A Phase 1, Dose Escalation, Open-Label Clinical Trial With Experimental Controlled Human Malaria Infections (CHMI) to Evaluate Safety and Protective Efficacy of an Anti-Malaria Human Monoclonal Antibody, VRC-MALMAB0100-00-AB (CIS43LS), in Healthy, Malaria-Naive Adults
Phase: PHASE1
Conditions: Malaria
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Protocol Title: A Phase 1, Dose Escalation, Open-Label Clinical Trial with
ExperimentalControlledHumanMalariaInfections(CHMI)toEvaluateSafetyand
Protective
Efficacy
of
an Anti-Malaria
Human
Monoclonal
Antibody,
VRC-MALMAB0100-00-AB
(CIS43LS),
in
Healthy,
Malaria-Naive
Adults
(VRC612)

NCT:04206332

Protocol(v8.026OCT2021)-StatisticalAnalysisConsiderationslocatedinSection6
oftheProtocol




Version8.0
October26,2021

VACCINERESEARCHCENTER

ProtocolVRC612
(NIH20I0017)

Title:APhase1,DoseEscalation,Open-LabelClinicalTrialwithExperimentalControlled
HumanMalariaInfections(CHMI)toEvaluateSafetyandProtectiveEfficacyofanAnti-
MalariaHumanMonoclonalAntibody,VRC-MALMAB0100-00-AB(CIS43LS),in
Healthy,Malaria-NaiveAdults

AbbreviatedTitle:APhase1TrialtoEvaluateCIS43LSinHealthyAdults


INDSponsor
VaccineResearchCenter(VRC)
NationalInstituteofAllergyandInfectiousDiseases(NIAID)
Bethesda,Maryland,US

IND142,632

InvestigationalProductCIS43LSManufacturer:
VaccineClinicalMaterialsProgram(VCMP)operatedundercontract
byLeidosBiomedicalResearch,Inc.,
Frederick,Maryland,US


NIHPrincipalInvestigatorand
ProtocolChair:
MartinGaudinski,M.D.
ClinicalTrialsProgram
VRC/NIAID
UMBPrincipalInvestigator: KirstenLyke,M.D.
UniversityofMarylandSchoolofMedicine
CenterforVaccineDevelopmentandGlobalHealth

APhase1TrialtoEvaluateCIS43LSinHealthyAdults
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TABLEOFCONTENTS

TABLEOFCONTENTS.................................................................................................................2
LISTOFTABLES...........................................................................................................................5
ABBREVIATIONS.........................................................................................................................7
PRINCIPALINVESTIGATORPROTOCOLSIGNATUREPAGE.............................................9
PRÈCIS
....................................................................................................................................10
STATEMENTOFCOMPLIANCE...............................................................................................11
1.
INTRODUCTION......................................................................................................12
1.1.
StudyRationale...........................................................................................................12
1.1.1.
CIS43LSDevelopment...............................................................................................12
1.1.2.
StudyDesign...............................................................................................................13
1.2.
Background.................................................................................................................14
1.2.1.
PreviousHumanExperience.......................................................................................14
1.2.2.
ControlledHumanInfections(CHI)...........................................................................15
1.3.
LaboratoryAssessmentsofCIS43LS.........................................................................15
1.3.1.
Pharmacokinetic(PK)Analysis..................................................................................16
1.3.2.
DetectionofAnti-DrugAntibody...............................................................................16
1.4.
MeasuresofmAb-MediatedProtectionandParasitemia...........................................16
2.
STUDYPRODUCTANDCHMI..............................................................................18
2.1.
StudyProduct:CIS43LS.............................................................................................18
2.2.
PreclinicalExperience................................................................................................18
2.2.1.
InvitroStudies............................................................................................................18
2.2.2.
InvivoStudies.............................................................................................................18
2.3.
ClinicalExperience.....................................................................................................20
2.4.
ControlledHumanMalariaInfection(CHMI)...........................................................21
3.
STUDYOBJECTIVES..............................................................................................22
3.1.
PrimaryObjectives.....................................................................................................22
3.2.
SecondaryObjectives.................................................................................................22
3.3.
ExploratoryObjectives...............................................................................................22
4.
STUDYDESIGNANDCLINICALPROCEDURES...............................................23
4.1.
StudyPopulation.........................................................................................................24
4.1.1.
InclusionCriteria........................................................................................................24

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4.1.2.
ExclusionCriteria.......................................................................................................25
4.2.
InclusionofVulnerableSubjects................................................................................26
4.2.1.
Children......................................................................................................................26
4.2.2.
ParticipationofSiteEmployees..................................................................................26
4.3.
ClinicalProceduresandEvaluations..........................................................................27
4.3.1.
RecruitmentandRetention.........................................................................................27
4.3.2.
Screening....................................................................................................................28
4.3.3.
EnrollmentandStudyDay0.......................................................................................28
4.3.4.
ProductAdministration...............................................................................................29
4.3.5.
Post-ProductAdministrationFollow-up.....................................................................29
4.3.6.
SolicitedAdverseEvents(Reactogenicity)................................................................30
4.3.7.
CHMIProcedures.......................................................................................................30
4.3.8.
Post-CHMIFollow-Up...............................................................................................31
4.3.9.
ParasitemiaManagement............................................................................................32
4.3.10.
Follow-UpthroughEndofStudy...............................................................................32
4.4.
ConcomitantMedications...........................................................................................33
4.5.
DoseEscalationPlan..................................................................................................33
4.6.
CriteriaforDiscontinuationofProductAdministrationorProtocol
Participation................................................................................................................34
4.6.1.
DiscontinuationofStudyProductAdministration.....................................................34
4.6.2.
DiscontinuationfromProtocolParticipation..............................................................34
4.7.
CriteriaforPausingandResumingtheStudy.............................................................35
4.7.1.
PlanforReviewofPausesandResumingRules........................................................35
5.
SAFETYANDADVERSEEVENTS........................................................................36
5.1.
AdverseEvents...........................................................................................................36
5.2.
SeriousAdverseEvents..............................................................................................36
5.3.
AdverseEventReportingtotheINDSponsor...........................................................37
5.4.
INDSponsorReportingtotheFDA...........................................................................37
5.5.
ReportingtotheInstitutionalReviewBoard..............................................................38
5.5.1.
UnanticipatedProblem...............................................................................................38
5.5.2.
Non-Compliance.........................................................................................................38
5.5.3.
ProtocolDeviation......................................................................................................39
5.5.4.
Death...........................................................................................................................40

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5.5.5.
NewInformation.........................................................................................................40
5.5.6.
SuspensionorTerminationofResearchActivities....................................................40
5.5.7.
ExpeditedReportingtotheIRB.................................................................................40
5.5.8.
AnnualReportingtotheIRB......................................................................................40
6.
STATISTICALCONSIDERATIONS.......................................................................41
6.1.
Overview.....................................................................................................................41
6.2.
SampleSizeandAccrual............................................................................................41
6.3.
StatisticalAnalysis......................................................................................................42
6.3.1.
AnalysisVariables......................................................................................................42
6.3.2.
SafetyAnalysis...........................................................................................................42
6.3.3.
PharmacokineticsAnalysis.........................................................................................43
6.3.4.
EfficacyAnalysis........................................................................................................44
6.3.5.
Interimanalyses..........................................................................................................45
7.
PHARMACYPROCEDURES...................................................................................46
7.1.
StudyProduct..............................................................................................................46
7.2.
StorageandTemperatureExcursions.........................................................................46
7.3.
LabelingofStudyProductVial..................................................................................46
7.4.
PreparationofStudyProductforAdministration.......................................................46
7.4.1.
PreparationforIVAdministration..............................................................................46
7.4.2.
PreparationforSCAdministration.............................................................................47
7.4.3.
HandlingofPreparedProductforIVorSCAdministration......................................47
7.5.
StudyProductAccountability.....................................................................................47
7.6.
StudyProductDisposition..........................................................................................48
8.
HUMANSUBJECTPROTECTIONSANDETHICALOBLIGATIONS................49
8.1.
InstitutionalReviewBoard.........................................................................................49
8.2.
InformedConsent.......................................................................................................49
8.3.
StudyDiscontinuationandClosure............................................................................49
8.4.
ConfidentialityandPrivacy........................................................................................50
8.5.
Risk/BenefitAssessment............................................................................................51
8.5.1.
PotentialRisks............................................................................................................51
8.5.2.
PotentialBenefits........................................................................................................52
8.5.3.
AssessmentofPotentialRisksandBenefits...............................................................52
8.6.
PlanforUseandStorageofBiologicalSamples........................................................53

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8.6.1.
UseofSamples,SpecimensandData.........................................................................53
8.6.2.
StorageandTrackingofBloodSamplesandOtherSpecimens.................................53
8.6.3.
DispositionofSamples,SpecimensandDataatCompletionoftheProtocol............53
8.6.4.
LossorDestructionofSamples,SpecimensorData..................................................53
8.7.
SafetyOversight.........................................................................................................54
9.
ADMINISTRATIVEANDOPERATIONALOBLIGATIONS................................55
9.1.
ProtocolAmendmentsandStudyTermination...........................................................55
9.2.
StudyDocumentationandStorage.............................................................................55
9.3.
ClinicalMonitoring....................................................................................................55
9.4.
DataCollectionandSharing.......................................................................................56
9.4.1.
DataCollection...........................................................................................................56
9.4.2.
SourceDocuments......................................................................................................56
9.4.3.
DataSharing...............................................................................................................56
9.5.
QualityAssuranceandQualityControl......................................................................56
9.6.
Language.....................................................................................................................57
9.7.
Research-RelatedInjuries...........................................................................................57
9.7.1.
NIH.............................................................................................................................57
9.7.2.
WRAIR.......................................................................................................................57
9.7.3.
UMB...........................................................................................................................57
9.8.
CHMIFacilitiesandManagement..............................................................................58
9.8.1.
RolesandResponsibilitiesfortheCHMI...................................................................58
9.9.
WRAIRProtocolReviewandReportingRequirements............................................58
10.
REFERENCES...........................................................................................................60
APPENDIXI:SCHEDULEOFEVALUATIONS.......................................................................62
PARTASCHEDULES.................................................................................................................63
PARTBSCHEDULES..................................................................................................................66
PARTCSCHEDULES..................................................................................................................73
APPENDIXII:ASSESSMENTOFAERELATIONSHIPANDSEVERITYGRADING.........83

LISTOFTABLES
Table1:
StudySchema.............................................................................................................23
Table2:
ProbabilityofEventsforDifferentSafetyScenarioswithinaGroup(n=6or
4).................................................................................................................................41

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Table3:
95%ConfidenceIntervalsfortheTrueRateatPossibleObservedNumberof
EventsinaGroup(n=6orn=4)oracrossGroups(n=24)..........................................42

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ABBREVIATIONS

Abbreviation
Definition
ADA
Anti-DrugAntibody
AE
Adverseevent
ALT
Alanineaminotransferase
ANA
Anti-nuclearantibody
AST
Aspartateaminotransferase
CBC
Completebloodcount
cGLP
CurrentGoodLaboratoryPractices
cGMP
CurrentGoodManufacturingPractices
CHI
Controlledhumaninfection
CHMI
Controlledhumanmalariainfection
CMP
ComprehensiveMetabolicPanel
CRF
CaseReportForm
CRO
ContractResearchOrganization
CSP
Circumsporozoiteprotein
CTP
ClinicalTrialsProgram
DoD
DepartmentofDefense
DoDI
DepartmentofDefenseInstruction
DNA
DeoxyribonucleicAcid
DOT
Directlyobservedtherapy
EKG
Electrocardiogram
ELISA
Enzyme-linkedimmunosorbentassay
FDA
FoodandDrugAdministration
GCP
GoodClinicalPractice
HBsAg
HepatitisBsurfaceantigen
HCV
HepatitisC virus
HIV
HumanImmunodeficiencyVirus
HRPP
HumanResearchProtectionsProgram
HSBP
HumanSubjectsProtectionBranch
ICH
InternationalConferenceonHarmonization
IND
InvestigationalNewDrugApplication
IV
Intravenous
LIMS
LaboratoryManagementInformationSystem
mAb
MonoclonalAntibody
MCG
Micrograms
MedDRA
Medicaldictionaryforregulatoryactivities
MO
MedicalOfficer
NAT
Nucleicacidtest
NHP
Non-HumanPrimate
NIAID
NationalInstituteofAllergyandInfectiousDiseases
NIH
NationalInstitutesofHealth
NIHCC
NIHClinicalCenter

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Abbreviation
Definition
PBMC
Peripheralbloodmononuclearcell
PCR
PolymeraseChainReaction
Pf
Plasmodiumfalciparum
PfCSP
Plasmodiumfalciparum circumsporozoiteprotein
PfSPZ
Plasmodiumfalciparum whole-sporozoite
PI
PrincipalInvestigator
PK
Pharmacokinetics
PSRT
ProtocolSafetyReviewTeam
QA
QualityAssurance
RBC
Redbloodcells
rPfCSP
RecombinantPlasmodiumfalciparum circumsporozoiteprotein
SAE
Seriousadverseevent
SARS-CoV-2
Severeacuterespiratorysyndromecoronavirus2
SC
Subcutaneous
SPZ
Sporozoite
SUSAR
Seriousandunexpectedsuspectedadversereaction
ULN
Upperlimitofnormal
UMB
UniversityofMaryland,Baltimore
U.S.
UnitedStates
UPnonAE
UnexpectedProblemthatisnotanAdverseEvent
VCMP
VaccineClinicalMaterialsProgram
VEC
VaccineEvaluationClinic
VIS
VolunteerInfectionStudies
VIP
VaccineImmunologyProgram
VRC
VaccineResearchCenter
WBC
Whitebloodcells
WHO
WorldHealthOrganization
WRAIR
WalterReedArmyInstituteofResearch

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PRINCIPALINVESTIGATORPROTOCOLSIGNATUREPAGE

VRC612:APhase1,DoseEscalation,Open-LabelClinicalTrialwithExperimental
ControlledHumanMalariaInfections(CHMI)toEvaluateSafetyandProtective
EfficacyofanAnti-MalariaHumanMonoclonalAntibody,VRC-MALMAB0100-00-AB
(CIS43LS),inHealthy,Malaria-NaiveAdults

I,thePrincipalInvestigatorforthestudysiteindicatedbelow,agreetoconductthestudyinfull
accordancewiththeprovisionsofthisprotocolandallapplicableprotocol-relateddocuments.I
agreetoconductthestudyincompliancewithUnitedStates(US)HealthandHumanServices
(HHS)regulations(45CFR46);applicableUSFoodandDrugAdministration(FDA)regulations;
standardsoftheInternationalConferenceonHarmonizationGuidelinesforGoodClinicalPractice
(E6);InstitutionalReviewBoard/EthicsCommittee(IRB/EC)determinations;allapplicablein-
country,state,andlocallawsandregulations;andotherapplicablerequirements(e.g.,USNational
InstitutesofHealth)andinstitutionalpolicies.Iwillcomplywithallrequirementsregardingthe
obligationsofinvestigatorsasoutlinedintheStatementofInvestigator(FormFDA1572),whichI
havealsosigned.Theprotocolsignaturepagewillbesignedforsubsequentprotocolapprovals.
Iagreetomaintainallstudydocumentationpertainingtotheconductofthisstudy,includingbut
notlimitedto,casereportforms,sourcedocuments,laboratorytestresults,andmedication
inventoryrecords,perFDAregulation(21CFR312.62)andallapplicablerequirements.Nostudy
recordswillbedestroyedwithoutpriorauthorizationfromVRC/NIAID.
PublicationoftheresultsofthisstudywillbegovernedbytheVRC/NIAIDpolicies.Any
presentation,abstract,ormanuscriptwillbemadeavailablebytheinvestigatorstoVRC
Leadershipforreviewpriortosubmission.
Ihavereadandunderstandtheinformationinthisprotocolandwillensurethatallassociates,
colleagues,andemployeesassistingintheconductofthestudyareinformedabouttheobligations
incurredbytheircontributiontothestudy.


_____________________________________________________________________
Name/TitleofPrincipalInvestigator
StudySiteName

___________________________________ __________________________________
SignatureofPrincipalInvestigator Date




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PRÈCIS
Title:
VRC612:APhase1,DoseEscalation,Open-LabelClinicalTrialwithExperimentalControlled
HumanMalariaInfections(CHMI)toEvaluatetheSafetyandProtectiveEfficacyofanAnti-
MalariaHumanMonoclonalAntibody,VRC-MALMAB0100-00-AB(CIS43LS),inHealthy,
Malaria-NaïveAdults.
Design:
ThisisthefirststudyoftheVRC-MALMAB0100-00-AB(CIS43LS)monoclonalantibody(mAb)
targetingthePlasmodiumfalciparum(Pf)circumsporozoiteprotein(PfCSP)inhealthyadults.
Thistwo-part,dose-escalation,adaptivedesignstudywillevaluatethesafety,tolerability,
pharmacokinetics(PK),andprotectiveefficacyofCIS43LS.Theprimaryhypothesisisthat
CIS43LSwillbesafeandtolerablewhenadministeredbyeitherintravenous(IV)orsubcutaneous
(SC)routes.ThesecondaryhypothesesarethatCIS43LSwillbedetectableinhumanserawitha
definablehalf-lifeandconferprotectionfollowingacontrolledhumanmalariainfection(CHMI).
StudyProduct: VRC-MALMAB0100-00-ABwasisolatedanddevelopedbytheVaccineResearchCenter(VRC),
NationalInstituteofAllergyandInfectiousDiseases(NIAID),NationalInstitutesofHealth(NIH)
andbindsauniqueandconservedepitopeatthejunctionoftheN-andrepeatregionsofPfCSP.
Subjects:
Healthysubjects,18-50yearsofage,whoaremalaria-naive.
StudyPlan:
PartA:PartAevaluatedthedosesandroutesasshownbelowintheStudySchematableinan
open-label,doseescalationdesign.
PartB:PartBevaluatedCIS43LSdosesandroutespriortoCHMIinPartAveteransubjectsand
newPartBenrollees.
PartC:PartCwillevaluateCIS43LSdosesandroutesneededtoreachathresholdofprotection
byassessingserumconcentrationpriortoCHMIinadosedowndesign.
VRC612StudySchema
Site
Group
Subjects
CIS43LSAdministration
CHMI
Dose(mg/kg)
Route
PartA
VRC
1
6
5
IV
Cancelled
2
6
5
SC
3
6
20
IV
4A
6
40
IV
4B
3
40
IV
N/A
5
6
Control
Cancelled
PartB
VRC
6
6
5
SC
X
7
61
20
IV
X
8
61
--
--
X
9
6
40
IV
X
10
61,2
Control
X
PartC
UMB
11
7
1
IV
X
12
4
5
IV
X
13
4
5
SC
X
14
4
10
IV
X
15
4
10
SC
X
16
62
Control
X

Total
923
1GroupincludesPartAsubjects
2Two(2)additionalcontrolsubjectswillbeenrolledasCHMIback-ups
3Upto100subjectsmaybeenrolledifneededforadditionalsafetyorefficacyevaluations. 
Duration:
SubjectswhoreceiveCIS43LSwillbefollowedthrough24weeksafterproductadministration.
Controlsubjectswillbefollowedthrough8weeksafterCHMI.

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STATEMENTOFCOMPLIANCE
ThetrialwillbecarriedoutinaccordancewithInternationalConferenceonHarmonisationGood
ClinicalPractice(ICHGCP)andthefollowing:
• UnitedStates(US)CodeofFederalRegulations(CFR)applicabletoclinicalstudies(45
CFRPart46,21CFRPart50,21CFRPart56,21CFRPart312,and/or21CFRPart812)
NationalInstitutesofHealth(NIH)-fundedinvestigatorsandclinicaltrialsitestaffwhoare
responsiblefortheconduct,management,oroversightofNIH-fundedclinicaltrialshave
completedHumanSubjectsProtectionandICHGCPTraining.
Theprotocol,informedconsentform(s),recruitmentmaterials,andallparticipantmaterialswill
besubmittedtotheInstitutionalReviewBoard(IRB)forreviewandapproval.Approvalofboth
theprotocolandtheconsentformmustbeobtainedbeforeanyparticipantisenrolled.Any
amendmenttotheprotocolwillrequirereviewandapprovalbytheIRBbeforethechangesare
implementedtothestudy.Inaddition,allchangestotheconsentformwillbeIRB-approved;a
determinationwillbemaderegardingwhetheranewconsentneedstobeobtainedfrom
participantswhoprovidedconsent,usingapreviouslyapprovedconsentform.

