Weeks rAd Ebola viruschallenge123401: Identify prime(s) that provides uniform protection against short term challenge2: Define regimen that induces durable immunityWeeks Ebola viruschallenge520

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or MVA 42Three platforms, all encoding Ebola GP as the vaccine targetDNA prime/Ad boost provides long lasting immunity (boost greater than one year after primerAd provides rapid immunityFor all of the vaccines that include rAd5 as a prime or boost, antibody against Ebola is the immune correlate of protection (important determination for licensure using the FDA animal rule)First generation vaccines were based on Ad5 but high titer prior immunity can interfere with vaccineTherefore, have moved to alternative serotype rAd vectors that demonstrate low or no preexisting immunity in humans Durable protection ChAd3Ebolavirus challenge

ChAd3 GP n = 4 /group Months: 0 1 2 3 4 5 One year Ebolavirus challenge % Protection 100 80 60 40 20 0 Ad5ChAd3Acute protectionChAd3-ZEBOV priming induces 50% protection from EBOV challenge at one year: need for boosting Stanley D, Nat Med. 2014

Durable protection ChAd3Ebolavirus challenge

ChAd3 GP n = 4 /group Months: 0 1 2 3 4 5 One year Ebolavirus challenge MVA GP% Protection 100 80 60 40 20 0 Ad5ChAd3Acute protectionChAd3-ZEBOV prime/MVA-ZEBOV boost induces 100% protection from EBOV at one yearChAd3/MVA Stanley D, Nat Med. 2014

Ebolavirus vaccines

Vaccination GSK long-term protectionVectorDose (PU)ProtectionaSingle shotChAd31 10112/450%ChAd31 10100/40%Prime-boostChAd3/ChAd31 1010/1 10101/333%ChAd3/ChAd631 1010/1 10101/425%ChAd3/MVA1 1010/1 1084/4100%Vaccine ethical dilemmas VSV-EBOV versus GSK ChAd or ChAd/MVA?Trial naturePlaceboStepped wedge trialWhere and who?Phase II or Phase II/IIIThe gains from increased effort

SummaryEbolavirus has been knocking on the door for a very long timeThe current outbreak unprecedentedPerfect storm for the virusFuture?Endemic?EradicatedHow?

Useful resourcesEbola outbreak and response mapshttp://maps.who.int/MapGallery/WHO situation reportshttp://www.who.int/csr/disease/ebola/situation-reports/en/CDC Ebola factshttp://www.cdc.gov/vhf/ebola/index.html