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1.
INTRODUCTION
Malariaisamosquito-borneprotozoandiseasebelongingtothegenusPlasmodiumthataffects
250-500millionpeople,andkillsapproximately500,000individualsannually,withanenormous
economicimpactinthedevelopingworld,especiallysub-SaharanAfrica[1-3].Thefive
recognizedspeciesofPlasmodiumthatcausehumanmalariainfectionarePlasmodium
falciparum(Pf),P.vivax,P.ovale,P.malariae,andP.knowlesi.Amongthese,Pfcausesmore
deathsinchildrenworldwidethananyothersingleinfectiousagent.Anestimated30,000
travelersfromNorthAmerica,Europe,andJapancontractmalariaperyear.Althoughmalariais
preventablewithchemoprophylaxisandcompletelycurablewithearlyintervention,drug
treatmentisnotreadilyaccessibleinmanypartsoftheworld.Additionally,theuseof
antimalarialdrugsovertimehasbeenassociatedwiththeemergenceofdrug-resistantstrains.
Lackofcompliancewithpreventivedrugtreatmentbyindividualstravellingtoendemicareas
mayalsoresultinfatalmalariainfection.Theworld’sfirstmalariavaccine,RTS,S/AS01
(Mosquirix™),arecombinantprotein-basedvaccinetargetingPf,wasapprovedforuseby
Europeanregulatoryauthoritiesin2015.Itiscurrentlybeingevaluatedinimmunization
programsinsub-SaharanAfricadespitehavingbeenfoundtoprovideonlypartialprotection(of
about30-50%)againstclinicalmalariatochildrenandinfants[4,5].Therefore,thedevelopment
ofasafeandmoreeffectivemalariavaccineisanurgentpriorityandmaytakemanyadditional
years.Alternatively,theuseofantibodiesforpassivepreventionofmalariaprovidesanewand
moreimmediateapproachformalariapreventionthat,ifsuccessful,wouldhaveamajorimpact
onimprovingpublichealthworldwide.Recentdevelopmentofhighlypotenthumanmonoclonal
antibodiesthathavechangesmadetoimprovetheirdurationinvivoandprotectindifferentpre-
clinicalmodelswillprovidethefirstassessmentofthisapproach.
1.1.
StudyRationale
1.1.1.
CIS43LSDevelopment
TheVaccineResearchCenter(VRC),NationalInstituteofAllergyandInfectiousDiseases
(NIAID),NationalInstitutesofHealth(NIH)hasbeeninvestigatingbroadly-neutralizinghuman
monoclonalantibodies(bNAbs)targetedatavarietyofpathogensthatmaybeutilizedinclinical
applicationsincludingpreventiveandtherapeuticmeasures.Inthecaseofmalaria,prevention
bypassiveimmunizationhaspotentialapplicationsforuseintravelers,militarypersonnel,
seasoncontrolandeliminationcampaignsinendemicareas.
VRCinvestigatorsisolatedthemonoclonalantibody(mAb),termedCIS43,fromasubject
immunizedwithanattenuatedPlasmodiumfalciparum(Pf)whole-sporozoite(SPZ)vaccine
(PfSPZVaccine(Sanaria)).ThemAbwasthenadaptedusingsite-directedmutagenesisinthe
Fcregion,resultinginanLSmutation(CIS43LS)thathasbeenfoundtoincreaseproducthalf-
lifeinplasma[6,7],whichwillbecriticalforoptimizingitsuse.ThisLSmodificationhasbeen
appliedtomultipleVRCclinicalmAbsandhasbeenshowntobesafeandsignificantlyincrease
thehalf-lifeinplasma[8,9].
CIS43LSrecognizesauniqueandhighlyconservedepitopeatthejunctionoftheN-andcentral
repeatregionsofthePlasmodiumfalciparum(Pf)circumsporozoiteprotein(PfCSP).Ina
publishedstudyintwodifferentmousemodelsofmalariainfection,passiveimmunization
withCIS43conferredhigh-levelprotection(70-100%)followingmalariachallengewith

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concentrationsofantibodyinvivorangingbetween10-200mcg/mlrespectively[10].Similar
protectiondatawereobservedwithCIS43LS[unpublisheddata].Thesedatashowthat
CIS43LSishighlyprotectiveinvivoandsuggestfurtherexplorationiswarrantedforpassive
preventionofmalariainhumans.
1.1.2.
StudyDesign
Thisstudyisaproof-of-conceptstudytoevaluateCIS43LS.ThePartAdoses(5,20,40mg/kg
intravenous(IV)and5mg/kgsubcutaneous(SC))wereselectedbasedonefficacydatafrom
challengestudiesperformedinmiceshowingthattheprotectiveconcentrationofantibodyin
vivoisbetween10-200µg/mlintwodifferentmodelsofmalariainfection.Pharmacokinetic
(PK)datafromnon-humanprimate(NHP)studieswithCIS43LSandourpriorclinical
experienceinhealthyadultswithhumanmAbstargetingHumanImmunodeficiencyVirus(HIV,
i.e.,VRC01,VRC01LS,andVRC07-523LS)andEbolavirus(mAb114)atthesamedosesand
regimens[11-14]suggestthatwewouldachieveadynamicrangeofantibodyconcentrationsin
vivoinhumanswiththisdoseescalationregimenthatshouldbeidealfordeterminingthe
expectedprotectivetiterfollowingcontrolledhumanmalariainfection(CHMI).Asthisisthe
firststudyinhumanstoassesstheprotectiveefficacyofamalariamAbs,itisimportanttoassess
protectiveefficacywithalldosesgiven.
TreatmentswithVRCmAbshavebeengenerallywelltoleratedatalldoselevelsevaluated(1to
40mg/kg).ThedesignoftheCHMIphaseofthestudywasbasedonpreviousclinicaltrial
experienceinpublishedPhase1malariavaccinetrialsthatinvolvedhumanPfcontrolledhuman
infections(CHI)[15,16].Toourknowledge,thisisthefirsttrialtoperformCHMIfollowing
administrationofamalariamAb.
Beyondacquiringsafetyandtolerabilitydata,theinitialintendedpurposeofPartAwasto
determinewhetheraCIS43LSserumconcentrationlevelcorrelatedwithprotectionfrommalaria
infectionfollowingCHMI.Thedoseescalationdesignwastoevaluatesafetyandtolerabilityof
theproductwhilealsoensuringthatparticipantspresentedatthetimeofCHMIwithawide
rangeofCIS43LSserumconcentrations.Asexpected,basedonreviewofavailablePKdata,
Group1participantswhoreceived5mg/kgIVofCIS43LSearlyinPartAhadalowerserum
concentrationattheintendedtimeofCHMIcomparedtosubjectsreceiving40mg/kgIVnearer
tothistime.
Twenty-onesubjectswereenrolledintoPartAbeginninginJanuary2020.Safetydataindicated
thatCIS43LSadministrationbytheIVandSCrouteswaswelltolerated;initialPK
measurementsshoweddoselinearitywithadefinedhalf-lifewithintheexpectedrange.
Unfortunately,thePartACHMIscheduledforMarch17,2020wascancelledduetoemerging
casesofCOVID-19inMarylandandtheWashingtonMetroarea.Theconsequenttravel
restrictions,localandstatestay-at-homeorders,andinterruptedNIHClinicalCenterpatientcare
servicesalsoalteredfollow-upvisits.Thus,subjectswhoreceivedstudyproductinPartAwere
primarilyfollowedviaremotecontacttocontinuesafetyoversightduringtheCOVID-19
pandemic.
WithprotocolVersion4.0,thestudydesignforPartBwasfinalizedfollowingreviewof
preliminarysafetyandPKdatafromPartAandinaccordancewiththeoverallgoalofattaininga
widerangeofCIS43LSserumconcentrationsinsubjectstosupportevaluationofcorrelatesof
protectionfollowingtheCHMI.PartBsubjectsprovidedadditionalsafetyandtolerabilitydata

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forCIS43LSwhilealsocontributingtothefirstefficacydataset.PartBgroupswereenrolled
basedonsubjectavailabilityandscientificpriorityduringtheongoingCOVID-19pandemic.
NewlyenrolledparticipantsinPartBreceived40mg/kgIVdosesofCIS43LSpriortotheCHMI
whileotherparticipantswhoreceivedCIS43LSinPartAwerere-dosedwithasingle20mg/kg
IVinfusiontoensuresubjectspresentedwithagradientofserumconcentrationspriortothe
CHMI.AsubsetofPartAsubjectswhoreceived40mg/kgIValsoparticipatedinthePartB
CHMIwithoutCIS43LSredosingtoassessfordurabilityafteradistantinfusionroughly8
monthspriortoCHMI.Group6(5mg/kgSCinPartB)wasneverenrolledinordertofocuson
thegroupsreceivingCIS43LSbyIV.ActualCIS43LSconcentrationsinbloodweremeasured
fromsamplescollected1daypriortoPartBCHMIforallsubjects.
ThePartBCHMIwasconductedonOctober20,2020,with9recipientsofCIS43LSplus6
controlsubjectsundergoingchallenge.Noneofthe9CIS43LSrecipientsdevelopedparasitemia
duringthe21-daypost-CHMImonitoringperiod,whereas5of6controlsubjectsbecame
parasitemiconday8or9.ThisindicatedthatCIS43LScouldprotecthumansubjectsinaCHMI
model.TherangeofCIS43LSserumconcentrationsatthetimeofCHMIwasapproximately50
to500mcg/mL.ThelackofinfectionsintheCIS43LSgroupsoverarangeofserum
concentrationswasunexpectedbecausethepreclinicalmousedatawouldnothavepredicteda
serumconcentrationof50mcg/mLtobeprotective.Thelackofinfectionsalsoprevented
completionofaregressionanalysistodeterminetheprotectiveserumconcentrationthreshold.
Thisthresholdwasstillfelttobescientificallyimportant,thereforeathirdparttothetrialis
neededinordertoassessforthiscriticalendpoint.
WithprotocolVersion6.0,PartCisbeingaddedtothetrialwiththeobjectiveofidentifyingthe
lowestdoseofCIS43LSthatcouldconferprotectionfollowingCHMI.PartCwillbeconducted
attheUniversityofMaryland,Baltimore(UMB)CenterforVaccineDevelopmentandGlobal
Health.UMBwillperformsubjectscreening,enrollment,productadministration,andthe
CHMI.ThesamplesizeforPartCgroupsisinformedbyPartBdatathatsuggestedmoredata
fromspecificlowerdosegroupsisneededtodefinethelowerthaninitiallypredictedserum
concentrationthreshold.Therefore,PartCwillallocategreaternumbersofsubjectstothe1
mg/kggroupinordertoaccumulatesufficientdata.
1.2.
Background
1.2.1.
PreviousHumanExperience
TherewasnohumanexperiencewithCIS43LSpriortothistrial.PreliminaryVRC612PartA
andPartBdataareprovidedinSection2.3.Priorclinicalexperienceincompletedandongoing
Phase1and2trialsofhealthyadultswithhumanmAbsmanufacturedandformulatedbythe
VRCthatrecognizepathogen-specificepitopes(i.e.,VRC01,VRC01LS,VRC07-523LS,and
mAb114)[11-14]areusedtosummarizethegeneralsafetyriskassociatedwithmAbs.
TreatmentswiththesemAbshavebeengenerallywelltolerated,withnoreporteddeathsor
seriousadverseevents(SAEs)assessedasrelatedtothestudyproducts.TypicalformAbs,the
predominantlocalreactogenicitycomplainthasbeenmildpain/tenderness,althoughreportsof
mildinjectionsitepruritus,rednessandswellinghaveoccurredatmodestlyhigherfrequencies
withSCadministration.Malaise,musclepain,andheadachehavebeenthemostfrequently
reportedsolicitedcomplaintsnotedinthe3dayspostproductadministrationandthesehavealso

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beenmostlytransientandmildinseverity.Urticariaandinfusionreactionscomprisedofchills,
rigors,myalgia,headache,and/orfeverhavebeenreportedafterIVinfusionsatproductdosesof
10to40mg/kg;thesereactionshavebeentransient,resolvedwithoutsequelaewithin24hoursof
onset,andtreatedwithover-the-counteranalgesicsandantipyretics.
1.2.2.
ControlledHumanInfections(CHI)
Controlledhumaninfection(CHI)trials(alsoreferredtoasVolunteerInfectionStudies(VIS))
resultintheexperimentalinfectionofhealthysubjectswiththeinfectiousagentofchoiceandare
anunparalleledtoolininfectiousdiseaseresearch.CHItrialsallowfortheaccelerated
evaluationofnoveldrugsandvaccinesforpotentialefficacy,whilealsoprovidingthe
opportunitytoprospectivelystudyclinicaldiseaseprogression.Thefirstcontrolledhuman
malariainfection(CHMI)wasperformedinthemid-1980s[17].Thisprocessinvolvesthe
deliberateinfectionwithmalariaparasiteseitherbymosquitobiteordirectinjection.VRChas
successfullyconductedthreePhase1CHMIstudies:VRC312[15],VRC314[18]andVRC612
PartB[9].
AccordingtoacomprehensivereviewofCHItrialsusingavarietyofpathogens,anestimated
6000subjectshavereceivedCHI[19].Onlyfourpossibly-relatedSAEshavebeenpublished,of
whichtwowereobservedfollowingmalariavaccinationandCHMI[19].Thefirstcardiacevent
ofpossiblemyocarditis,reportedin2008[20],promptedrecommendationbyapanelofexperts
thatconsiderationofcardiacriskberequiredforclinicalchallengetrialsandthatindividuals
identifiedasatincreasedcardiovascularriskbeexcludedfrommalariaclinicalchallengetrials
[21].Asecondcardiaceventwasobservedin2013followingmalariavaccinationandCHMI
[22].VRCwasalsoinformedofapossible3rd,unpublished,myocarditiseventin2014.Asa
resultoftheseeventsandtherecommendations,evidenceofincreasedcardiovasculardisease
riskoranelectrocardiogram(ECG)withclinicallysignificantabnormalitieswillprecludetrial
enrollmentasdescribedinSection4.1.2.
AllchallengephasesinthisstudywillbeperformedwithPfstrain3D7,sensitivetoChloroquine
andMalarone(atovaquoneandproguanil),viamosquitobite,whichisthenaturalrouteof
exposureandtransmissioninthefield.Whilesubjectswillbemonitoredcloselythroughout
studyduration,monitoringintensitywillincreasefollowingexposuretoPf-infectedmosquitoes
toensurerapiddiagnosisandtreatment.Appropriatedrugtherapywillbeusedtotreatandcure
anysubjectwithaconfirmedPfinfectionafterdiagnosisbyPCR,themostsensitiveassessment
fordetectingearlymalariainfection,inordertominimizetheriskofdevelopingaserious
complication.ThePfstraintobeusedforCHMIinthisstudycanbeeffectivelytreatedwithand
curedbytheantimalarialmedicationstobeusedinthistrial[23,24].
Thereisnegligibleriskoftransmittingmalariatoapersoninthecommunitysincesubjectsare
exposedtomalaria-infectedmosquitosonlyduringtheCHMIatacontainedfacility.
1.3.
LaboratoryAssessmentsofCIS43LS
Somelaboratoryassessmentsinthisstudyarealsodesignedtocharacterizetheinvestigational
product.ThisincludesPKanalysisandevaluationforanti-drugantibody(ADA)development
afterproductexposure.Thesearefurtherdescribedinthesubsequentsections.Otherassays
mayalsobecompletedfromstoredsamplesatalaterdateifadditionalassessmentsareneeded.

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TheVRC’sVaccineImmunologyProgram(VIP),formerlyNVITAL,Gaithersburg,MD,will
processbloodandstorecodedsamples,andwilleitherperformsampletestingorshipcoded
samplestodesignatedresearchlaboratoriesattheVRCorotherapprovedcollaborators.See
APPENDIXIforschedules,volumesandtubetypestobeusedforresearchsamplecollection.
Researchassayswillbeperformedonsamplesfrombothstudyproductrecipientsandinfectivity
controlsatbaselineandthroughoutthestudy.
Tubetypesforclinicallabsareaccordingtoinstitutionalrequirementsandareshowninthe
ScheduleofEvaluationstoestimatebloodvolumes.Differenttubesforclinicalevaluationsmay
beusedtomeetsiterequirements.Researchsampletubetypesandbloodvolumesmustbeused
asshownorasotherwiseinstructedbytheINDSponsor.Insomeinstances,codedsamplesmay
betransporteddirectlybystudystafftothelaboratoryofanapprovedcollaborator.
1.3.1.
Pharmacokinetic(PK)Analysis
ConcentrationsofCIS43LSwillbemeasuredbyMesoScaleDiscovery(MSD)based
automationplatformandsimilarmethodologyaspreviouslydescribedforotherVRCmAb
products[12].
1.3.2.
DetectionofAnti-DrugAntibody
AssaysfordetectionofADAwillbeperformedatspecifiedtimepointsfollowingproduct
administrationandCHMIcomparedtobaselinestatususingasimilarmethodologyaspreviously
describedforotherVRCmAbproducts[12].Athree-leveltieredapproachwillbeusedto
screen,confirm,andfunctionallycharacterizeforADAintheclinicalserumsamplesaccording
totheFoodandDrugAdministration(FDA)guidance.Screeningandconfirmationwillinvolve
aMesoScaleDiscovery(MSD)electrochemiluminescence(ECL)bridgingassay.Intheabsence
ofanadequateinvivosporozoiteentryinhibitionassay,acompetitivetargetbindingassayof
CIS43LStoitscognateepitopeswillbeusedasaproxyforsporozoiterecognitionand
neutralization.
1.4.
MeasuresofmAb-MediatedProtectionandParasitemia
CIS43LS-mediatedprotectionwillfirstbeassessedafterCHMIandcomparedtoinfectionin
controlsubjects.TheendpointdefiningmAb-mediatedprotectionfortheCHMIistheabsence
ofPfparasitesinbloodsamplesobtainedfromCIS43LS-recipientscollectedfromDay7through
Day21post-CHMI.Thecriteriaforacaseofmalariaisconfirmationofparasitemiaeitherby
theMalariareal-timePCRassayorbloodsmear.TheMalariareal-timePCRassaytargetsthe
18SrRNA(ribosomalRNA)geneofPfparasites,whichisaDNAtarget.Itisthedefaultmeans
ofmonitoringforparasitemiainthisprotocol,andasinglepositivePCRresultwillconfirm
infection[15,25,26].Themalariareal-timePCRassaywillbeperformedbytheNIHClinical
CenterDepartmentofLaboratoryMedicineforPartBortheUMBDivisionofMalaria
LaboratoriesResearchforPartC.
AbloodsmearwillbeperformedbytheNIHClinicalCenterMicrobiologyServiceorUMB
MalariaGrouppersonnelpertheirdepartmentalSOPsforanysubjectwhodevelopssymptoms
likelyduetomalariadespitenothavingapositivePCRresult.Withtraditionalmicroscopy,
positivityisdefinedasthepresenceoftwoormoreparasitesin0.5mcLofblood.Laboratory
personnelperformingPCRandbloodsmeartestingwillbeblindedtosubjectgroupand

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treatmentreceivedorlackthereof,inthecaseofcontrols.Researchbloodsamplesmayalsobe
usedforparasitegenomeanalysis.

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2.
STUDYPRODUCTANDCHMI
2.1.
StudyProduct:CIS43LS
MAbVRC-MALMAB0100-00-AB(CIS43LS)wasdiscoveredanddevelopedbytheVRC,
NIAID,NIH.CIS43LSbindsauniqueandconservedepitopeatthejunctionoftheN-and
centralrepeatregionsofthePfCSP.ThestudyproductwasmanufacturedundercurrentGood
ManufacturingPractice(cGMP)bytheVaccineClinicalMaterialsProgram(VCMP)operated
undercontractbyLeidosBiomedicalResearch,Inc.,Frederick,MD.
2.2.
PreclinicalExperience
ToassessCIS43LSasacandidateforclinicaltrials,recombinant,researchgrademAbwas
evaluatedonbindingproperties,auto-reactivity,pharmacokinetics,twomousemodelsofinvivo
protectionfollowingchallenge,andPKstudiesinNHPswereperformed.Inmice,CIS43LS
conferred100%protectionfollowingmosquitobitechallenge.InNHPPKstudies,CIS43LS
exhibitedsubstantiallylongerhalf-life,bothinbloodandinskinbiopsysamplesascomparedto
CIS43antibodywithouttheLSmutation.
PreclinicaltoxicologystudieswereconductedtoassesssafetyincompliancewithcurrentGood
LaboratoryPractices(cGLP)inSpragueDawleyratsusingCIS43LS.Thetoxicologypre-
clinicalmaterialwastestedinthefinalformulationbufferandmanufacturedusingthesame
VCMPmanufacturingprocessasusedtoproduceclinicaltrialmaterial.Therewerenofindings
oftoxicologicsignificanceattributedtoCIS43LSfromtheresults.
2.2.1.
InvitroStudies
DifferencesinthebindingpropertiesofCIS43LSandCIS43wereassessed.Bindingof
CIS43LSandCIS43toaspecifictargetantigenexpressedonmalariaparasiteswasdetermined
byELISA.CIS43LSandCIS43exhibitedsimilarbindingtorecombinantPlasmodium
falciparumcircumsporozoiteprotein(rPfCSP).AvidityandstoichiometryofCIS43LSand
CIS43bindingtorPfCSPwerealsocomparableasassessedbyisothermaltitrationcalorimetry
(ITC).
CIS43LSautoreactivitywasassessedusingtheanti-nuclearantibody(ANA)HEp2cellstaining
systemfromZeusScientific(Branchburg,NJ).Antibodiesweretestedat25and50mcg/mL.At
25mcg/mL,testantibodieswerescoredincomparisontonegativeandpositivecontrolsamples.
NeitherCIS43norCIS43LSshowsanautoreactivitysignalbyANAstaining.Autoreactivity
wasalsoassessedbyananti-cardiolipinQUANTALiteACAIgGIIIELISA(InovaDiagnostics,
SanDiego,CA).UsingasimilarcontrolschematothatdescribedforANAHEp2Cellstaining,
anti-cardiolipinreactivitywasnegativebyELISA.
2.2.2.
InvivoStudies
a. ProtectionstudiesinC57BL/6miceandRhesusmacaques
ToassessprotectionfollowingpassivetransferofmAb,naïveC57BL/6micereceived300mcg
byIVinoculationofCIS43,CIS43LS,ornegativecontrolantibody.Chimericparasites
comprisingPlasmodiumberghei(Pb)sporozoites(SPZ)whichnaturallyinfectmicethat
expressedPlasmodiumfalciparumCSP(Pb-PfCSPSPZ)wereadministeredbyoneoftworoutes

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(injectedbytailveinorbyexposuretobitesbyinfectedmosquitos).Inthetwomousechallenge
models,passivetransferofCIS43andCIS43LSyieldednearlyindistinguishableresults.
AdministrationofeitherCIS43orCIS43LSreducedliverparasiteburdenbyabouttwologs
whenchallengedbyIVroute,whichdeliverstheparasitesdirectlyintotheliverandbypassesthe
normalrouteofinfectionthroughtheskin.Moreover,passivetransferofCIS43orCIS43LS
conferred100%sterileprotectioninmiceasassessedbyparasitemiainbloodfollowinganatural
challengebyfivemosquitobitesintheskin.Thistypeofchallengeissimilartowhatisusedin
thehumanCHMI.
Toconfirmtheimprovedhalf-lifeofCIS43LSandinformclinicalprotocoldevelopment,
particularlyconcerningthetimingofCHMI,a20-weekPKstudywasconductedinNHPs
(Rhesusmacaques).TwoanimalspergroupreceivedCIS43orCIS43LS,administeredbyIV
routeatadoseof10mg/kg.CIS43LSexhibitedsubstantiallylongerhalf-life,bothinbloodand
skinbiopsysamplesthanCIS43.Inblood,CIS43LSmaintainedatiterofmorethan35mcg/mL
onthelastsampleday(day140).Incontrast,CIS43droppedtoapproximately30ug/mLbyDay
49.Skinbiopsydatawereconcordant.
b. ToxicologyStudiesinSpragueDawleyRats
Astudyofrepeatdosingat10-dayintervalsbyIVandSCadministrationofCIS43LSinmale
andfemaleSpragueDawleyrats(SRIStudyNo.M416-19)wasconductedincompliancewith
cGLPtoevaluatetoxicityandtoxicokinetics.Thetestarticleandcontrol(formulationbuffer)
wereadministeredonDays1and11byIVadministrationatdosesof0,40or400mg/kg/day
(Groups1−3,respectively)orbySCadministrationatdosesof5or50mg/kg/day(Groups4−5,
respectively).NecropsieswereperformedonDays12and46.Endpointsincludedclinical
observations,bodyweight,foodconsumption,bodytemperature,dosesiteirritation,clinical
pathology,andorganweights.
Allanimalssurvivedtotheirscheduledsacrificetimepoint.Notestarticle-relatedchangeswere
observedinclinicalobservations,bodyweights,foodconsumption,dosesiteirritation,clinical
chemistry,coagulation,andorganweights.Bodytemperaturewasnormal(≤101.0°F)forall
malesat24hourspost-dose.Elevatedbodytemperaturesrangingfrom101.1to102.1°Fwere
seenfromoneormorefemalesinhigh-doseIVorbothSCtreatedgroupsforatleast24hours
afterdosingonDays1and/or11.Bodytemperaturereturnedtonormallevelswithin48hours
post-dose.Thesefindingsareconsideredtestarticle-relatedalthoughreversibleandatlevels
consideredtobenon-adverse.
Statisticallysignificantanddose-dependentchangesinsomehematologyparameterswere
observedonDays12and46.Thechangesincludedincreasedplateletcount(1.4fold)and
absolutereticulocytecount(1.2fold)inGroup5females;anddecreasedpercentmonocyte(by
30.6to32.2%)inGroup3and4femalesonDay12.OnDay46,increasedabsoluteneutrophils
(2.0to2.3fold)inGroup3and4malesanddecreasedhemoglobin(by6.1to7.6%)and/or
hematocrit(by5.6to7.6%)inalltreated-groupfemaleswereobserved.Thechangesin
neutrophilsandmonocytesseenafterSCadministrationareconsistentwithanimmuneresponse
andareconsideredtestarticle-relatedalthoughreversibleandatlevelsconsideredtobenon-
adverse.Withoutchangesinredbloodcell(RBC)counts,thefindingsinplateletcount,
reticulocytes,hemoglobinorhematocritarenotconsideredtobebiologicallymeaningfulor
toxicologicallyadverse.Insummary,nofindingsoftoxicologicsignificancewereattributedto
CIS43LSfromtheresultsavailableasofthisreport.

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Takentogether,thesestudiessupportthecontinueddevelopmentofCIS43LSforclinical
evaluation.Thedataconfirmthepredictedlongerhalf-lifeeffectoftheLSmutationandshow
thatthereisnofunctionaldifferenceintermsofinvitrobindingorinvivoprotectioncompared
toCIS43.Nosafety,efficacy,ormanufacturabilityconcernswerenotedthatprecluded
proceedingtofurthertoxicologystudies,GMPmanufacturing,INDfiling,andclinical
investigations.
2.3.
ClinicalExperience
PartAandBdatafromthistrialisthefullextentofcurrenthumanexperiencewithCIS43LS.
SeeSection1.2.1formoreinformationaboutsimilarVRCmAbproducts.
VRC612wasinitiatedinJanuary2020withaccrualintoPartA.PartBofthetrialbeganin
September2020.AsofFebruary15,2021,25subjectsreceived29administrationsofCIS43LS.
Whilemostsubjects(n=21)receivedonlyasingledose,4subjectsoriginallydosedinPartA
receivedaseconddoseof20mg/kgIVinPartB.CIS43LSadministrationsweregivenbyIV
(n=25)andSC(n=4)routes.Atthetimeofthissummary,subjectsareinfollowup;dataquality
assuranceandmonitoringareongoing.
Humanexperiencedatacollectedthusfar,includingfrequencyandseverityofsolicitedand
unsolicitedadverseevents,aresummarizedbelow.Overall,VRC612datademonstratethat
CIS43LSissafeandwelltolerateduponIVandSCadministration.Therehavebeennoreported
SAEsrelatedtostudyproductandnostudypausecriteriamet.
LocalReactogenicity:Mildpain/tendernessattheinjectionsitewasthemostfrequently
reportedsolicitedlocalsymptom,reportedby4/25(16%)IVrecipientsand3/4(75%)SC
recipients.Allpaineventsresolvedwithinthe7-daysolicitedperiod.Oneeventofmoderate
bruisingbeganonDay4inanIVrecipientandcontinuedthrough4daysafterthesolicited
periodtoDay11.Nootherlocalsymptomswerereported.
SystemicReactogenicity:Mildheadachewasthemostfrequentlyreportedsolicitedsystemic
symptom,reportedby5/25(20%)IVrecipientsand1/4(25%)SCrecipients.Mildmyalgiawas
reportedby3/25(12%)IVrecipientsand2/4(50%)SCrecipients.OthereventsreportedbyIV
recipientsincludemild(2/25,8%)andmoderate(1/25,4%)malaise,moderatenausea(1/25,
4%),mildjointpain(1/25,4%),andmildfever(1/25,4%).Alleventsresolvedwithinthe7-day
solicitedperiodwiththeexceptionofonereporteachofmoderatemalaiseandmildheadacheby
anIVrecipientthatbeganonDay4andlasteduntilDay10,andonereportofmildmyalgiaby
anIVrecipientthatbeganonthedayofproductadministration(Day0)andlasteduntilDay10.
UnsolicitedAEs:Ofthe25subjectswhoreceivedCIS43LS,9subjects(36%)hadatleastone
AEwiththehighestseverityofmildfor5(20%)subjects,moderatefor3(12%)subjectsand
severefor1(4%)subject.ThemostfrequentlyreportedunsolicitedAEby3of21(14%)
subjectswasupperrespiratorytractinfection(URTI),whichwasassessedasnotrelatedtothe
studyproductforallsubjects.ThreemildAEswereassessedasrelatedtostudyproduct
includingoneeventeachofbloodcreatinineincreaselasting7days,transientasymptomatic
neutropenialasting6daysanddizzinesslasting1day.Allrelatedeventsresolvedwithno
residualeffects.

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2.4.
ControlledHumanMalariaInfection(CHMI)
PreparationofinfectedmosquitoesforCHMIwillbeperformedaccordingtoaTypeIIMaster
File033797,MalariaChallengeModel,StandardOperatingProceduresforthePfmodelused.
Toprepareinfectedmosquitoes,Pfasexualandsexualerythrocyticstageparasiteswillbegrown
innormalhumanerythrocytesusingstandardculturemediumcontaining10%normalhuman
serum.ThebloodandserumforculturearepurchasedfromaFoodandDrugAdministration
(FDA)-accreditedbloodbank.Eachshipmentcarriesacertificateofanalysiscertifyingthatthe
bloodproductsarenegativeornon-reactiveforimmunologicevaluationandinfectiousdisease
testing.

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3.
STUDYOBJECTIVES
3.1.
PrimaryObjectives
• ToevaluatethesafetyandtolerabilityofCIS43LSadministeredIVat1,5,10,20,and40
mg/kginhealthy,malaria-naiveadults
• ToevaluatethesafetyandtolerabilityofCIS43LSadministeredSCat5and10mg/kgin
healthy,malaria-naiveadults
3.2.
SecondaryObjectives
• ToevaluatethepharmacokineticsofCIS43LSateachdoselevelthroughoutthestudy
• TodetermineifIVorSCadministrationofCIS43LSmediatesprotectionagainst
infectiousP.falciparumfollowingCHMI
• ToestimatethelowestdoseofCIS43LSadministeredIVandSCthatconfersprotection
againstinfectiousP.falciparumfollowingCHMI
3.3.
ExploratoryObjectives
• Todeterminewhetheranti-drugantibody(ADA)toCIS43LScanbedetectedinseraof
recipientsatspecifictimepointsthroughoutthestudy
• ToassessforIgG1allotypesandallotype-specificeffectsonCIS43LSpharmacokinetics
• ToexploreandcharacterizethehumoralandcellularresponsetoCIS43LS
• ToassessdurabilityofmAb-mediatedprotectionofCIS43LS

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4.
STUDYDESIGNANDCLINICALPROCEDURES
PartsAandBofthisopen-label,doseescalationstudywereconductedattheVRCVaccine
EvaluationClinic(VEC)intheNIHClinicalCenter(NIHCC)andtheCHMIwasconductedat
theWalterReedArmyInstituteofResearch(WRAIR)insectarywiththeoversightofNIHCC
staff.AllofPartC(includingtheCHMI)willbeconductedattheUMBCenterforVaccine
DevelopmentandGlobalHealth.TheprimaryhypothesisisthatCIS43LSwillbesafeand
tolerablewhenadministeredbyeitherIVorSCroutes.Thesecondaryhypothesesarethat
CIS43LSwillbedetectableinhumanserawithadefinablehalf-lifeandwillconferprotection
followingaCHMI.
PartA:ThestudybeganwithsubjectenrollmentintoGroup1.Thedoseescalationsafety
reviewsproceededasdescribedinSection4.5.PartAsafetydatashowthatCIS43LSissafeand
tolerableatalldosegroups.PreliminaryPKdatasuggestthatagradientofserumconcentrations
willbepresentacrossgroupsatthetimeofCHMI.
PartBfurtherevaluatedtheCIS43LSdosesandroutesneededtoreachathresholdofprotection
byassessingserumconcentrationspriortoCHMIinPartAveteransubjectsaswellasinnew
enrollees.
PartCwillevaluateCIS43LSdosesandroutesneededtoreachathresholdofprotectionby
assessingserumconcentrationpriortoCHMIinadosedowndesign.
Theoverallstudyschemaisasfollows:
Table1:
StudySchema
VRC612StudySchema
Site
Group
Subjects
CIS43LSAdministration
CHMI
Dose(mg/kg)
Route
PartA
VRC
1
6
5
IV
Cancelled
2
6
5
SC
3
6
20
IV
4A
6
40
IV
4B
3
40
IV
N/A
5
6
Control
Cancelled
PartB
VRC
6
6
5
SC
X
7
61
20
IV
X
8
61
--
--
X
9
6
40
IV
X
10
61,2
Control
X
PartC
UMB
11
7
1
IV
X
12
4
5
IV
X
13
4
5
SC
X
14
4
10
IV
X
15
4
10
SC
X
16
62
Control
X

Total
923
1GroupincludesPartAsubjects
2Two(2)additionalcontrolsubjectswillbeenrolledasCHMIback-ups
3Upto100subjectsmaybeenrolledifneededforadditionalsafetyorefficacyevaluations.


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4.1.
StudyPopulation
SubjectswillbescreenedtoconfirmeligibilityrequirementsforparticipationusingtheVRC500
screeningprotocol.Thescreeningandeducationprocessrequiredpriortoenrollmentisdesigned
toensurethatsubjectscomprehendthepurpose,detailsandrisks/benefitsofthestudy.
Eligibilitywillbere-assessedpriortoPartBenrollmentforanyPartAsubjectswhoareinvited
toparticipateinPartB.
4.1.1.
InclusionCriteria
Asubjectmustmeetallofthefollowingcriteriatobeincluded:
1. Ableandwillingtocompletetheinformedconsentprocess
2. Abletoprovideproofofidentitytothesatisfactionofthestudycliniciancompletingthe
enrollmentprocess
3. Availableforclinicalfollow-upthroughthelaststudyvisit
4. 18to50yearsofage
5. Ingoodgeneralhealthwithoutclinicallysignificantmedicalhistory
6. Physicalexaminationwithoutclinicallysignificantfindingswithinthe56dayspriorto
enrollment
7. Weight≤115kg(forallgroupsexceptGroups5,10,and16)and<100kgforGroup15
8. AdequatevenousaccessifassignedtoanIVgrouporadequatesubcutaneoustissueif
assignedtoaSCgroup
9. Willingtohavebloodsamplescollected,storedindefinitely,andusedforresearch
purposes
10.Agreestoparticipateinacontrolledhumanmalariainfection(CHMI)andtocomplywith
post-CHMIfollow-uprequirements(exceptGroup4B)
11.Agreestorefrainfromblooddonationtobloodbanksfor3yearsfollowingparticipation
inCHMI(exceptGroup4B)
12.Agreesnottotraveltoamalariaendemicregionduringtheentirecourseofstudy
participation
LaboratoryCriteriawithin56dayspriortoenrollment:
13.WBC2,500-12,000/mm3
14.WBCdifferentialeitherwithininstitutionalnormalrangeoraccompaniedbythe
PrincipalInvestigator(PI)ordesigneeapproval
15.Platelets=125,000–500,000/mm3
16.HemoglobinwithininstitutionalnormalrangeoraccompaniedbythePIordesignee
approval
17.Creatinine≤1.1xupperlimitofnormal(ULN)
18.Alanineaminotransferase(ALT)≤1.25xULN

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19.NegativeforHIVinfectionbyanFDAapprovedmethodofdetection
LaboratoryCriteriadocumentedanytimepriortoenrollment:
20.Negativesicklecellscreeningtest
21.Negativetroponintest(exceptGroup4B)
22.Electrocardiogram(ECG)withoutclinicallysignificantabnormalities(examplesmay
include:pathologicQwaves,significantST-Twavechanges,leftventricular
hypertrophy,anynon-sinusrhythmexcludingisolatedprematureatrialcontractions,right
orleftbundlebranchblock,advancedA-Vheartblock).ECGabnormalitiesdetermined
byacardiologisttobeclinicallyinsignificantasrelatedtostudyparticipationdonot
precludestudyenrollment(exceptGroup4B)
23.Noevidenceofincreasedcardiovasculardiseaserisk;definedas>10%five-yearriskby
thenon-laboratorymethod[27](exceptGroup4B)
CriteriaSpecifictoWomen:
24.Postmenopausalforatleast1year,post-hysterectomyorbilateraloophorectomy,orifof
childbearingpotential:
a. Negativebeta-humanchorionicgonadotropin(β-HCG)pregnancytest(urineor
serum)ondayofenrollment,andpriortoproductadministrationandCHMI,and
b. Agreestouseaneffectivemeansofbirthcontrolthroughthedurationofstudy
participation
4.1.2.
ExclusionCriteria
Asubjectwillbeexcludedifoneormoreofthefollowingconditionsapply:
1. Womanwhoisbreast-feedingorplanningtobecomepregnantduringstudyparticipation
2. Previousreceiptofamalariavaccine
3. Historyofmalariainfection
4. Historyofsevereinfectionwithsevereacuterespiratorysyndromecoronavirus2(SARS-
CoV-2)definedperFDAguidance[28]
5. ActiveSARS-CoV-2infection
6. Anyhistoryofasevereallergicreactionwithgeneralizedurticaria,angioedemaor
anaphylaxispriortoenrollmentthathasareasonableriskofrecurrenceduringthestudy
7. Hypertensionthatisnotwellcontrolled
8. Receiptofanyinvestigationalstudyproductwithin28dayspriortoenrollment(note:
EmergencyUseAuthorizationCOVID-19vaccineisnotexclusionary)
9. Receiptofanyliveattenuatedvaccineswithin28dayspriortoenrollment
10.Bleedingdisorderdiagnosedbyadoctor(e.g.factordeficiency,coagulopathy,orplatelet
disorderrequiringspecialprecautions)orsignificantbruisingorbleedingdifficultieswith
intramuscularinjectionsorblooddraws

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11.Historyofasplenectomy,sicklecelldiseaseorsicklecelltrait
12.Historyofskeetersyndromeoranaphylacticresponsetomosquito-bites(exceptGroup
4B)
13.Knownintolerancetochloroquinephosphate,atovaquoneorproguanil(exceptGroup
4B)
14.Useorplanneduseofanydrug,includingantibiotics,withantimalarialactivitywithin4
weekspriortoCHMI
15.Historyofpsoriasisorporphyria,whichmaybeexacerbatedaftertreatmentwith
chloroquine(exceptGroup4B)
16.Anticipateduseofmedicationsknowntocausedrugreactionswithchloroquineor
atovaquone-proguanil(Malarone)suchascimetidine,metoclopramide,antacids,and
kaolin(exceptGroup4B)
17.Anyotherchronicorclinicallysignificantmedicalconditionthatintheopinionofthe
investigatorwouldjeopardizethesafetyorrightsofthevolunteer,includingbutnot
limitedto:diabetesmellitustypeI,chronichepatitis;ORclinicallysignificantformsof:
drugoralcoholabuse,asthma,autoimmunedisease,psychiatricdisorders,heartdisease,
orcancer
4.2.
InclusionofVulnerableSubjects
4.2.1.
Children
Childrenarenoteligibletoparticipateinthisclinicaltrialbecausethestudyproducthasnotbeen
previouslyevaluatedinadults.Iftheproductisassessedassafeforfurtherstudy,otherprotocols
specificallydesignedforchildrenmaybeconducted.
4.2.2.
ParticipationofSiteEmployees
4.2.2.1.
VRCSite
NIHemployeesandmembersoftheirimmediatefamiliesmayparticipateinthisprotocol.We
willfollowtheGuidelinesfortheInclusionofEmployeesinNIHResearchStudiesandwillgive
eachemployeeacopyofthe“NIHInformationSheetonEmployeeResearchParticipation”and
acopyofthe“LeavePolicyforNIHEmployeesParticipatinginNIHMedicalResearch
Studies.”
Neitherparticipationnorrefusaltoparticipatewillhaveaneffect,eitherbeneficialoradverse,on
theparticipant’semploymentorworksituation.FortheVRCsite,theNIHinformationsheet
regardingNIHemployeeresearchparticipationwillbedistributedtoallpotentialsubjectswho
areNIHemployees.Theemployeesubject’sprivacyandconfidentialitywillbepreservedin
accordancewithapplicablepoliciesatthestudysite.Foranyemployeesubjects,consentwillbe
obtainedbyanindividualwhoisindependentoftheemployee’steam.AtNIH,iftheindividual
obtainingconsentisaco-workertothesubject,independentmonitoringoftheconsentprocess
willbeincludedthroughtheBioethicsConsultationService.Protocolstudystaffwillbetrained
onobtainingpotentiallysensitiveandprivateinformationfromco-workersorsubordinates.

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4.2.2.2.
UMBSite
TheUMBsitewillfollowinstitutionalpoliciesrelatedtostudyparticipationofstudentsor
Universityemployees.Neitherparticipationnorrefusaltoparticipatewillhaveaneffect,either
beneficialoradverse,onthesubject’seducational,employmentorworksituation.
4.3.
ClinicalProceduresandEvaluations
Evaluationofstudyproductsafetywillincludelaboratorystudies,medicalhistory,physical
assessmentbyclinicians,andsubjectself-assessment.Thestudyscheduleispresentedinthe
ScheduleofEvaluations,APPENDIXI.Totalbloodvolumedrawnfromeachsubjectwillnot
exceedtheNIHClinicalCenterGuidelines(PartAandPartB)orUMBCenterforVaccine
DevelopmentandGlobalHealthlimits(PartC).
4.3.1.
RecruitmentandRetention
StudyenrollmentswillbeconductedattheNIHClinicalCenter(PartAandPartB)andatthe
UMBCenterforVaccineDevelopmentandGlobalHealth(PartC).Studysubjectswillbe
recruitedthroughon-siteandoff-siteIRB-approvedadvertisingdonethroughtheVRC’s
screeningprotocol,VRC500(NCT01375530).Effortwillbemadetoincludewomenand
minoritiesinproportionssimilartothatofthecommunityfromwhichtheyarerecruited.
4.3.1.1.
Costs
Therearenocoststosubjectsfortheirparticipationinthistrial.
4.3.1.2.
Compensation
4.3.1.2.1. NIHCompensation
Subjectswillbecompensatedfortimeandinconvenienceinaccordancewiththestandardsfor
compensationoftheClinicalResearchVolunteerProgram.Compensationforstudyproduct
administrationintheIVgroupsaccompaniedbythesamedayPKblooddrawswillbe$430;
productadministrationvisitsintheSCgroupwithoutPKblooddrawswillbe$375.
Compensationwillbe$200forscheduledvisitsthatincludeblooddraws,$85forclinicvisits
thatdonotincludeablooddraworprocedure,$55forSARS-CoV-2testinginPartsAandBof
thestudybynasopharyngealswab,and$25fortimelycompletionoftheelectronicdiarycard.
CompensationforaCHMIvisitincludingthepre-CHMIvisitthepriordayis$400.
Thetotalamountofcompensationvariesdependingupongroupandthevisitscompleted.
Compensationmayalsovarydependinguponthenumberofdaysrequiredforthedaily
evaluationsintheperiodafteraCHMIasthosewhobecomeparasitemicearlywillrequirefewer
daysofin-clinicevaluationvisitsthanthosewhohavedelayedornoparasitemia.CHMIcontrol
subjectswillbecompensatedsimilarlyforcomparablevisittypes.
4.3.1.2.2. UMBCompensation
Subjectswillbecompensatedfortimeandinconvenienceinaccordancewiththestandardsfor
compensationoftheUMBCenterforVaccineDevelopmentandGlobalHealth.Compensation
forstudyproductadministrationintheIVgroupsaccompaniedbythesamedayPKblooddraws
willbe$400;productadministrationvisitsintheSCgroupwithoutPKblooddrawswillbe

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$175.Compensationwillbe$75forscheduledin-personvisits,withorwithoutblooddraws;
and$10/dayfortimelycompletionofthe7-daydiarycard,toatotalofupto$70.Compensation
foraCHMIvisitincludingthepre-CHMIvisitthepriordayis$325.
Thetotalamountofcompensationvariesdependingupongroupandthevisitscompleted.
Compensationmayalsovarydependinguponthenumberofdaysrequiredforthedaily
evaluationsintheperiodafteraCHMIasthosewhobecomeparasitemicearlywillrequirefewer
daysofin-clinicevaluationvisitsthanthosewhohavedelayedornoparasitemia.CHMIcontrol
subjectswillbecompensatedsimilarlyforcomparablevisittypes.
4.3.2.
Screening
ScreeningforthisstudywillbecompletedthroughtheVRC’sscreeningprotocol,VRC500
(NIH11-I-0164).SubjectswillberecruitedthroughInstitutionalReviewBoard(IRB)-approved
advertising.Screeningevaluationsareperformedtoconfirmeligibilityandwillincludemedical
historyreview,physicalexam,andtheclinicallaboratorytestsdetailedinAPPENDIXI.
Womenpresumedtobeofreproductivepotentialwillbegivenapregnancytest.Abaseline
electrocardiogram(EKG)willbeperformed.Additionalassessmentsofhealthmaybe
conductedatscreeningbasedonclinicaljudgment.Pre-exposureresearchbloodsamplesmaybe
collectedanytimeduringscreeningthroughenrollmentandwillnotbesubjecttothe“56-day
priortoenrollment”restriction.
Informedconsentdocumentswillbereviewedduringscreening.Counselingrelatedtopotential
risksofthestudyproduct,pregnancyprevention,andavoidingexposuretomalariawillbe
performed.AnAssessmentofUnderstanding(AoU)willbecompletedinassociationwith
enrollmentintoVRC612.Recordswillbekeptdocumentingthereasonthatscreenedsubjects
donotenroll.
4.3.3.
EnrollmentandStudyDay0
Inthisstudy,enrollmentisdefinedastheassignmentofastudyidentificationnumberanda
studygroupintheclinicaldatabase.Aclinicianwilldiscussthetargetdatesandtimingofthe
studyproductadministration,CHMI,andsamplecollectionsbeforecompletinganenrollmentto
helpensurethatthesubjectcancomplywiththeprojectedschedule.Informedconsentmustbe
obtainedpriortoenrollment.ForCIS43LSrecipients,enrollmentwilloccuratVisitA1Ror
B1R(Day-28toDay0)andmayoccuronthesamedayasproductadministrationatVisitA2or
B2(Day0)inadvanceofproductadministration.ForCHMIcontrolsubjects,VisitA1RorB1R
(Day-56toDay-1)istheenrollmentday,whichwillbewithin56dayspriortotheCHMI.
ForCIS43LSrecipients,Day0isdefinedasthedayofproductadministration.IfDay0doesnot
coincidewithenrollment,thentheenrollmentdaymaybereferredtobyanegativenumberof
days(i.e.,Day-1).ForcalculatingelapseddaysfollowingDay0,eachsubsequentcalendardate
islabeledbythenextsequential“StudyDay”asshowninAPPENDIXI.Sincetheremaybe
morethanoneresearchsamplingtimepointofinterestperstudyday,eachsamplecollection
timepointhasitsown“VisitNumber.”Forthisreason,theremaybemorethanonevisitnumber
recordedonthesamecalendardate.
ThestudystartedinPartAwithsubjectenrollmentdirectlyintoGroup1.Additionaldose
groups(Groups2,3,4A,and4B)openedperthedoseescalationrulesasoutlinedinSection4.5,
andsubjectsweredirectlyenrolledintothesubsequentopengroups.SubjectsinGroup5were

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abletochoosetoparticipateinthecontrolgroup(andwillbeofferedtoenrollintoGroup10as
PartBCHMIcontrols)andundergoCHMIwithoutreceivingproductadministration.PartB
subjectswillalsobedirectlyenrolled.Becausethisisanopen-labeldesign,subjectswillknow
whatgrouptheyareinonthedayofenrollment.
MedicalhistoryandDay0evaluations(priortoproductadministration,asapplicableperstudy
group)arethebaselineforsubsequentsafetyassessmentsexceptthatthescreeningevaluations
willbethebaselineforthoseonlydoneatscreening.
InPartC,thegroupswillbeenrolleddirectlystartingwiththelowestdosegroup(Group11)and
thenenrollmentswillcontinueintotheadditionaldosegroups.Group16maybefilledatany
timeinordertoensureanadequatenumberofcontrolparticipantsforCHMI.
4.3.4.
ProductAdministration
Allproductadministrationswillbecompletedaccordingtotheassignedgroup.
Onthedayof,andpriortoproductadministration,vitalsigns(temperature,bloodpressure,heart
rateandrespiratoryrate)willberecorded,atargetedphysicalexamination(basedonsigns,
reportedsymptomsorinterimmedicalhistory)maybeconductedasneeded,andwomenof
childbearingpotentialmusthaveanegativepregnancytest.
IfasubjectisassignedtoanIVadministrationgroup,theIVaccesswillbeplacedinanarmvein
inanasepticmanner.AdifferentsitemaybeusedforcollectionofPKbloodsamples;however,
thesamesitemaybeusedafterflushingthelineifanothersiteisnotavailable.CIS43LSwillbe
administeredwithapproximately100mLofnormalsalineIVoverabout15-30minutes,witha
targetof30minutesfortheinitialinfusionforeachsubject.Infusionslastinglongerthan30
minutesareallowed.Ifthesubjectexperiencessideeffectsduringtheinfusion,therateof
infusionmaybeslowedorstoppedtoalleviatethesymptoms.
IfasubjectisassignedtoaSCadministrationgroup,theSCadministrationsite(s)tobeused
mustbeassessedasacceptablebytheclinicianandthesubject.ThepreferredSCadministration
siteistheabdomen,buttheupperarmorthighmaybeused.Giventheweightcriterioninthis
studygroup,themaximumvolumeneededtoadministera10mg/kgSCdoseisnotexpectedto
exceed10mL.TheSCdosewillbeadministeredbystandardneedleinamaximumvolumeof
about2.5mLperinjectionsite.Upto6SCinjectionsitesmaybeusedifdeemednecessaryby
theclinician.SCadministrationsitesshouldbeatleast2inchesapart.
ProceduresforCIS43LSpreparationandadministrationaredescribedinSection7.
4.3.5.
Post-ProductAdministrationFollow-up
InallstudygroupsinPartA,thefirstsubjectineachdosegrouptoreceiveauniquedoselevel
(5,20,or40mg/kg)orroutewillbeobservedforatleast4hoursfollowingcompletionofinitial
productadministration.Allothersubjects(includingthoseinPartsBandC)willbeobserved
foratleast2hoursfollowingcompletionofproductadministration.CollectionofPKsamples
willbeconductedaccordingtotheScheduleofEvaluationsforthesubject’sstudygroup.
Priortodischargefromtheclinic,subjectswillbeassessedforlocalandsystemicreactogenicity
andvitalsignswillberecorded.Anysubjectwhoisassessedasbeingunwellorhasongoing

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reactogenicitysymptomswillbeaskedtoremainintheclinicuntilevaluationanddischargebya
studyclinician.Thisincludesthepossibilityofanovernightinpatientstaytoevaluateforsafety.
4.3.6.
SolicitedAdverseEvents(Reactogenicity)
Eachsubjectwillbegivena7-daydiary(paperandelectronic-basedavailable),athermometer,
andameasuringdevice.Subjectswillusethediarytorecordtheirhighesttemperature,localand
systemicsymptoms,andconcomitantmedicationsdailyfor7daysaftereachproduct
administration.Subjectswillbeprovidedtrainingondiarycompletionandproperusageofthe
thermometertomeasuretemperatureandthemeasuringdevicetomeasureinjectionsite
symptoms.Completionofdiarytrainingwillbenotedinthesourcedocuments.Whilethe
electronicdiaryispreferred,subjectswillhavetheoptiontouseapaperdiary.Thepaperdiary,
ifused,willbetranscribedintothestudydatabaseandstoredinthesubjectfileformonitoring
purposes.Whenneitherpapernorelectronicdiaryisavailablefromthesubject,thestudy
clinicianwilldocumentthesourceofreactogenicityinformationrecordedinthestudydatabase.
Thesignsandsymptomssolicitedbythediarywillincludesystemiceventsoftemperature,
feelingunusuallytiredorunwell,musclesaches,headache,chills,nausea,andjointpain,and
localeventsattheproductadministrationsiteofpain/tenderness,swelling,redness,bruising,and
pruritus.Subjectdiarieswillbereviewedbyaclinicianforaccuracyandcompletenessat
follow-upvisits.Clinicianswillfollowanysolicitedsymptomsthatareongoingafter7days
untiltheyhaveresolved.
Diarydatawillbeavailableinreal-timetocliniciansforsubjectswhousetheelectronicdiary.
Subjectsusingapaperdiarywillbeencouragedtocontacttheclinicassoonaspossibleforany
moderateorseveresideeffectsthattheyexperienceinthe7dayspostproductadministration.A
studyclinicianmaycontactthesubjectbyphoneifanymoderateorseveresideeffectis
reported.Eventsthatmayrequireaclinicvisitincluderash,urticaria,feverof38.6˚C(Grade2)
orhigherlastinggreaterthan24hoursorsignificantimpairmentintheactivitiesofdailyliving
(suchasthoseconsistentwithGrade2orhigherimpairment).Additionally,otherclinical
concernsmaypromptastudyvisitbasedonthejudgmentofastudyclinician.
4.3.7.
CHMIProcedures
TheintervalbetweenadministrationofstudyproductandCHMIwillvarydependingonwhena
subjectisenrolled.TheCHMIwillonlyoccurfollowinganevaluationofDay7safetydatapost
productadministrationandmaybeadministeredatanytime≥8daysthrough12weekspost
productadministration.SomeflexibilityaroundtheintervalbetweenthetimeofCIS43LS
administrationandCHMIispermittedgiventheneedtoworkwitheachsubject’spersonal
schedule,availabilityoftheCHMIfacilityandpost-CHMIfollow-up.
PriortoschedulingtheCHMI,atleasttwoemergencycontactnumberswillbeconfirmedand
verifiedasauthenticforeachsubjectwhowillparticipateinthechallenge.Theclinicalstudy
teamwillrevieweachsubject’sadherencetothescheduleandsafetyfollow-uptodate.This
reviewwillattempttoidentifyanylikelihoodofunreliabilityonthepartofthesubjectduringthe
CHMIphaseofthestudy.Anysubjectexpressinginabilitytocomplywithstudyrequirements
maybedeemedunsuitableforCHMIandwillbeexcludedfromtheCHMIphaseofthestudy.
Anysubjectwhoreceivesstudyproduct,however,willbeencouragedtoremaininthestudyfor
safetyfollow-upvisits.

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Womenofchildbearingpotentialmusthaveanegativepregnancytestwithin2dayspriorto
CHMI.UseofantibioticswithantimalarialactivitybyCHMIparticipantsshouldbeavoidedat
least4weekspriortoandduringtheCHMIunlessmedicallywarranted.
CHMIwillbeconductedbyexperiencedinsectaryandclinicalstaffatWRAIRandUMB.
MosquitoesinfectedviamembranefeedsinpreparationfortheCHMIcontainsporozoitesin
theirsalivaryglandsandupto5atatimewillbeallowedtofeedoneachsubjectunder
controlledconditions.Followingexposure,themosquitoeswillbeimmediatelydissectedto
confirmthepresenceofabloodmealandtodeterminetheinfectivityrateandthesalivarygland
score.Additionalmosquitoeswillbeallowedtofeeduntil5bitesshowingpresenceofablood
mealandaminimum2+salivaryglandscorehasbeenachievedforeachsubject.
OnthedayofCHMI,subjectswillbeprovidedwithcounselingandwrittenrecommendationsto
reduceriskofnaturalmosquitoexposurebeginning5daysafterCHMIandcontinuinguntil
completionoftreatment.
4.3.8.
Post-CHMIFollow-Up
Thestudyteamwillbeincontactwithsubjectsatleast2timesinthefirst7daysaftertheCHMI
toprovideclosemonitoringofclinicalstatus.Bloodsamplestoevaluateformalariaparasitemia
willbecollecteddailyandrunonPCRfromdays7through18post-CHMI.Regularparasitemia
evaluationswillstopaftertreatmentisinitiatedforpositivecasesofparasitemia.Intheabsence
ofmalariainfection,allsubjectswhohavenotalreadystartedtreatmentwillbeprovidedwith
directlyobserveddefinitiveantimalarialtreatmentatDay21.
TheCOVID-19pandemicdemonstratedthatlargescaledisruptionofclinicaltrialactivitiesis
possible.Whilesuchlarge-scaledisruptionsarenotexpectedatthetimeofPartBorPartC
CHMI,theprotocolisrevisingthepost-CHMIfollow-updurationfrom28daysto21daysasa
riskmitigationprocedure.Ashorterfollow-uptimelimitstravelandpublicexposuretoboth
subjectsandtrialstaffintheeventsocialdistancingisrequired,whileconcomitantlyensuring
thescientificintegrityofefficacydatafrombothcontrolsubjectsandCIS43LSrecipients.
Duringthepost-CHMIfollow-upperiod,subjectsmayparticipateintheirnormaldailyactivities.
Astudyphysicianwillbeavailable24hoursadaybytelephoneorinpersontothesitestaffin
caseneededforconsultationaboutsubjectsignsandsymptoms.Anysubjectwhoisassessedas
beingunwellduringthepost-CHMIfollow-upwillbeaskedtoremainintheclinicuntil
evaluationanddischargebyastudyclinician.Thisincludesthepossibilityofanovernight
inpatientstaytoevaluateforsafety.
AtroponinlevelwillbeobtainedatbaselineduringscreeningforallCHMIparticipants.Ifa
subjectinpost-CHMIfollow-upcomplainsofchestpainorhasothersignsand/orsymptoms
consistentwithacardiovascularevent,anothertroponinlevelwillbeobtainedandother
cardiovascularevaluationswillbeperformed,asmedicallyindicated.ConsultationwiththeNIH
CCCardiologyService(forPartsAandB)andUMBCardiologyService(forPartC)willbe
obtainedwhenindicatedbythesignsandsymptoms.
RegardlessofCHMIoutcomeandfollowingparasitemiaevaluations,subjectswhoreceived
CIS43LSwillcontinuetofollowtheScheduleofEvaluations,asoutlinedinAPPENDIXI.

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4.3.9.
ParasitemiaManagement
FollowingCHMI,acaseofmalariaparasitemiawillbedefinedaseitherasinglepositivePCR
resultorathickbloodsmearthatmeetsthecriteriaforpositivity.Thisallowsforcasesof
malariatobeidentifiedbeforegametocytescandevelopandthusbeforedetectionof
gametocytesbybloodsmeararedetectable.Malariainfectionwillbetreatedwhenthecriterion
foracaseismet.
RegardlessofPCRorbloodsmearresults,allCHMIparticipantswillreceivedirectlyobserved
antimalarialtreatmentatDay21postCHMI,iftheyhavenotalreadybeentreatedfor
parasitemiabythistimepoint.Subjectsmayalsobeprovidedwithtreatmentslikeantiemetics
andibuprofenasneededformanagementofsymptoms.
RefertotheScheduleofEvaluations,APPENDIXI,forthesafetylaboratoryevaluationsthatare
requiredtobeperformedattheonsetoftreatmentand2dayslater.
Malariainfectionsinallsubjectswillbetreatedpromptlyandadministeredasdirectlyobserved
therapy(DOT)byaclinicianuntilthespecifiedcourseoftreatment.Treatmentregimens
subsequentlydescribedareknowntobeeffectiveagainstthePfstrainbeingusedintheCHMI.
• Firstlineoftreatment:astandardatovaquone/proguanil(Malarone®)regimen:
FourMalaroneTablets(adultstrengthtablet=250mgatovaquone/100mgproguanil;
totaldailydose1gatovaquone/400mgproguanilhydrochloride)takenasasingle
dosedailyfor3consecutivedayswithfoodoramilkydrink.
• Alternativetreatment:astandardchloroquineregimen:
Totalof1500mgchloroquinebase(2500mgsalt)givenorallyindivideddoses:600
mgbase(1000mgsalt)initially,followedby300mgbase(500mgsalt)given6,24,
and48hourslater]
AlternativemedicationsandregimensknowntobeeffectiveincuringthePfstrainadministered
fortheCHMImaybeusedintheeventofallergies,intolerancesorlackofavailabilityof
treatmentslistedabove.
Followingtreatmentforapositivecaseofmalaria,curewillbedocumentedbyaPCRnegative
resultat26days(±5days)afterthecompletionoftreatment.
4.3.10.
Follow-UpthroughEndofStudy
Studyfollow-upwillcontinueviaclinicalvisitsthrough24weeksaftertheproduct
administrationor8weekspostfinalCHMI,whicheverismoststringent.Thevisitscheduleis
basedonintervalsoftimeafterproductadministrationorCHMI.Thescheduleofvisits,
allowablewindowsforcompletingthevisits,andevaluationsperformedateachvisitareshown
intheScheduleofEvaluations,APPENDIXI.Outofwindowstudyvisitswillbediscouraged
andrecordedasprotocoldeviationsbutmaybepermittedatthediscretionofthePIinthe
interestofobtainingsafetyandPKevaluationsfollowingexposuretotheinvestigationalstudy
productorconductofaCHMI.
Anysubjectwhoreceivesinvestigationalproductwillberequiredtofollowtheproduct
administrationscheduleforacompletesafetyandresearchevaluationthroughstudyduration.
SubjectswhoundergoCHMIwillberequiredtofollowtheCHMIScheduleofEvaluationsto

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completion.Whenvisitsfrombothschedulesoccuronthesameday,allrequiredcomponentsof
therequiredvisitsforeachschedulemustbecompleted.
SubjectswhoreceivestudyproductbutdonotreceiveCHMIasscheduledareexpectedto
continuefollow-upaccordingtothescheduleforIVorSCgroupthrough24weeks,exceptthat
researchsamplecollectionsmaybediscontinuedforpregnantwomenorothersinwhichitis
contraindicated.
RefertoSection4.6forcriteriafordiscontinuingproductadministrationand/orstudy
participation.
4.4.
ConcomitantMedications
Onlyroutineprescriptionmedicationswillbeenteredinthedatabaseatthetimeofenrollment.
Subsequently,concomitantmedicationsareonlyupdatedorrecordedinthestudydatabaseif
thereisanoccurrenceofanadverseevent(AE)thatrequiresexpeditedreportingorifthesubject
developsanewchronicconditionthatrequiresongoingmedicalmanagement.Treatmentwith
antimalarialdrugswillberecordedonaMalariaEndpointCaseReportForm(CRF).Otherwise,
theconcomitantmedicationchangesthroughoutthestudywillberecordedinthesubject’schart
asneededforgeneralmedicalrecordsbutwillnotberecordedinthestudydatabase.
4.5.
DoseEscalationPlan
Therearetwodoseescalationreviewsinthisstudy.Theactivationofadditionaldosegroups
willproceedinastagedmannerthatisgovernedbytheoutcomeoftheseplannedinterimPSRT
datareviews.ThePSRTmustassessthedataasshowingnosignificantsafetyconcernsbefore
proceedingwithgroupactivation.
PartAofthestudywillbeginwithdirectenrollmentofsubjectsintoGroup1.Followingthe
firstproductadministrationinGroup1,thestudyteamwillwaitatleast3daysbefore
administeringCIS43LStoadditionalsubjectswithinthatgroup.
Thefirstdoseescalationreview(from5mg/kgIVto5mg/kgSCand20mg/kgIV)willoccur
when3subjectswhoreceivedthe5mg/kgdosebyIVhavecompletedtheDay7safetyfollow-
upvisit.ThePSRTreviewwilldeterminewhetherenrollmentintoGroups2and3maybegin.
Theseconddoseescalationreview(from20mg/kgIVto40mg/kgIV)willoccurwhen3
subjectswhoreceivedthe20mg/kgIVdosehavecompletedtheDay7safetyfollow-upvisit.
ThePSRTreviewwilldeterminewhetherenrollmentintoGroups4Aand4Bmaybegin.
Iftherearediscontinuationsfromthestudybeforetherearesufficientdatatoconductthedose
escalationreviewforaspecificgroup,thenadditionalsubjectsmaybeenrolledtocompletethe
doseevaluation.Additionally,AEsassessedasrelatedtostudyproductatthetimeofadose
escalationreviewmaywarrantenrollmentofadditionalsubjectsintoadosegrouptoreassess
safetybeforeproceedingtoahigherdose.
ConsultationwiththeIRBorFDA,ifneeded,asperstudypausecriteria(Section4.5)willoccur
ifindicated.Oneoutcomeofadoseescalationreviewmaybetorecommendevaluationof
additionalsubjectsatthecurrentdoselevelandreassessforsafetybeforeproceedingtoahigher
doselevel.

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4.6.
CriteriaforDiscontinuationofProductAdministrationorProtocol
Participation
DecisionsbythePIordesigneetodiscontinueasubjectfromreceivingadditionalproduct
administrationsorfromprotocolparticipationforasubjectwillbemadewiththefollowing
criteria.
4.6.1.
DiscontinuationofStudyProductAdministration
PartAsubjectswillnotbepermittedtoreceiveadditionalstudyproductinPartBifanyofthe
followingapply:
1. Pregnancy;
2. Malariainfection;
3. Grade3AEassessedasrelatedtostudyproduct(exceptGrade3solicitedreactogenicity
lastinglessthan48hours);
4. Grade4AEassessedasrelatedtostudyproduct;
5. AnSAEofanygradeassessedasrelatedtostudyproduct;
6. Immediatehypersensitivityreactionassociatedwithstudyproduct;
7. Intercurrentillnessthatisnotexpectedtoresolvepriortothenextscheduledproduct
administration(ifapplicable);
8. Diagnosisofanewchronicorclinicallysignificantmedicalconditionthatintheopinion
oftheinvestigatorwouldjeopardizethesafetyorrightsofthesubject;
9. Repeatedfailuretocomplywithprotocolrequirements;
10.TheINDSponsororthestudyPIdecidetoterminatethestudy;or
11.TheIRB,OfficeforHumanResearchProtections(OHRP)ortheFDAhaltthestudy.
4.6.2.
DiscontinuationfromProtocolParticipation
Asubjectwillbediscontinuedfromprotocolparticipationforthefollowingreasons:
1. Subjectvoluntarilywithdraws;
2. Subjectdevelopsamedicalconditionthatisacontraindicationtocontinuingstudy
participation;
3. TheINDSponsororregulatoryauthoritystopstheprotocol;or
4. TheINDSponsororPIassessesthatisitnotinthebestinterestofthesubjecttocontinue
participationinthestudyorthatthesubject’scompliancewiththestudyisnotsufficient.
Forsubjectswhowishtodiscontinueprotocolparticipation,thefollowingrulesapplywiththe
exceptionthatresearchsamplecollectionswillbediscontinuedforpregnantwomenorothersin
whichitiscontraindicated:
• SubjectswhohavereceivedatleastonedoseofCIS43LSbutdonotparticipateinthe
CHMIareexpectedtocontinuewithsafetyfollow-upthroughatleastVisitA9orB9.

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• SubjectswhohavecompletedtheCHMIareexpectedtocontinuewithsafetyfollow-up
throughVisitC20orC40asapplicable.
4.7.
CriteriaforPausingandResumingtheStudy
Thestudyteamwillcloselymonitorandreviewstudydataastheybecomeavailabletomake
determinationsregardingthepresence,severityandattributionofAEs.Studyproduct
administrationsandnewenrollmentswillbepausedifanyofthefollowingcriteriaaremet:
• One(ormore)subjectexperiencesaSAEthatisassessedasrelated(possibly,probablyor
definitely)tothestudyproduct,or
• Two(ormore)subjectsexperiencethesameGrade3orhigherAEthatisassessedas
related(possibly,probablyordefinitely)tothestudyproduct(otherthanself-limited
Grade3solicitedreactogenicity).
4.7.1.
PlanforReviewofPausesandResumingRules
Intheeventofapause,theINDSponsorMedicalOfficer(MO)andthePSRTwillbepromptly
notified.
TheINDSponsorMOandPI,inconsultationwiththePSRT,willconductareviewofavailable
information,includingtheeventsthatleadtothepause,andwillmakethedecisiontoresume,
amendorclosethestudy.Aspartofthepausereview,thereviewersmayalsoadviseonwhether
thestudyneedstobepausedagainforanysubsequenteventsofthesametype.
StudyproductadministrationsandnewenrollmentswouldresumeonlyifreviewoftheAEsthat
causedthepauseresultsinarecommendationtopermitfurtherstudyproductadministrationsand
studyenrollments.Safetydatareportsandchangesinstudystatuswillbesubmittedtorelevant
regulatoryauthoritiesinaccordancewithSection5andinstitutionalpolicy.

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5.
SAFETYANDADVERSEEVENTS
5.1.
AdverseEvents
Anadverseevent(AE)isanyuntowardorunfavorablemedicaloccurrenceinahumansubject,
includinganyabnormalsign(e.g.,abnormalphysicalexamorlaboratoryfinding),symptom,or
diseasetemporallyassociatedwiththesubject’sparticipationinresearch,whetherornot
consideredrelatedtothesubject’sparticipationintheresearch.InthecontextofFDA-required
reporting,anAEmeansanyuntowardmedicaloccurrenceassociatedwiththeuseofadrugin
humans,whetherornotconsidereddrugrelated.
• SolicitedAEs(i.e.,reactogenicityparametersasdefinedinSection4.3.6)willbe
recordedwithoutattributionassessmentsbythesubjectonpaperoranelectronicdiary
for7daysaftereachproductadministration.
• UnsolicitedAEswillberecordedinthestudydatabasewithattributionassessments
duringthefollowingperiods:
1)fromproductadministrationthroughtheDay28post-productadministrationvisit;and
2)fromCHMIthroughtheDay28post-CHMIvisit.
Afterandbetweentheindicatedtimeperiods,onlySAEs(asdetailedinSection5.3)andnew
chronicmedicalconditionswillberecordedasAEsthroughthelastexpectedstudyvisitor
contact.
Malariaandtheassociatedsignsandsymptomsofparasitemiaeventsoccurringatanytime
duringthestudywillberecordedonaMalariaEndpointCRFandwillnotberecordedasanAE.
APPENDIXIIdescribeshowattributionassessments,therelationshipbetweenanAEandthe
studyproduct,CHMIorboth,willbedetermined.AlsoavailableinAPPENDIXIIisthelinkto
theDivisionofAIDS(DAIDS)TableforGradingtheSeverityofAdultandPediatricAdverse
Events,CorrectedVersion2.1[July2017],whichwillbeusedtodeterminetheseveritygrades
ofAEsinthisprotocolwithseveralmodificationsasnoted.
5.2.
SeriousAdverseEvents
Theterm“SeriousAdverseEvent”(SAE)isdefinedin21CFR312.32asfollows:“Anadverse
eventorsuspectedadversereactionisconsideredseriousif,intheviewofeithertheinvestigator
orthesponsor,itresultsinanyofthefollowingoutcomes:Death,alife-threateningadverse
event,inpatienthospitalizationorprolongationofexistinghospitalization,apersistentor
significantincapacityorsubstantialdisruptionoftheabilitytoconductnormallifefunctions,ora
congenitalanomaly/birthdefect.Importantmedicaleventsthatmaynotresultindeath,belife-
threatening,orrequirehospitalizationmaybeconsideredseriouswhen,baseduponappropriate
medicaljudgment,theymayjeopardizethepatientorsubjectandmayrequiremedicalor
surgicalinterventiontopreventoneoftheoutcomeslistedinthisdefinition.Examplesofsuch
medicaleventsincludeallergicbronchospasmrequiringintensivetreatmentinanemergency
roomorathome,blooddyscrasiasorconvulsionsthatdonotresultininpatienthospitalization,
orthedevelopmentofdrugdependencyordrugabuse.”

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“Lifethreatening”referstoanAEorsuspectedadversereactionthatrepresentsanimmediate
riskofdeathtothesubject.ItdoesnotincludeanAEorsuspectedadversereactionthat,hadit
occurredinamoresevereform,mighthavecauseddeath.Similarly,ahospitaladmissionforan
electiveprocedureisnotconsideredaSAE.
5.3.
AdverseEventReportingtotheINDSponsor
AEsthatmeetSAEcriteriamustbereportedandsubmittedbytheclinicalsiteonanexpedited
basistotheINDSponsor,VRC/NIAID/NIH,accordingtosponsorguidelinesasfollows:
• Resultsindeath;
• Islifethreatening(placesthesubjectatimmediateriskofdeathfromtheeventasit
occurred);
• Resultsininpatienthospitalizationorprolongationofexistinghospitalization;
• Resultsinapersistentorsignificantdisability/incapacity;
• Resultsinacongenitalanomaly/birthdefectintheoffspringofastudysubject;OR
• Baseduponappropriatemedicaljudgment,mayjeopardizethesubject’shealthandmay
requiremedicalorsurgicalinterventiontopreventoneoftheotheroutcomeslistedinthis
definition(examplesofsucheventsincludeallergicbronchospasmrequiringintensive
treatmentintheemergencyroomorathome,blooddyscrasiasorconvulsionsthatdonot
resultininpatienthospitalization,orthedevelopmentofdrugdependencyordrugabuse).
Inaddition,anyevent,regardlessofseverity,whichinthejudgmentofaninvestigatorrepresents
aSAE,maybereportedonanexpeditedbasis.
AninvestigatorwillcommunicateaninitialSAEreportwithin24hoursofsiteawarenessof
occurrencetotheINDSponsorbydataentryintothedatabase,whichtriggersanalerttotheIND
SponsorMO.Within3workingdays,awrittensummarybytheinvestigatorshouldbe
submittedtotheINDSponsor.
InorderfortheINDSponsortocomplywithregulationsmandatingsponsornotificationof
specifiedSAEstotheFDAwithin7and/or15calendardays,theinvestigatormustsubmit
additionalinformationassoonasitisavailable.
5.4.
INDSponsorReportingtotheFDA
TheINDSponsorisresponsibleformakingthedeterminationofwhichSAEsare“seriousand
unexpectedsuspectedadversereactions”(SUSARs)asdefinedin21CFR312.32.
• SuspectedAdverseReactionmeansanyAEforwhichthereisareasonablepossibilitythat
thedrugcausedtheAE.
• UnexpectedAdverseEventmeansanAEthatisnotlistedatthespecificityorseveritythat
hasbeenobserved.
AllSUSARs(asdeterminedbytheINDSponsor)willbereportedtotheFDAasINDSafety
Reportsper21CFR312.32assoonaspossiblebutnotexceeding7calendardaysforunexpected

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fatalorlife-threateningevents,andnotexceeding15calendardaysforotherqualifyingevents.
INDSafetyReportswillalsobeprovidedtotheIRB.
TheINDSponsorwillalsosubmitanINDAnnualReportoftheprogressoftheinvestigationto
theFDAasdefinedin21CFR312.33.
5.5.
ReportingtotheInstitutionalReviewBoard
ThefollowinginformationisconsistentwithNIHIRBPolicy801:ReportingResearchEvents.
ReportableEvent-Aneventthatoccursduringthecourseofhumansubjectresearchthat
requiresnotificationtotheIRB.
Forthepurposesofthispolicy,reportableeventsincludethefollowing:
• UnanticipatedProblems(UPs)involvingriskstosubjectsorothers
• Non-compliance(includingmajorprotocoldeviationsandnoncompliancethatisnot
relatedtoaprotocoldeviation)
• Deathsrelatedorpossiblyrelatedtoresearchactivities
• Newinformationthatmightaffectthewillingnessofsubjectstoenrollorcontinue
participationinthestudy
5.5.1.
UnanticipatedProblem
AnUnanticipatedProblem(UP)isdefinedasanyincident,experience,oroutcomethatmeetsall
thefollowingcriteria:
• Unexpected(intermsofnature,severity,orfrequency)given(a)theresearchprocedures
thataredescribedintheprotocol-relateddocuments,suchastheIRBapprovedresearch
protocolandinformedconsentdocument;and(b)thecharacteristicsofthesubject
populationbeingstudied;and
• Relatedorpossiblyrelatedtoparticipationintheresearch(possiblyrelatedmeansthereis
areasonablepossibilitythattheincident,experience,oroutcomemayhavebeencaused
bytheproceduresinvolvedintheresearch);and
• Suggeststhattheresearchplacessubjects,orothers(whichmayincluderesearchstaff,
familymembersorotherindividualsnotdirectlyparticipatingintheresearch)atagreater
riskofharm(includingphysical,psychological,economic,orsocialharm)relatedtothe
researchthanwaspreviouslyknownorexpected.
AUPmustbereportedwithin7calendardaysofaninvestigatorbecomingawareoftheactualor
suspectedUP.
5.5.2.
Non-Compliance
Non-complianceisthefailureofinvestigator(s)tofollowtheapplicablelaws,regulations,or
institutionalpoliciesgoverningtheprotectionofhumansubjectsinresearch,ortherequirements
ordeterminationsoftheIRB,whetherintentionalornot.

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Non-compliancemaybeunintentional(e.g.duetolackofunderstanding,knowledge,or
commitment),orintentional(e.g.duetodeliberatechoicetoignoreorcompromisethe
requirementsofanyapplicableregulation,organizationalpolicy,ordeterminationoftheIRB).
Non-complianceisfurthercharacterizedasseriousorcontinuingasfollows:
• Seriousnon-compliance–Non-compliance,whetherintentionalornot,thatresultsin
harmorotherwisemateriallycompromisestherights,welfareand/orsafetyofthesubject.
Non-compliancethatmateriallyeffectsthescientificintegrityorvalidityoftheresearch
maybeconsideredseriousnon-compliance,evenifitdoesnotresultindirectharmto
researchsubjects.
• Continuingnon-compliance–Apatternofrecurringnon-compliancethateitherhas
resulted,or,ifcontinued,mayresultinharmtosubjectsorotherwisematerially
compromisetherights,welfareand/orsafetyofsubjects,affectthescientificintegrityof
thestudyorvalidityoftheresults.Thepatternmaycompriserepetitionofthesamenon-
compliantaction(s),ordifferentnoncompliantevents.
Anyactualorsuspectednon-compliancebyanyinvestigatororentityassociatedwiththe
protocolmustbereportedtotheIRBbythePI/designeewithin7calendardaysofany
investigatororindividualassociatedwiththeprotocolfirstbecomingaware.
5.5.3.
ProtocolDeviation
AProtocolDeviation(PD)isdefinedasanychange,divergence,ordeparturefromtheIRB-
approvedresearchprotocolandarefurthercharacterizedasmajorandminorasfollows:
• MajorDeviations–DeviationsfromtheIRBapprovedprotocolthathave,ormayhavethe
potentialto,negativelyimpact,therights,welfareorsafetyofthesubject,orto
substantiallynegativelyimpactthescientificintegrityorvalidityofthestudy.
• MinorDeviations–Deviationsthatdonothavethepotentialtonegativelyimpactthe
rights,safety,orwelfareofsubjectsorothers,orthescientificintegrityorvalidityofthe
study.
Forthereportingpurposes,failureofsubjectstocomplywiththeresearchprotocoldoesnot
representnon-complianceunlessthatfailureisduetoanactionoromissionofamemberofthe
researchteam,forexample,thefailuretogiveadequateinstructiontothesubject.
Amajordeviationmustbereportedwithin7calendardaysofaninvestigatorbecomingawareof
anactualorsuspecteddeviation.AlthoughPDsarealsonon-compliance,theseshouldonlybe
reportedonceasdeviations.Majordeviationsresultingindeathmustbereportedwithin24
hoursoftheoccurrenceoftheeventorofanymemberofthestudyteambecomingawareofthe
death.
Researchersareresponsibleformonitoringtheirstudiesthroughouttheyearforadherencetothe
IRBapprovedprotocol.Thepurposeofthismonitoringistoidentifymajordeviationsandto
lookfortrendsinminordeviationsthatmayindicateasystemicissueinhowthestudyisbeing
conductedthatcouldpotentiallynegativelyimpacttherights,safety,orwelfareofparticipantsor
thestudy’sabilitytoproducescientificallyvalidresults.Aseriesofminordeviationspointing
towardamoreglobalissuethatcouldaffecttherights,safetyorwelfareoftheparticipantor

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affectthevalidityofthestudyshouldbereportedasamajordeviation.Inallotherinstances,a
summaryofminordeviationsshouldbeprovidedtotheIRBatthetimeofcontinuingreview.
5.5.4.
Death
Anydeathofaresearchsubjectthatispossibly,probablyordefinitelyrelatedtotheresearch
mustbereportedwithin24hoursofaninvestigatorbecomingawareofthedeath.
5.5.5.
NewInformation
Newinformationthatmightaffectthewillingnessofasubjecttoenrollorremaininthestudy
shouldbereportedwithin7calendardaysofaninvestigatorfirstbecomingaware.
5.5.6.
SuspensionorTerminationofResearchActivities
Anysuspensionorterminationofresearchactivities,includingholdsonnewenrollment,placed
upontheresearchbythestudysponsor,NIHorICleadership,oranyregulatoryagencymustbe
reportedwithin7calendardaysofaninvestigatorbecomingaware.
5.5.7.
ExpeditedReportingtotheIRB
Deathrelatedtoresearchmustbereportedwithin24hours.
Thefollowingwillbereportedwithin7calendardaysofinvestigatorawareness:
• ActualorsuspectedUPs;
• Actualorsuspectednon-compliance;
• ActualorsuspectedMajorPDs;
• SAEsthatareactualorsuspectedUPs;
• Newinformationthatmightaffectthewillingnessofasubjecttoenrollorremaininthe
study;
• Suspensionorterminationofresearchactivities,includingholdsonnewenrollment,
placedupontheresearchbythestudysponsor,NIHorICleadership,oranyregulatory
agency.
5.5.8.
AnnualReportingtotheIRB
ThefollowingwillbereportedtotheIRBinsummaryatthetimeofContinuingReview:
• SummaryofUPsandnon-compliance;
• AEs,includingSAEs,thatarenotUPs,asanarrativesummarystatementindicating
whethertheseeventswerewithintheexpectedrange;
• MinorPDs(aggregatesummary);
• Anytrendsoreventswhichintheopinionoftheinvestigatorshouldbereported.

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6.
STATISTICALCONSIDERATIONS
6.1.
Overview
ThisstudyisaPhase1,dose-escalationstudyinhealthyadultstoassessthesafety,PKand
protectiveefficacyofCIS43LS,aninvestigationalhumanantimalarialmAb.
6.2.
SampleSizeandAccrual
Trialrecruitmentwilltargetabout92healthyadults,ages18to50years,asshowninTable1.
Thepermittedaccrualis100subjectsintotaltoallowforadditionalenrollmentsintheeventthat
anenrolledsubjectdoesnotcompletetheminimumevaluationsneededtomeettheprotocol
criteriaforadose-escalationevaluation.DoseescalationrulesaredescribedinSection4.5.Ifa
subjectenrollsintoastudyproductgroupbutdoesnotreceiveaproductadministrationor
withdrawsbeforethechallengeforreasonsthatarenotsafetyrelated,oracontrolgroupsubject
withdrawsbeforethemalariachallengeoccurs,thenadditionalsubjectsmaybeenrolledto
achievetheaccrualtarget.Followingawithdrawalfromastudyproductgroup,additional
enrollmentsmaybemadeifthereissufficienttimetocompleteproductadministrationpriorto
thescheduledCHMI.
TheprimarygoalofthisstudyistoidentifysafetyconcernsassociatedwithCIS43LSatdifferent
doses.Primarysamplesizeconsiderationsareexpressedintermsoftheabilitytodetectserious
adverseexperiences.TheabilityofthestudytoidentifySAEswillbeexpressedintermsofthe
probabilityofobservingacertainnumberofseriousadverseevents.Withsamplesizen=6,there
isover90%chancetoobserveatleast1SAEifthetruerateisatleast0.319andover90%
chancetoobservenoSAEifthetruerateisnomorethan0.017.Withsamplesizen=4,thereis
over90%chancetoobserveatleast1SAEifthetruerateisnolessthan0.438andover90%
chanceofobservingnoSAEifthetruerateisnomorethan0.025.Probabilitiesofobserving0
ormorethan1SAEwithinagrouparepresentedinTable2forarangeofpossibletrueevent
rates.
Table2:
ProbabilityofEventsforDifferentSafetyScenarioswithinaGroup(n=6or
4)
TrueEventRate
n=6
n=4
Pr(0)
Pr(>1)
Pr(0)
Pr(>1)
0.005
0.970
0.000
0.980
0.000
0.01
0.941
0.001
0.961
0.001
0.02
0.886
0.006
0.922
0.002
0.035
0.808
0.017
0.867
0.007
0.05
0.735
0.033
0.815
0.014
0.1
0.531
0.114
0.656
0.052
0.15
0.377
0.224
0.522
0.110
0.2
0.262
0.345
0.410
0.181
0.3
0.118
0.580
0.240
0.348




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Table3givestheupperandlowerboundsfor95%exactbinomialconfidenceintervalsofthe
trueSAErateatpossiblenumbersofeventswithinagroup.Withinagroupofsizen=6,ifnone
experienceanSAE,the95%exactconfidenceintervalhasupperbound0.459.Withinagroup
ofsizen=4,ifnoneexperienceanSAE,theexact95%confidenceintervalhasanupperbound
0.602.
Table3:
95%ConfidenceIntervalsfortheTrueRateatPossibleObservedNumberof
EventsinaGroup(n=6orn=4)oracrossGroups(n=24)
Observed
Numberof
Events
95%ConfidenceInterval
(n=6)
95%ConfidenceInterval
(n=4)
95%ConfidenceInterval
(n=24)
Lower
Bound
Upper
Bound
Lower
Bound
Upper
Bound
Lower
Bound
Upper
Bound
0
0.000
0.459
0.000
0.000
0.000
0.142
1
0.004
0.641
0.001
0.001
0.001
0.211
2
0.043
0.777
0.010
0.010
0.010
0.270
3
0.118
0.882
0.027
0.027
0.027
0.324
4
0.223
0.957
0.047
0.047
0.047
0.374
5
0.359
0.996
0.071
0.071
0.071
0.422
6
0.541
1.000
0.098
0.098
0.098
0.467
6.3.
StatisticalAnalysis
EnrollmentofCIS43LSrecipientsmayoccuronthesamedayasproductadministrationatVisit
02(Day0)orinadvanceofproductadministrationatVisitA1RorB1R(Day-28toDay0),
exceptinthecaseofcontrols.Allsubjectswhoreceiveproductadministrationwillprovide
safetydata.
Threeanalysiscohortsareinvolvedinstatisticalanalysis.TheIntent-to-treat(ITT)cohortwill
includeallenrolledsubjectswhoreceiveproductadministrationandwillbeanalyzedaccording
totheassignedgroup.ThePer-Protocol(PP)cohortwillincludeallenrolledsubjectswho
receiveproductadministrationandwillbeanalyzedaccordingtotheactualdosetheyreceive.
TheModifiedintent-to-treat(mITT)cohortwillincludeallenrolledsubjectswhoreceiveproduct
administrationfollowedbyCHMIchallengeandwillbeanalyzedaccordingtotheassigned
group.
AllstatisticalanalyseswillbeperformedusingSASandRstatisticalsoftware.
6.3.1.
AnalysisVariables
Theanalysisvariablesconsistofbaseline,safetyparameters,PK,andpresenceorabsenceof
malariainfectionafterCHMI.Descriptivestatisticswillbeusedtosummarizebaseline
characteristics,inclusiveofdemographicsandsafetylaboratorymeasurements.
6.3.2.
SafetyAnalysis
SafetyevaluationwillbeperformedovertheITTcohort.Thenumberandpercentageofsubjects
withoneormoreAEswillbesummarizedbydosegroupalongwiththeexact95%confidence
intervalsoftheAErate.ForsubjectsexperiencingmorethanoneAE,theywillbecountedonce
undertheeventofhighestseverity.Inaddition,acompletelistingofAEsforeachsubjectwill
providedetailssuchasseverity,duration,andrelationshiptostudyproduct.Summarieswillbe
providedforanysolicitedorunsolicitedAEs.

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a. SolicitedReactogenicity
SolicitedAEdatawillbecollectedafterproductadministration.Thenumberandpercentageof
subjectsexperiencingeachtypeofsolicitedsignorsymptomwillbetabulatedbyseverityandby
dosegroupandoverall(i.e.,pooledIVdosegroupsandpooledSCandIVdosegroups).
Subjectswithmultipleoccurrencesofthesameeventwillbecountedonceusingtheeventof
highestseverity.
b. AdverseEvents
AllreportableAEswillberecordedandcodedbyMedicalDictionaryforRegulatoryActivities
(MedDRA)systemorganclass(SOC)andpreferredterm(PT).Thenumberandpercentagesof
subjectswitheachunsolicitedAEwillbetabulatedbyseverityandrelationshiptothestudy
product,andbydosegroupandoverall(i.e.,pooledIVdosegroupsandpooledSCandIVdose
groups).Subjectswithmultipleoccurrencesofthesameeventwillbecountedonceusingthe
eventhighestseverityorstrongestrelationshiptothestudytreatment.
Aby-subjectlistingofallunsolicitedAEswillprovidedetailsincludingseverity,relationshipto
treatmenttype,seriousness,newmedicalconditionstatus,onsetandenddate,duration,and
outcome.
c. LocalLaboratoryValues
Boxplotsoflocallaboratoryvalueswillbegeneratedforbaselinevaluesandforvaluesmeasured
duringthecourseofthestudy.Eachboxplotwillshowthe1stquartile,themedian,andthe3rd
quartile.Outliers,orvaluesoutsidetheboxplot,willalsobeplotted.Ifappropriate,horizontal
linesrepresentingboundariesforabnormalvalueswillbeplotted.
6.3.3.
PharmacokineticsAnalysis
PKanalysiswillbeperformedoverthePPcohort.BloodsamplesforPKevaluationswillbe
collectedatdefinedtime-pointsaslistedinAPPENDIXII.
IndividualSubjectPharmacokineticAnalysis:Anon-compartmental(NC)PKanalysiswill
beperformedusingPhoenix7.0(CertaraR),PKPlusorasimilarprogramontheCIS43LS
concentrationdatageneratedfromeachsubject.Individualsubjectanddosinggroup
concentrationvstimeprofileswillbeconstructedinlinearandsemi-logscales.IntheNC
analysisthemaximumconcentration(Cmax)andtimeofmaximalconcentration(Tmax)willbe
takendirectlyfromtheobserveddata.Theareaundertheconcentrationsvs.timecurve(AUC)
willbecalculatedusingthetrapezoidalmethodanddeterminedouttothefinalconcentration
collected.IfasubjectsCIS43LSconcentrationfallsbelowthequantitativelimit(QL)ofthe
assaybeforethefinalofPKsamplecollection,thesamplewithconcentrationbelowtheQLwill
beassignedaCIS43LSconcentrationvalueof“0”forAUCcalculations.LaterPKsamplesafter
theinitialconcentrationbelowtheQLsamplewillbeignoredinAUCcalculationsbecause
partialAUCisnotcontributorytothetotalAUC.InadditiontocalculationofthetotalAUC
fromTime=0tothelastCIS43LSconcentration(AUC0-last),partialAUCsfromTime=0toWeek
16(AUC0-16WK),Time=0totheCHMIchallenge(AUC0-CHMI)andTimeofCHMItoWeek16
(AUCCHMI-16WK)willbedetermined.Thetimeweightedaverageconcentrations(Cave)during
theseintervalswillbecalculatedastheAUCdividedbytheAUCcollectioninterval,e.g.Cave0-
16WK=(AUC0-16WK)/16weeks.Theterminalslope,λzwillbedeterminedbyregressionofthe
terminal,log-linearportionoftheconcentrationvs.timeprofile.IfthefinalPKsamplehas

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measurableCIS43LSconcentrationsgreaterthantheassayQL,theAUCpostfinalPKcollection
(AUClast-infinity)willbeestimatedasClast/λzandAUC0-infinitywillbecalculatedassumAUC0-last+
AUClast-infinity.
PopulationPharmacokineticAnalyses:PopulationPKanalyseswillbeperformedonthePK
datafollowingIVandSCadministrationtodeterminecompartmentalPKparameterswiththe
PKprogramNONMEM7.3orlater(ICONR).BasedonpreclinicalPKresultsforCIS43LSand
knownPKbehaviorstudiesofmAbs,two-compartmentmodelwillbeused(subroutine
ADVAN4TRANS4).BothzeroorderandfirstorderabsorptionfollowingSCadministration
willbeevaluatedandalagtimeincludedifadelayisseenintherawdatafigures.TheFirst
OrderConditionalEstimationMethodwithInteraction(FOCEI)willbeused.Thepopulation
analysiswillgenerateestimatesforclearance(CL)centralandperipheralvolumesofdistribution
(Vd1andVd2),inter-compartmentalclearance(Q),CLandSCbioavailability(F).Totalvolume
ofdistributionatsteady-state(Vdss),willbecalculatedasthesumofVd1+Vd2.Alphaandbeta
half-liveswillbecalculatedfromCL,Q,Vd1andVd2usingstandardequations(M.Gilbaldiand
DPerrier,PharmacokineticsMarcelDekker,1975).Whilethenumberofsubjectsisexpectedto
besufficienttocharacterizethetypicalPKparametersandtheirbetween-subjectvariabilities
(BSVs),thesamplenumberistoosmallforarobustbroadpopulationPKcovariateanalysis.
Therefore,theimpactofsubjects’sizewillbeaccountedforusingallometricscalingnormalized
to70kgwithdoselevelandCHMIresponsebeingtheonlycovariatesexplored.Individual
subjects’empiricBayesianPKparameterestimateswillbegeneratedusingtheposthoc
subroutine.
Finalmodelselectionwillbebasedonchangesintheobjectivefunction,agoodnessoffit
statisticgeneratedbyNONMEM,andgraphicallybygoodnessoffitplots.Thefinalpopulation
PKmodelwillbeassessedusingbootstrapanalysis.Dosingstrategiesandtheirabilityto
achieveandmaintaintargetCIS43LSconcentrationswillbeperformedusingthefinalpopulation
PKmodelandMonteCarlosimulationswithatleast5000replicates.
6.3.4.
EfficacyAnalysis
EfficacyanalysiswillbeperformedoverthemITTcohort.Theprimaryefficacyanalysiswillbe
basedonatwo-sidedBarnardtestontheproportionofinfectionamongthosewhoreceive
CIS43LSversusthecontrolswhoundergoCHMIconcurrently.Thesecondaryefficacyanalyses
willbebasedontimetoparasitemia,whereCIS43LSrecipientswillbecomparedwiththe
controlsviaalog-ranktest.Kaplan-Meiercurveswillalsobeprovidedforeachgroup.Efficacy
analyseswillbeperformedforPartBandPartCseparately.Anefficacyanalysisoverall
participantsinPartBandPartCcombinedwillalsobeperformed.
Duetovariabletimingofchallengeamongstudyparticipants,alogisticregressionwillbe
performedtoestimatetheinfectionriskasafunctionofthemAbconcentrationatthetimeof
challenge.Forthesamereason,aCoxproportionalhazardsregressionwillbeperformedto
estimatethehazardfunctionwiththemAbconcentrationatthetimeofchallengeasaregressor.
BothregressionswillbecarriedoutoverthesubjectsinPartBandPartCcombined,aswellas
ineachPartseparately,providedthattherearecasesofinfectionamongCIS43LSrecipients.

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6.3.5.
Interimanalyses
SafetyandPKdatawillbeanalyzedatthecompletionofeachdosegroupinPartsAandB.
PreliminaryPKanalysesmaybedoneonceperdoselevelasthedataforeachdoselevelis
obtained.Thismaybeperformedbeforeadosegroup’sPKdataiscompleteandmayonly
generateasubsetofthefinalPKparameters.Theinterimanalyseswillbeusedtoinform
decisionsaboutdoselevels,timingofCHMI,andsubjectpopulationforPartsBandC.

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7.
PHARMACYPROCEDURES
ThestudygroupsareshowninTable1.
7.1.
StudyProduct
VRC-MALMAB0100-00-AB(CIS43LS)isasterilebufferedsolutionthatisfilledintosingle-
dosevials.Eachvialcontains5.5±0.10mLofCIS43LSataconcentrationof100±10mg/mL
informulationbuffercomposedof10mMAcetate-Phosphate,25mMSodiumChloride,10mM
SodiumCitrate,100mMArginineHydrochloride,and0.02%(w/v)Polysorbate-68atpH6.0.
7.2.
StorageandTemperatureExcursions
Thesitepharmacistmustpromptlyreportanystoragetemperatureexcursionsoutsideofthe
normalallowancetotheINDSponsor.Theaffectedproductmustbequarantinedinaseparate
areaunderprotocol-specifictemperaturerangesuntilfurthernoticefromtheSponsor.Ifthe
excursionresultsinthawedmaterial,DONOTREFREEZE;storethethawed,vialedmaterialat
2°Cto8°C.
Whenastorage/shipping/handlingexcursionoccurs,theINDSponsordesigneemustsenda
notificationoftheoccurrenceofanexcursionto
Anautomatic
emailreplywillbesenttothenotifier,including(asanattachment)theClinicalExcursion
ReportingForm,whichcanbefilledelectronically(ormanuallyandscanned,ifneeded).The
completedformandrelevantattachments(e.g.temperaturecharts)mustbeemailedtotheVRC
viathesameemailaddress
usingthe“reply”function.The
INDSponsorwillnotifythesitepharmacistifcontinuedclinicaluseoftheproductisacceptable
orwillprovidefurtherinstructions.
7.3.
LabelingofStudyProductVial
Vialsofstudyproductwillbeindividuallylabeledwiththenameofthematerial,volume,lot
number,concentration,storageinstructions,InvestigationalUseStatement(“LimitedbyFederal
LawtoInvestigationalUse”),andmanufacturerinformation.
7.4.
PreparationofStudyProductforAdministration
Thissectiondescribeshowtopreparestudyinjectionsandwillbeupdatedwheninformationis
available.
7.4.1.
PreparationforIVAdministration
ForeachIVinfusionorder,thesubject’sweight,doselevel,andstudygroupcodewillbe
includedinthepharmacyorder.ToprepareanIVinfusion,thepharmacistwill:1)calculatethe
totalmilligramsofCIS43LSneeded,2)retrievetheminimumnumberofthawedvialsrequired
topreparethefulldose,3)withdrawthenecessaryamountofCIS43LS,and4)addthisvolume
toa150mLcapacity,partialfill,100mLbagofnormalsalineusingsterilecompounding
techniquestomaintainsterility.
Thawandequilibratevialsforaminimumof1hourand30minutesatambienttemperature
(15°Cto32°C).Ifthawedvialsareremovedfrom2°Cto8°C,equilibrateatambient

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temperatureforaminimumof30minutes.PriortopreparationforadministrationintheIVbag,
vialsshouldbegentlyswirledforapproximately30secondswhileavoidingfoaming.DONOT
SHAKETHEVIAL.
Anin-linefilterinfusionsetmustbeusedforIVproductadministrationsandMUSTcomply
withthefollowingspecifications:1.2-micronPES(polyethersulfone)filtermembrane,DEHP-
free,latex-free(equivalenttoBraun#473994filterextensionset).Whenthein-linefilteris
addedtothetubing,theadministrationsetmustthenbeprimed.
ThestudyproductsolutionwilltypicallybeadministeredIVoverabout15-30minutesusinga
volumetricpump.Thetotaltimeneededtoadministerthedosemaybelongerthan30minutes
basedonfactorssuchassubjecttolerance.Therateofinfusionmayrangefrom10-20mg/kg/hr
atthelowestdoselevelto80-160mg/kg/hratthehighestdoselevel.ThemL/hrinfusionrate
mayvarybasedonthetotalvolumeneededtoadministerafulldose.
Attheendofproductadministration,theIVadministrationsetmustbeflushedwithabout30mL
(orappropriatevolume)ofnormalsaline.
7.4.2.
PreparationforSCAdministration
ForeachSCadministrationorder,thesubject’sweight,doselevel,andstudygroupcodewillbe
includedinthepharmacyorder.ToprepareaSCadministrationdose,thepharmacistwill
calculatethetotalmgneededandretrievetheminimumnumberofvialsneededtopreparethe
fulldose.Thawandequilibratevialsforaminimumof1hourand30minutesatambient
temperature(15°Cto32°C).Ifthawedvialsareremovedfrom2°Cto8°C,equilibrateat
ambienttemperatureforaminimumof30minutes.Priortopreparationforadministration,vials
shouldbegentlyswirledforapproximately30secondswhileavoidingfoaming.DONOT
SHAKETHEVIALS.
TheneededvolumeofCIS43LSmustbewithdrawnfromthevialinto1to6syringesusinga5-
micronfilterneedle.Anewfilterneedlemustbeusedforeachsyringe.Thefilterneedlemust
bediscardedpriortodispensingandreplacedwithaneedlesuitableforSCinjectionatthetime
ofadministration.TheproductmaybeadministeredbydirectSCinjectionwithneedleand
syringe.TheclinicianwilluseproperSCtechniquetoensureadministrationintoSCfattylayer
andaslowpushtominimizediscomfortortheexcessivedistentionofoverlyingskin.
7.4.3.
HandlingofPreparedProductforIVorSCAdministration
AfterproductpreparationinanIVbag,thepreparedCIS43LSmaybestoredat2°Cto8°Cfora
maximumof24hoursand/oratambienttemperature(15°Cto32°C)foramaximumof4hours
totalincludingtheinfusiontime.Productmaynotbestoredindirectsunlight.
AfterpreparationinsyringesforSCadministration,thepreparedCIS43LSmaybestoredat2°C
to8°Cupto24hoursand/oratambienttemperature(15°Cto32°C)upto4hours.Productmay
notbestoredindirectsunlight.
7.5.
StudyProductAccountability
Astudypharmacistordesigneewillberesponsibleformaintaininganaccuraterecordofthe
studygroupcodes,inventory,andanaccountabilityrecordofstudyagentsupplies.Electronic
documentationaswellaspapercopiesmaybeused.

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7.6.
StudyProductDisposition
Theemptyvialsandtheunusedportionofavialwillbediscardedinabiohazardcontainment
bagandincineratedorautoclavedinaccordancewiththeinstitutionalorpharmacypolicy.Any
unopenedvialsthatremainattheendofthestudywillbereturnedtotheproductionfacilityor
discardedatthediscretionofthesponsorinaccordancewithpoliciesthatapplytoinvestigational
agents.Partiallyusedvialswillnotbeadministeredtoothersubjectsorusedforinvitro
experimentalstudies.Thesevialswillbedisposedofinaccordancewithinstitutionalor
pharmacypolicy.

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8.
HUMANSUBJECTPROTECTIONSANDETHICAL
OBLIGATIONS
Thisresearchwillbeconductedincompliancewiththeprotocol,InternationalConferenceon
Harmonisation(ICH)GoodClinicalPractice(GCP)guidelinesandallapplicableregulatory
requirements.
8.1.
InstitutionalReviewBoard
ARelianceAgreementwillbeestablishedwiththecollaboratingUMBsiteandWRAIRCHMI
facilitysuchthattheNIHIRBistheIRBofRecordfortheconductoftheVRC612protocol.
Theprotocol,proposedinformedconsentform,otherwrittensubjectinformation,andany
proposedadvertisingmaterialwillbesubmittedbytheCoordinatingSite(VRC)totheIRBfor
reviewandwrittenapproval.
TheProtocolChairmustsubmitand,wherenecessary,obtainapprovalfromtheIRBforall
subsequentprotocolamendmentsandchangestotheinformedconsentdocument.TheProtocol
ChairwillnotifytheNIHIRBofresearcheventsthatoccuronstudyasdescribedinSection5.5.
TheProtocolChairwillberesponsibleforobtainingIRBapprovaloftheannualContinuing
Reviewthroughoutthedurationofthestudy.
8.2.
InformedConsent
Thestudyinformedconsentform(ICF)isprovidedasaseparatedocumentanddescribesthe
investigationalproducttobeusedandallaspectsinvolvedinprotocolparticipation.
ThesitePIordesigneeisresponsibleforobtainingwritteninformedconsentfromthesubject
afteradequateexplanationoftheaims,methods,anticipatedrisksandbenefitsofthestudyand
beforeanyprotocol-specificproceduresorstudyproductisadministered.TheAoUwillbe
completedbeforethestudyICFissigned.
Theacquisitionofinformedconsentwillbedocumentedinthesubject’smedicalrecords,as
requiredby21CFR312.62,andtheICFwillbesignedandpersonallydatedbythesubjectand
thepersonwhoconductedtheinformedconsentdiscussion.ThesignedICFwillberetainedin
themedicalchartandacopyoftheICFwillbeprovidedtothesubject.
8.3.
StudyDiscontinuationandClosure
Thisstudymaybetemporarilysuspendedorprematurelyterminatedifthereissufficient
reasonablecause.Writtennotification,documentingthereasonforstudysuspensionor
termination,willbeprovidedbythesuspendingorterminatingpartytostudyparticipants,the
investigators,theInvestigationalNewDrug(IND)andregulatoryauthoritiesasappropriate.If
thestudyisprematurelyterminatedorsuspended,thePrincipalInvestigator(PI)willpromptly
informstudyparticipants,theInstitutionalReviewBoard(IRB),andSponsorandwillprovide
thereason(s)fortheterminationorsuspension.Studyparticipantswillbecontacted,as
applicable,andbeinformedofchangestostudyvisitschedule.
Circumstancesthatmaywarrantterminationorsuspensioninclude,butarenotlimitedto:
• Determinationofunexpected,significant,orunacceptablerisktoparticipants

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• Demonstrationofefficacythatwouldwarrantstopping
• Insufficientcompliancetoprotocolrequirements
• Datathatarenotsufficientlycompleteand/orevaluable
• Determinationthattheprimaryendpointhasbeenmet
• Determinationoffutility
Thestudymayresumeonceconcernsaboutsafety,protocolcompliance,anddataqualityare
addressed,andsatisfytheSponsor,IRBand/orFDA.
8.4.
ConfidentialityandPrivacy
Participantconfidentialityandprivacyarestrictlyheldintrustbytheparticipatinginvestigators,
theirstaff,andtheSponsorandtheirrepresentatives.Thisconfidentialityisextendedtocover
testingofbiologicalsamplesinadditiontotheclinicalinformationrelatingtoparticipants.
Therefore,thestudyprotocol,documentation,data,andallotherinformationgeneratedwillbe
heldinstrictconfidence.Noinformationconcerningthestudyorthedatawillbereleasedtoany
unauthorizedthirdpartywithoutpriorwrittenapprovalofthesponsor.
Allresearchactivitieswillbeconductedinasprivateasettingaspossible.
Thestudymonitor,otherauthorizedrepresentativesoftheSponsor,representativesofthe
InstitutionalReviewBoard(IRB),and/orregulatoryagenciesmayinspectalldocumentsand
recordsrequiredtobemaintainedbytheinvestigator,includingbutnotlimitedto,medical
records(office,clinic,orhospital)andpharmacyrecordsfortheparticipantsinthisstudy.The
clinicalstudysitewillpermitaccesstosuchrecords.
Thestudyparticipant’scontactinformationwillbesecurelystoredattheclinicalsiteforinternal
useduringthestudy.Attheendofthestudy,allrecordswillcontinuetobekeptinasecure
locationforaslongaperiodasdictatedbythereviewingIRB,Institutionalpolicies,orSponsor
requirements.
Studyparticipantresearchdata,whichisforpurposesofstatisticalanalysisandscientific
reporting,willbetransmittedtoandstoredby
theDataCoordinatingCenter.Thiswill
notincludetheparticipant’scontactoridentifyinginformation.Rather,individualparticipants
andtheirresearchdatawillbeidentifiedbyauniquestudyidentificationnumber.Thestudydata
entryandstudymanagementsystemsusedbytheclinicalsiteandbyEmmesresearchstaffwill
besecuredandpasswordprotected.Attheendofthestudy,allstudydatabaseswillbede-
identifiedandarchived.
Tofurtherprotecttheprivacyofstudyparticipants,aCertificateofConfidentialityhasbeen
issuedbytheNationalInstitutesofHealth(NIH).Thiscertificateprotectsidentifiableresearch
informationfromforceddisclosure.Itallowstheinvestigatorandotherswhohaveaccessto
researchrecordstorefusetodiscloseidentifyinginformationonresearchparticipationinany
civil,criminal,administrative,legislative,orotherproceeding,whetheratthefederal,state,or
locallevel.Byprotectingresearchersandinstitutionsfrombeingcompelledtodisclose
informationthatwouldidentifyresearchparticipants,CertificatesofConfidentialityhelpachieve
theresearchobjectivesandpromoteparticipationinstudiesbyhelpingassureconfidentialityand
privacytoparticipants.

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8.5.
Risk/BenefitAssessment
8.5.1.
PotentialRisks
RiskofCIS43LS:WhileCIS43LShasbeenwell-toleratedtodateinthisstudy,only
preliminarysafetydatainhumansexistsandrisksarenotfullyknown.SeeSection2.3fora
summaryofavailableinterimdatacollectedinVRC612.
RisksofmAbAdministration:AdministrationofmAbsmaycauseimmunereactionssuchas
acuteanaphylaxis,serumsicknessandthegenerationofantibodies.However,thesereactions
arerareandmoreoftenassociatedwithmAbstargetedtohumanproteinsorwiththeuseof
mousemAbsthatwouldhaveariskofhumananti-mouseantibodies[29].Inthisregard,
becauseCIS43LSistargetedtoaparasiteantigenandisahumanmAb,itisexpectedtohavea
lowriskofsuchsideeffects.
Typically,thesideeffectsofmAbsaremildtomoderateandmayincludelocalreactionsatthe
injectionsite(includingpain,redness,bruising,swelling)andsystemicreactionssuchasfever,
chills,rigors,nausea,vomiting,pain,headache,dizziness,shortnessofbreath,bronchospasm,
hypotension,hypertension,pruritus,rash,urticaria,angioedema,diarrhea,tachycardiaorchest
pain.ClinicaluseofmAbsthataretargetedtocytokinesorantigensassociatedwithhumancells
maybeassociatedwithanincreasedriskofinfections[29];however,thisisnotexpectedtobea
riskforamAbtargetedtoaparasiteantigen.
Severereactions,suchasanaphylaxis,angioedema,bronchospasm,hypotensionandhypoxia,are
infrequentandmoreoftenassociatedwithmAbstargetedtohumanproteinsorwithnon-human
mAb,suchasamousemAb[29].Mostinfusion-relatedeventsoccurwithinthefirst24hours
afterinitiationofmAbadministration.
PublishedexperiencewithhumanmAbsdirectedagainstcellsurfacetargetsonlymphocytes
showsthatinfusionofamAbmaybeassociatedwithcytokinerelease,causingareactionknown
ascytokinereleasesyndrome(CRS)[30].CRSreactionscommonlyoccurwithinthefirstfew
hoursofinfusionstartandwiththefirstmAbinfusionreceived.Thisisbecausethecytokine
releaseisassociatedwithlysisofthecellstargetedbythemAbandtheburdenoftargetcellsis
greatestatthetimeofthefirstmAbtreatment.WithlicensedtherapeuticmAbs,CRSis
managedbytemporarilystoppingtheinfusion,administeringhistamineblockersandrestarting
theinfusionataslowerrate[31].Supportivetreatmentmayalsobeindicatedforsomesignsand
symptoms.
Delayedallergicreactionsthatincludeaserumsicknesstypeofreactioncharacterizedby
urticaria,fever,lymphnodeenlargement,andjointpains,typicallyoccurseveraldaysaftermAb
exposureandaremorecommonlyassociatedwithchimerictypesofmAbs[29].Ingeneral,and
withdueconsiderationoftheneedsdictatedbyindividualsubjectsymptomsandtreating
cliniciandiscretion,immediateanddelayedreactionstostudyproductwouldbemanaged
accordingtotheprinciplesoftheAmericanAcademyofAllergy,Asthma,andImmunology
guidelinesestablishedintheDrugAllergy:PracticeParameters(2010).
Participationinthisstudymaylimitasubject’seligibilityforfuturemAbstudies.
RisksofBloodDrawing:Blooddrawingmaycausepain,bruising,andafeelingof
lightheadednessorfainting.Rarely,itmaycauseinfectionatthesitewherebloodistaken.Inthis

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study,anIVlinethatcanbeusedforbloodcollectionmaybeplacedinthearmandleftinplace
forseveralhoursondayswhenthereisproductadministrationforfrequentPKblooddraws.
ProblemsfromuseofanIVforblooddrawingaregenerallymildandmayincludepain,bruising,
minorswellingorbleedingattheIVsiteandrarely,infection,veinirritation(phlebitis),orblood
clot.
RisksofMosquitoBitesforCHMI:RisksassociatedwithCHMIincludelocalinflammatory
reactions,lymphadenitis,persistentlocalpruritusandlargerlocalreactionsinvolvingthewhole
forearm,allergicreactionstomosquitobites.Anotherremotelypossibleriskincludesasystemic
allergicreactiontothemosquitoes.
RisksofAcquiringMalariaInfection:Thereisalsothepossibilityofcomplicationsof
malaria,whichareseenduringnaturallyacquiredmalariawhendiagnosisandtreatmentare
delayedandhighlevelsofparasitemiadevelop.Underthecarefullycontrolledconditionsofthis
studythatsupportsearlydiagnosisandtreatment,thechanceofsuchcomplicationsishighly
unlikelyandtheriskofdeathfrommalariainfectionisverysmall.Transientabnormalities,e.g.
fever,headache,myalgia,shakingchills,abdominaldiscomfort,nausea,vomiting,mildanemia,
leukopenia,thrombocytopenia,hepatosplenomegaly,hepatictendernessandfatigue,areexpected
consequencesofmalaria,butarenearlyabsentwithearlyRT-qPCRdetection[32].In
uncontrolledcircumstances,malariainfectionscanleadtokidney,liverorbraininjury(seizures,
coma)anddeath.
RisksofAntimalarialMedication:Additionalrisksincludepossiblesideeffectsofthe
antimalarialmedicationtaken(chloroquine)followingchallengewithchloroquine-sensitivePf.
Thesesideeffectsincludenausea,vomiting,diarrhea,abdominalpain,dizziness,headaches,
sleepdisturbances,blurredvision,pruritus,skinrash,exacerbationofpsoriasisorporphyria,
tinnitus,andphotosensitivity.Rarely,theremaybechangesinelectrocardiogramsand
hypotension.Sideeffectsofatovaquone/proguanil(Malarone®)includenausea,vomiting,
abdominalpain,anorexia,diarrhea,headache,coughandrarely,anemia,oralulcerations,
insomnia,fever,edema,rashandalopecia.Anotherremotelypossibleriskincludesasystemic
allergicreactiontochloroquine(orMalarone®).Thestudyteamwilldiscussthesemedications
andtheirpossiblesideeffectsindetailbothaspartoftheinformedconsentprocess,priorto
CHMI,andpriortoinitiationoftreatmentfordiagnosedmalariainfections.
8.5.2.
PotentialBenefits
Studysubjectswillnotreceivedirecthealthbenefitfromstudyparticipation.Othersmaybenefit
fromknowledgegainedinthisstudythatmayaidinthedevelopmentofmalariaprevention.
8.5.3.
AssessmentofPotentialRisksandBenefits
Thisresearchstudywillbeconductedincompliancewiththeprotocol,GCPguidance,andall
applicableregulatoryrequirements.
Theplanforreductionofknownandunknownriskstoparticipantsincludesappropriatetraining
ofstudypersonnel;educationofstudysubjectsforparticipationincarethroughoutthestudy;
monitoringofstudysubject’shealthstatusandexperiences;withdrawalfromstudyprocedures
uponevidenceofdifficulty,contraindication,orasignificantadverseevent;andreferralfor
treatment,counselingorothernecessaryfollow-up.TheVRCCTPRiskManagementPlan

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guidesthereductionandmitigationstrategiesappliedtotheknownandunknownrisks
associatedwithstudyparticipationandtrialmanagement/operations.
Asstudysubjectswillnotreceivedirecthealthbenefitfromstudyparticipationorproduct
administration,noalternativeproceduresareplanned.Thealternativecourseofactionisto
choosenottoparticipate.
8.6.
PlanforUseandStorageofBiologicalSamples
Theplanforuseandstorageofbiologicalsamplesfromthisprotocolisoutlinedinthefollowing
sections.
8.6.1.
UseofSamples,SpecimensandData
Samples,specimensanddatacollectedunderthisprotocolmaybeusedtoconductprotocol-
relatedsafety,parasitologyandimmunogenicityevaluations,exploratorylaboratoryevaluations
relatedtomalaria,exploratorylaboratoryevaluationsrelatedtomAb,vaccineorinfectious
diseaseresearchingeneralandforresearchassayvalidation.
8.6.2.
StorageandTrackingofBloodSamplesandOtherSpecimens
Allresearchsamplesusecodedlabelsthatonlythesitestaffcanlinktothesubject.Samplesare
storedatVIP,VRClaboratoriesin
Bethesda,MD,oratUMBlaboratories,which
areallsecurefacilitieswithlimitedaccess.Datawillbekeptinpassword-protectedcomputers.
Onlyinvestigatorsortheirdesigneeswillhaveaccesstothesamplesanddata.Sampleswillbe
trackedintheLaboratoryInformationManagementSystem(LIMS)databaseorusinganother
softwaredesignedforthispurpose(e.g.,Freezerworks).
8.6.3.
DispositionofSamples,SpecimensandDataatCompletionoftheProtocol
Inthefuture,otherinvestigators(bothatNIHandoutside)maywishtostudythesesamples
and/ordata.IRBapprovalmustbesoughtpriortoanysharingofsampleswithnon-NIH
investigatorsandanyclinicalinformationsharedaboutthosesampleswouldsimilarlyrequire
priorIRBapproval.Theresearchuseofstored,unlinkedorunidentifiedsampleswillbeexempt
fromtheneedforprospectiveIRBreviewandapproval.Exemptionrequestswillbesubmitted
inwritingtotheNIHOfficeofHumanSubjectsResearch,whichisauthorizedtodetermine
whetheraresearchactivityisexempt.
Atthetimeofprotocoltermination,sampleswillremainintheVIPfacility,VRClaboratories,or
UMBLaboratoriesor,afterIRBapproval,willbetransferredtoanotherrepository.Regulatory
oversightofthestoredsamplesanddatamaybetransferredtoastoredsamplesprotocolaspart
oftheIRBapprovedterminationplan.DatawillbearchivedbytheVRCincompliancewith
requirementsforretentionofresearchrecords,orafterIRBandstudysponsorapproval,itmay
beeitherdestroyedortransferredtoanotherrepository.
8.6.4.
LossorDestructionofSamples,SpecimensorData
Anylossorunanticipateddestructionofsamples(forexample,duetofreezermalfunction)or
data(forexample,misplacingaprintoutofdatawithidentifiers)willbereportedtotheIRB.

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TheProtocolChairorsitePIwillalsonotifytheIRBifthedecisionismadetodestroythe
remainingsamples.
8.7.
SafetyOversight
ClosecooperationbetweenthedesignatedmembersoftheProtocolTeamwilloccurtoevaluate
andrespondtoindividualAEsinatimelymanner.TheVRCclinicdesignatedSafetyOfficer
(SO)forthedayconductsadailysafetyreviewofclinicaldataperVRCStandardOperating
Procedures.
TheProtocolSafetyReviewTeam(PSRT)willbecomprisedoftheProtocolChair,Site
PrincipalInvestigator(PI),AssociateInvestigators,StudyCoordinator,ProtocolSpecialists,
otherstudyclinicians,theINDMO,andexternal(non-VRC)collaborators.ThePSRTwill
reviewthesummarystudysafetydatareportsonaweeklybasisthrough4weeksafterthelast
subjectreceivesthelastproductadministration.ThePSRTwillalsoperformweeklysafety
reviewthrough4weekspostCHMI.Otherwise,iftherehavebeennoproductadministrationsor
CHMIintheprior4weeks,thePSRTwillmonitorthestudysafetydatareportsonamonthly
basisthroughcompletionofthelaststudyvisit.ThePSRTwillevaluateandrespondtosafety
concernsinatimelymanner.
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9.
ADMINISTRATIVEANDOPERATIONALOBLIGATIONS
9.1.
ProtocolAmendmentsandStudyTermination
ProtocolamendmentsmustbemadeonlywithpriorapprovaloftheINDSponsorandwith
agreementfromtheProtocolChairandINDMO.Allstudyamendmentswillbesubmittedtothe
centralIRBforapproval.
TheINDSponsor,theIRB,OHRP,thesitePIs,ProtocolChairs,and/ortheFDAreservethe
righttoterminatethestudy.TheProtocolChairwillnotifytheIRBinwritingofthestudy’s
completionorearlytermination.
9.2.
StudyDocumentationandStorage
TheProtocolChairwilldelegatethestudyresponsibilitiestothestudyteam,andalistof
appropriatelyqualifiedpersonstowhomtrialdutieshavebeendelegatedwillbemaintained.
Sourcedocumentsareoriginaldocuments,data,andrecordsfromwhichthesubject’sdataare
obtained.Theseincludebutarenotlimitedtohospitalrecords,clinicalandofficecharts,
laboratoryandpharmacyrecords,andcorrespondence.Long-termstorageofsourcedocuments
maybeintheformofelectronicfiles.
TheProtocolChairandstaffareresponsibleformaintainingacomprehensiveandcentralized
filingsystemofallstudy-related(essential)documentation,suitableforinspectionatanytimeby
representativesfromtheINDSponsor,VRC/NIAID/NIH,IRB,NIH,FDA,and/orapplicable
regulatoryauthorities.Elementsinclude:
• Subjectfilescontainingcompletedinformedconsentforms,andsupportingcopiesof
sourcedocumentation.
• Studyfilescontainingtheprotocolwithallamendments,IBs,copiesofallcorrespondence
withtheIRB.
Inaddition,alloriginalsourcedocumentationmustbemaintainedandbereadilyavailable.
Allessentialdocumentationshouldberetainedbytheinstitutionforthesameperiodoftime
requiredformedicalrecordsretention.TheFDArequiresstudyrecordstoberetainedforupto
twoyearsaftermarketingapprovalorrefusal(21CFR312.62).Ifnomarketingapplicationis
filed,oriftheapplicationisnotapproved,therecordswillberetainedfortwoyearsafterthe
investigationisdiscontinuedandtheFDAisnotified.TheHHSprotectionofhumansubjects’
regulationsrequirethatinstitutionsretainrecordsofIRB/ECactivitiesanddocumentationof
informedconsentofsubjectsforatleast3yearsafterstudycompletion(45CFR46).
NostudydocumentshouldbedestroyedwithoutpriorwrittenagreementbetweentheVRCand
theinvestigator.Shouldtheinvestigatorwishtoassignthestudyrecordstoanotherpartyor
movethemtoanotherlocation,theymustnotifytheVRCinwritingofthenewresponsible
personand/orthenewlocation.
9.3.
ClinicalMonitoring
Clinicalsitemonitoringisconductedtoensurethattherightsandwell-beingoftrialparticipants
areprotected,thatthereportedtrialdataareaccurate,complete,andverifiable,andthatthe

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conductofthetrialisincompliancewiththecurrentlyapprovedprotocol/amendment(s),with
ICHGCP,andwithapplicableregulatoryrequirement(s).
Monitoringforthisstudywillbeperformedbyadesignatedcontractresearchorganization
(CRO),
Detailsofclinicalsitemonitoringare
documentedinaClinicalMonitoringPlan.TheClinicalMonitoringPlandescribesindetailwho
willconductthemonitoring,atwhatfrequencymonitoringwillbedone,atwhatlevelofdetail
monitoringwillbeperformed,andthedistributionofmonitoringreports.
9.4.
DataCollectionandSharing
9.4.1.
DataCollection
Clinicalresearchdatawillbecollectedinasecureelectronicweb-basedclinicaldata
managementsystem(CDMS)throughaCRO,Emmes(Rockville,MD).Extracted,anonymized
datawillbesenttothePSRTforsafetyreviewandtoProtocolStatisticianforstatisticalanalysis.
9.4.2.
SourceDocuments
Thesitewillmaintainappropriatemedicalandresearchrecordsforthistrial,incompliancewith
ICHE6(R2)GCP,applicableregulations,andinstitutionalrequirementsfortheprotectionof
confidentialityofsubjects.Sourcedataareallinformation,originalrecordsofclinicalfindings,
observations,orotheractivitiesinaclinicaltrialnecessaryforthereconstructionandevaluation
ofthetrial.Examplesoftheseoriginaldocumentsanddatarecordsinclude,butarenotlimited
to,medicalrecords,laboratoryreports,pharmacyrecordsandotherresearchrecordsmaintained
fortheclinicaltrial.
9.4.3.
DataSharing
Datageneratedinthisstudywillbesharedasde-identifieddatainthegovernment-fundedpublic
repository,www.clinicaltrials.gov.Datamaybesharedpriortopublicationatapprovedpublic
presentationsorforcollaborativedevelopmentandwillbesharedatthetimeofpublicationor
withinoneyearoftheprimarycompletiondate.
9.5.
QualityAssuranceandQualityControl
Theclinicalsitewillperforminternalqualitymanagementofstudyconduct,dataandbiological
specimencollection,documentationandcompletion.TheVEC’sQualityManagementPlanwill
beusedtoperformqualitymanagementforthistrial.
Qualitycontrol(QC)procedureswillbeimplementedbeginningwiththedataentrysystemand
dataQCchecksthatwillberunonthedatabasewillbegenerated.Anymissingdataordata
anomalieswillbecommunicatedtothesiteforclarification/resolution.
Themonitorswillverifythattheclinicaltrialisconducted,anddataaregenerated,and
biologicalspecimensarecollected,documented(recorded),andreportedincompliancewiththe
protocol,ICHGCP,andapplicableregulatoryrequirements.
Thesitewillprovidedirectaccesstoalltrialrelatedsites,sourcedata/documents,andreportsfor
thepurposeofmonitoringandauditingbythesponsor,andinspectionbylocalandregulatory
authorities.

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9.6.
Language
Allwritteninformationandothermaterialtobeusedbysubjectsandinvestigativestaffmustuse
vocabularyandlanguagethatareclearlyunderstood.
9.7.
Research-RelatedInjuries
9.7.1.
NIH
TheNIHClinicalCenterwillprovideshort-termmedicalcareforanyinjuryresultingfrom
participationinresearchhere.Ingeneral,nolong-termmedicalcareorfinancialcompensation
forresearch-relatedinjurieswillbeprovidedbytheNIH,theNIHClinicalCenter,ortheFederal
Government.However,subjectshavetherighttopursuelegalremedyiftheybelievethattheir
injuryjustifiessuchaction.
9.7.2.
WRAIR
IfsubjectsareinjuredbecauseofparticipationinthisresearchduringtheCHMIandtheyarea
DODhealthcarebeneficiary(e.g.,activedutyinthemilitary,militaryspouseordependent,
retiree),theyareentitledtomedicalcarefortheirinjurywithintheDODhealthcaresystem,as
longastheyremainaDODhealthcarebeneficiary.
IfsubjectsareinjuredbecauseofparticipationinthisresearchduringtheCHMIandtheyarenot
aDODhealthcarebeneficiary,theyareentitledtomedicalcarefortheirinjuryataDODhospital
orclinic,butsuchcarefortheinjuryatDODhospitalsorclinicsmaybetime-limited,andthe
subject’sinsurancemaybebilled.ItcannotbedeterminedinadvancewhichDODhospitalor
clinicwillprovidecare.Ifsubjectsobtaincareforresearch-relatedinjuriesoutsideofaDOD
hospitalorclinic,theyortheirinsurancewillberesponsibleformedicalexpenses.
ForDODhealthcarebeneficiariesandnon-DODhealthcarebeneficiaries:Transportationtoand
fromhospitalsorclinicswillnotbeprovided.Noreimbursementisavailableifsubjectsincur
medicalexpensestotreatresearch-relatedinjuries.Nocompensationisavailableforresearch-
relatedinjuries.Subjectsarenotwaivinganylegalrights.Ifsubjectsbelievetheyhavesustained
aresearch-relatedinjury,theymaycontactthePI.Ifsubjectshaveanyquestions,theycan
contactthePI.
9.7.3.
UMB
TheCenterforVaccineDevelopmentandGlobalHealthandtheUniversityofMarylandwill
provideshort-termmedicalcareorassessmentforanyinjuryresultinginparticipatingin
research.Ifaninjuryisdirectlyrelatedtoparticipationinthisproject,andrequiresintervention,
UMBand/oroneofitsaffiliatedinstitutionsorhealthcaregroupswillhelpthesubjectobtain
medicaltreatmentforthespecificinjuryandprovidereferralstootherhealthcarefacilities,as
appropriate.UMBand/oritsaffiliatedinstitutionsorhealthcaregroupswillnotprovidesubjects
withfinancialcompensationorreimbursementforthecostofcareprovidedtotreataresearch-
relatedinjuryorforotherexpensesarisingfromaresearch-relatedinjury.Theinstitutionor
groupprovidingmedicaltreatmentwillchargethesubject’sinsurancecarrier.Subjectsdonot
waivetheirrighttopursuelegalcompensationordamagestorecoverlossesrelatedtoinjury.

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9.8.
CHMIFacilitiesandManagement
TheVRC,NIAID,NIHisthecoordinatingcenterforthisprotocol.Dr.MartinGaudinski,VRC,
NIAID,NIH,istheProtocolChairandNIHsitePIoverseeingthemanagementandmonitoring
oftheprotocolconductoverall.
UMBwillbeaclinicalsiteandalsotheCHMIadministratorforPartCoftheprotocol.Dr.
KirstenLykewillbetheUMBsitePI.UMBinvestigatorsandstaffwillberesponsiblefor
completionofallclinicalandpost-CHMIvisitsaswellasadministrationoftheCHMI(with
WRAIRstaffsupport)forparticipantsinPartC.
InvestigatorsfromWRAIR,thefacilitythatadministeredthePartBCHMI,willhavelimited
interactionwithstudysubjectsduringtheadministrationoftheCHMI.InPartC,WRAIR
investigatorswillprovideentomologicsupporttoUMBduringCHMI.Certainimmediatepre-
andpost-CHMIassessmentsofsubjectswilltakeplaceintheCHMIfacilitywithsome
participationbyCHMIfacilitypersonnelandNIHstaff.Allotherpost-CHMIclinicalvisitsfor
subjectswilltakeplaceattheNIHclinicalsite.
ARelianceAgreementwillbeestablishedwiththecollaboratingCHMIfacilitiessuchthatthe
NIHIRBistheIRBofRecordfortheconductoftheVRC612protocol.ReferringtoSection5
oftheVRC612protocol,anySeriousAdverseEvents,UnanticipatedProblemsorProtocol
DeviationwhicharereportabletotheNIHIRBwhichareinrelationtotheconductoftheCHMI
willalsobecommunicatedtothecollaboratingCHMIfacilitywithinthesamereportingperiod
specifiedintheprotocol.
9.8.1.
RolesandResponsibilitiesfortheCHMI
TheProtocolChairandsitePIwilldelegateresponsibilityforoverseeingtheadministrationof
theCHMIatthecollaboratingCHMIfacilities(i.e.,applicationofandassessmentofthe
mosquitobites)todesignatedAssociateInvestigatorsfromthosefacilities.Follow-upand
medicalcareofthestudysubjectsaftertheCHMIisadministeredremainstheresponsibilityof
thesitePIandthedesignatedpersonnelattheclinicalsite.
TheAuthorizedRepresentativefromtheCHMIfacilitymayreviewresearchrecordsrelatedto
theCHMIconductedattheirownfacility.
Therolesandresponsibilitiesforthiscollaboratinginstitutionandfacilitypersonnelforthe
conductofCHMIasdescribedabovearedelineatedinthecorrespondingVRC612Study
PersonnelPage.
9.9.
WRAIRProtocolReviewandReportingRequirements
InitialProtocolReview
WRAIRwilldefertheirIRBreviewtotheNIHIRBoncearelianceagreementisinplace.
WRAIRHumanSubjectsProtectionBranch(HSBP)willstillperformanadministrativereview
oftheprotocoltoensurethattheWRAIRreportingrequirementsaremet.WRAIRCommander
ApprovalAuthorizationwillbeissuedoncetheNIHIRBapprovalhasbeensubmittedtothe
WRAIRHSPBandtheadministrativeWRAIRcommentshavebeenadequatelyaddressed.
Headquarterslevelreviewwillbeconductedasappropriate.

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ProtocolModifications/Amendments
Allamendments/modificationstotheprotocolandsupportingdocuments(informedconsent,
recruitmentmaterials,etc.)mustbereviewedbytheWRAIRHSPBandaWRAIRCommander
AuthorizationApprovalissuedpriortoWRAIRparticipationontheamended/modifiedprotocol.
ContinuingReviewsandCloseoutReport
TheWRAIRPointofContactwillberesponsibleforpreparingandsubmittingcontinuingreview
reportsasperUWZ-C-618andacloseoutreportasperWRAIRPolicy12-12.TheWRAIR
HSPBwillreviewandacknowledgethereportsinorderforWRAIRpersonneltocontinuetheir
participationonthestudy.Onceallstudyactivitieshavebeencompleted,toincludedata
analysis,acloseoutreportwillneedtobesubmittedtotheWRAIRHSPBtoclosethestudy.
Thefollowingreportingrequirementsapply:
UnanticipatedProblemsInvolvingRiskstoSubjectsorOthers
Unanticipatedproblems,asdefinedinSection5.5.1,shouldbepromptlyreported(48hours)by
telephone,email,orfaxtotheWRAIRHSPB.Acompletewrittenreportshouldfollowthe
initialnotificationwithin10workingdays.Allunanticipatedproblemsoccurringwithinthe
reportingperiodshouldalsobesummarizedinthecontinuingreviewreportssubmittedtothe
WRAIRHSPB(contactinformationisbelowatendofsection).
SeriousAdverseEvents
AllrelatedSAEsanddeaths,asdefinedinSection5.2,shouldbereportedtotheWRAIRHSPB
within48hoursbytelephone,email,orfax.Acompletewrittenreportshouldfollowtheinitial
notificationwithin10workingdays.AllSAEsoccurringwithinthereportingperiodshouldalso
besummarizedinthecontinuingreviewreportssubmittedtotheWRAIRHSPB.
ProtocolDeviations
Allmajorprotocoldeviationsthatadverselyaffectthesafetyorrightsofasubjectorscientific
integrityofthestudy,asdefinedinSection5.5.3,willbereportedtotheWRAIRHSPBwithin
48hoursandawrittenreportshouldbesubmittedwithin10workingdays.Allprotocol
deviationsoccurringwithinthereportingperiodshouldbesummarizedinthecontinuingreview
reportsthataresubmittedtotheWRAIRHSPB.
PendingInspections/IssuanceofReports
Theknowledgeofanypendingcomplianceinspection/visitbytheFDA,OfficeforHuman
ResearchProtections(DepartmentofHealthandHumanServices),orothergovernmentagency
concerningclinicalinvestigationorresearch,theissuanceofInspectionReports,FDAForm483,
warningletters,oractionstakenbyanyregulatoryagencyincludinglegalormedicalactionsand
anyinstancesofseriousorcontinuingnoncompliancewiththeregulationsorrequirementswill
bereportedimmediatelytotheWRAIRHSPB.
WRAIRHSPBContactInformation
Director,HumanSubjectsProtectionBranch


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10.
REFERENCES

1.
Sachs,J.andP.Malaney,Theeconomicandsocialburdenofmalaria.Nature,2002.
415(6872):p.680-5.
2.
RollBackMalaria.GlobalMalariaActionPlan20082008;Availablefrom:
http://www.rbm.who.int/keyfacts.html.
3.
Breman,J.G.,Eradicatingmalaria.SciProg,2009.92(Pt1):p.1-38.
4.
EfficacyandsafetyofRTS,S/AS01malariavaccinewithorwithoutaboosterdosein
infantsandchildreninAfrica:finalresultsofaphase3,individuallyrandomised,
controlledtrial.Lancet,2015.386(9988):p.31-45.
5.
Mahmoudi,S.andH.Keshavarz,Efficacyofphase3trialofRTS,S/AS01malaria
vaccine:Theneedforanalternativedevelopmentplan.HumVaccinImmunother,2017.
13(9):p.2098-2101.
6.
Zalevsky,J.,etal.,Enhancedantibodyhalf-lifeimprovesinvivoactivity.NatBiotechnol,
2010.28(2):p.157-9.
7.
Roy,C.J.,etal.,Chikungunyavaccinecandidateishighlyattenuatedandprotects
nonhumanprimatesagainsttelemetricallymonitoreddiseasefollowingasingledose.J
InfectDis,2014.209(12):p.1891-9.
8.
Gaudinski,M.R.,etal.,SafetyandpharmacokineticsoftheFc-modifiedHIV-1human
monoclonalantibodyVRC01LS:APhase1open-labelclinicaltrialinhealthyadults.
PLoSMed,2018.15(1):p.e1002493.
9.
Gaudinski,M.R.,etal.,AMonoclonalAntibodyforMalariaPrevention.NewEngland
JournalofMedicine,2021.385(9):p.803-814.
10.
Kisalu,N.K.,etal.,Ahumanmonoclonalantibodypreventsmalariainfectionby
targetinganewsiteofvulnerabilityontheparasite.NatMed,2018.24(4):p.408-416.
11.
Gaudinski,M.R.,etal.,SafetyandpharmacokineticsoftheFc-modifiedHIV-1human
monoclonalantibodyVRC01LS:APhase1open-labelclinicaltrialinhealthyadults.
PlosMedicine,2018.15(1):p.e1002493.
12.
Ledgerwood,J.E.,etal.,Safety,pharmacokineticsandneutralizationofthebroadly
neutralizingHIV-1humanmonoclonalantibodyVRC01inhealthyadults.ClinExp
Immunol,2015.182(3):p.289-301.
13.
Gaudinski,M.R.,etal.,Safety,tolerability,pharmacokinetics,andimmunogenicityofthe
therapeuticmonoclonalantibodymAb114targetingEbolavirusglycoprotein(VRC608):
anopen-labelphase1study.Lancet,2019.393(10174):p.889-898.
14.
Gaudinski,M.R.,etal.,Safetyandpharmacokineticsofbroadlyneutralisinghuman
monoclonalantibodyVRC07-523LSinhealthyadults:aphase1dose-escalationclinical
trial.LancetHIV,2019.
15.
Seder,R.A.,etal.,Protectionagainstmalariabyintravenousimmunizationwitha
nonreplicatingsporozoitevaccine.Science,2013.341(6152):p.1359-65.
16.
Ishizuka,A.S.,etal.,Protectionagainstmalariaat1yearandimmunecorrelates
followingPfSPZvaccination.NatMed,2016.22(6):p.614-23.
17.
Chulay,J.D.,etal.,Malariatransmittedtohumansbymosquitoesinfectedfromcultured
Plasmodiumfalciparum.AmJTropMedHyg,1986.35(1):p.66-8.
18.
Lyke,K.E.,etal.,AttenuatedPfSPZVaccineinducesstrain-transcendingTcellsand
durableprotectionagainstheterologouscontrolledhumanmalariainfection.ProcNatl
AcadSciUSA,2017.114(10):p.2711-2716.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults
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
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Page61of84
19.
Roestenberg,M.,etal.,Experimentalinfectionofhumanvolunteers.LancetInfectDis,
2018.18(10):p.e312-e322.
20.
Nieman,A.E.,etal.,Cardiaccomplicationafterexperimentalhumanmalariainfection:
acasereport.MalarJ,2009.8:p.277.
21.
Moorthy,V.S.,etal.,Reportofaconsultationontheoptimizationofclinicalchallenge
trialsforevaluationofcandidatebloodstagemalariavaccines,18-19March2009,
Bethesda,MD,USA.Vaccine,2009.27(42):p.5719-25.
22.
vanMeer,M.P.,etal.,Idiopathicacutemyocarditisduringtreatmentforcontrolled
humanmalariainfection:acasereport.MalarJ,2014.13:p.38.
23.
Deye,G.A.,etal.,Prolongedprotectionprovidedbyasingledoseofatovaquone-
proguanilforthechemoprophylaxisofPlasmodiumfalciparummalariainahuman
challengemodel.ClinInfectDis,2012.54(2):p.232-9.
24.
Stanisic,D.I.,etal.,DevelopmentofculturedPlasmodiumfalciparumblood-stage
malariacellbanksforearlyphaseinvivoclinicaltrialassessmentofanti-malariadrugs
andvaccines.MalarJ,2015.14:p.143.
25.
Mejia,R.,etal.,Peripheralbloodstemcelltransplant-relatedPlasmodiumfalciparum
infectioninapatientwithsicklecelldisease.Transfusion,2012.52(12):p.2677-82.
26.
Shokoples,S.E.,etal.,Multiplexedreal-timePCRassayfordiscriminationof
Plasmodiumspecieswithimprovedsensitivityformixedinfections.JClinMicrobiol,
2009.47(4):p.975-80.
27.
Gaziano,T.A.,etal.,Laboratory-basedversusnon-laboratory-basedmethodfor
assessmentofcardiovasculardiseaserisk:theNHANESIFollow-upStudycohort.
Lancet,2008.371(9616):p.923-31.
28.
FDA,COVID-19:DevelopingDrugsandBiologicalProductsforTreatmentor
PreventionGuidanceforIndustry,U.S.D.o.H.a.H.Services,etal.,Editors.2020.
29.
Hansel,T.T.,etal.,Thesafetyandsideeffectsofmonoclonalantibodies.Naturereviews.
Drugdiscovery,2010.9(4):p.325-38.
30.
Bugelski,P.J.,etal.,Monoclonalantibody-inducedcytokine-releasesyndrome.Expert
reviewofclinicalimmunology,2009.5(5):p.499-521.
31.
Vogel,W.H.,Infusionreactions:diagnosis,assessment,andmanagement.ClinJOncol
Nurs,2010.14(2):p.E10-21.
32.
Friedman-Klabanoff,D.J.,etal.,TheControlledHumanMalariaInfectionExperienceat
theUniversityofMaryland.AmJTropMedHyg,2019.100(3):p.556-565.

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APPENDIXI:SCHEDULEOFEVALUATIONS
ThereisasystemincompatibilitybetweenthestudyclinicaldatabasesoftwareandtheLIMSsample
trackingsystemusedbytheVIP.Theincompatibilitycreatesadiscrepancyofvisitnumbernomenclature
betweentheapprovedprotocolandthedatabase.TheVRCclinicusedtheprotocol-basedconventionfor
sourcedocuments.
Inaddition,thevisitnumbernomenclatureintheclinicalstudydatabasemanagedbyEmmeshasbeen
modifiedfromthevisitnumbernomenclatureintheapprovedprotocolduetoaninabilitytomatchthe
protocolwithinitslimitations.ThisisbecausetheEmmesdatabaserequiresvisitnumberstohavea
leadingzerotoassurepropersorting.Theprotocolvisitnumbersdonotcontainaleadingzerobecause
suchaconventionwouldbeoutofspecificationsrequiredbytheLIMSsystem.Theselimitationswillnot
interferewiththeabilitytoidentifyandtrackstudysamples.
RefertothefollowingtableforanexampleofthedifferencesbetweentheEmmesdatabaseandthe
protocolScheduleofEvaluations,sourcedocumentsandLIMS:
ProtocolScheduleofEvaluations SourceDocumentation
LIMS
EmmesDatabase
VisitA1R
VisitA1R
VisitA1R
VisitA01R
VisitA2
VisitA2
VisitA02
VisitA02
VisitB1R
VisitB1R
VisitB1R
VisitB01R
VisitB2
VisitB2
VisitB02
VisitB02
VisitC2
VisitC2
VisitC02
VisitC02
VisitC2A
VisitC2A
VisitC2A VisitC02A




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PARTASCHEDULES

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ScheduleofEvaluations:PartAIVGroups(Groups1,3,4A,4B)
VisitNumber
01
1A1R
1A2
A2A
A2B
A2C
A2D
A3
A4
A6
A7
A8
A9
A10
A11
A12
A13
A14
TimeAfterInfusion


Pre
EOI
1hr
3h
6h
24hr
48hr
Wk1 Wk2 Wk3 Wk4 Wk8 Wk12 Wk16 Wk20 Wk24
DayofStudy -56to-1 -28to0
D0
D0
D0
D0
D0
D1
D2
D7
D14
D21
D28
D56
D84 D112 D140 D168
StudyProcedures
Tube
Screen
Enroll
Dayofinfusion











VRC500ScreeningConsent

X

















VRC612InformedConsent,AoU


X
















2PhysicalExam

X
X
X
X



X
X
X
X
X
X
X
X
X
X
X
3MedicalHistory

X
X
X




X
X
X
X
X
X
X
X
X
X
X
EKG

X

















ConcomitantMedications

X
X
X




X
X
X
X
X
X
X
X
X
X
X
ProductAdministration



X















Begin7-dayDiaryCard



X















4PregnancyPreventionCounseling

X
X
X







X




X

X
ClinicalEvaluations
4PregnancyTest(urineorserum)

X
X
X







X




X

X
CBCwithdifferential
EDTA
3

3




3

3
3

3

3



ALT,creatinine
GLT
X

X




4

4
4

4

4



5CMP
GLT
4

4















HIVAg/AbCombo
EDTA
3

















SickleCellTest
EDTA
3

















Troponin
GLT
4

















ResearchSamples
6PK
SST


4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMC
EDTA
20









40







Serum
SST
8

16†





8
8†
8
8
8†
8
8†
8
8
8†
DailyVolume(mL)

45
0
27
4
4
4
4
11
12
19
59
12
19
12
19
12
12
12
CumulativeVolume(mL)

45
45
72
76
80
84
88
99
111
130
189
201
220
232
251
263
275
287
Visitwindows:ScheduleVisitsA2A–A14withrespecttoVisitA2.VisitA2A(within10minofEOI);VisitsA2B,A2C(±10min);VisitA2D(-2hrs);VisitsA3,A4(±6hrs);VisitsA6,A7,A8,A9(±2
days);VisitsA10,A11,A12,A13,A14(±7days).VisitA5isnotapplicabletothisschedule.
1VisitA1RisthedayofenrollmentandmaybedoneonthesamedayasDay0.VA2/Day0isdayofproductadministrationandpreferablyscheduledwithin14daysafterenrollmentatVisitA1Rbutmaybe
scheduledupto28daysafterVisitA1R.
2Screeningincludesphysicalexam,vitalsigns(bloodpressure(BP),temperature,pulse,respiratoryrate(RR)),height,weight.Day0includesvitalsignsandweight(fororderingstudyproductdose).Atother
visits,performatargetedexamifmedicallyindicated,otherwiseonlyvitalsignsarerequired.
3Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.
4Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialbeforeproductadministration.CompletePregnancyPreventionCounselingFormwhenpregnancytestisdone.
5CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartateaminotransferase,totalbilirubin,calcium,totalprotein
6PKblooddraws,definedbytimeafteraninfusion,arerelativetotheexacttimeoftheendofinfusion(EOI).Recordtheexactstart/endtimesofproductadministrationandofblooddrawtoensureaccurate
PKanalysis.
†Anti-drugantibodies(ADA)assessedfromserumsamplesattimepointsasindicated.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page65of84
ScheduleofEvaluations:PartA SCGroup(Group2)
VisitNumber
01
1A1R
1A2
A2A
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
TimeafterInfusion


Pre
EOI
24hr
48hr
72hr
Wk1
Wk2
Wk3
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24
StudyDay
-56to-1 -28to0
D0
D0
D1
D2
D3
D7
D14
D21
D28
D56
D84
D112
D140
D168
StudyProcedures
Tube
Screen
Enroll Dayofinjection












VRC500ScreeningConsent

X















VRC612InformedConsent,AoU


X














2PhysicalExam

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3MedicalHistory

X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
EKG

X















ConcomitantMedications

X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
ProductAdministration



X













Begin7-dayDiaryCard



X













4PregnancyPreventionCounseling

X
X
X





X




X

X
ClinicalEvaluations
4PregnancyTest(urineorserum)

X
X
X





X




X

X
CBCwithdifferential
EDTA
3

3

3


3
3

3

3



ALT,creatinine
GLT
X

X

4


4
4

4

4



5CMP
GLT
4

4













HIVAg/AbCombo
EDTA
3















SickleCellTest
EDTA
3















Troponin
GLT
4















ResearchSamples
6PK
SST


4

4
4
4
4
4
4
4
4
4
4
4
4
PBMC
EDTA
20







40







Serum
SST
8

16†


8
8
8†
8
8
8†
8
8†
8
8
8†
DailyVolume(mL)

45
0
27
0
11
12
12
19
59
12
19
12
19
12
12
12
CumulativeVolume(mL)

45
45
72
72
83
95
107
126
185
197
216
228
247
259
271
283
Visitwindows:ScheduleVisitsA2A–A14withrespecttoVisitA2.VisitA2A(within10minofEOI);VisitsA3,A4,A5(±6hrs);VisitsA6,A7,A8,A9(±2days);VisitsA10,A11,A12,A13,A14(±7
days).
1VisitA1RisthedayofenrollmentandmaybedoneonthesamedayasDay0.VA2/Day0isdayofproductadministrationandpreferablyscheduledwithin14daysafterenrollmentatVisitA1Rbutmaybe
scheduledupto28daysafterVisitA1R.
2Screeningincludesphysicalexam,vitalsigns(BP,temperature,pulse,RR),height,weight.Day0includesvitalsignsandweight(fororderingstudyproductdose).Atothervisits,performatargetedexamif
medicallyindicated,otherwiseonlyvitalsignsarerequired.
3Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.
4Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialbeforeproductadministration.CompletePregnancyPreventionCounselingFormwhenpregnancytestisdone.
5CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartateaminotransferase,totalbilirubin,calcium,totalprotein
6PKblooddraws,definedbytimeafterinfusion,arerelativetotheexacttimeoftheendofinfusion(EOI).Recordexactstart/endtimesofproductadministrationandofblooddrawtoensureaccurateanalysis.
†ADAassessedfromserumsamplesattimepointsasindicated.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page66of84
PARTBSCHEDULES

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page67of84
ScheduleofEvaluations:PartBIVGroups(Groups7and9)InitialorRepeatDose
VisitNumber
01
1B1R
1B2
B2A
B2B
B2C
B2D
B3
B4
B6
B7
B8
B9
B10
B11
B12
B13
B14
TimeAfterInfusion


Pre
EOI
1hr
3h
6h
24hr
48hr
Wk1 Wk2
Wk3
Wk4
Wk8 Wk12 Wk16 Wk20 Wk24
DayofStudy -56to-1 -28to0
D0
D0
D0
D0
D0
D1
D2
D7
D14
D21
D28
D56
D84 D112 D140 D168
StudyProcedures
Tube
Screen
Enroll
Dayofinfusion











VRC500ScreeningConsent

X

















VRC612InformedConsent,AoU7


X
















2PhysicalExam

X
X
X
X



X
X
X
X
X
X
X
X
X
X
X
3MedicalHistory

X
X
X




X
X
X
X
X
X
X
X
X
X
X
EKG

X
[X]
















ConcomitantMedications

X
[X]
X




X
X
X
X
X
X
X
X
X
X
X
ProductAdministration



X















Begin7-dayDiaryCard



X















4PregnancyPreventionCounseling

X
X
X







X




X

X
ClinicalEvaluations
4PregnancyTest(urineorserum)

X
X
X







X




X

X
CBCwithdifferential
EDTA
3
[X]
3




3

3
3

3

3



ALT,creatinine
GLT
X
[X]
X




4

4
4

4

4



5CMP
GLT
4
[X]
4















HIVAg/AbCombo
EDTA
3
[X]
















SickleCellTest
EDTA
37

















Troponin
GLT
4
[X]
















SARS-CoV-2(PCR)
Swab
X
[X]
















ResearchSamples
6PK
SST


4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMC
EDTA
20









40







Serum
SST
8

16†





8
8†
8
8
8†
8
8†
8
8
8†
DailyVolume(mL)

45
0
27
4
4
4
4
11
12
19
59
12
19
12
19
12
12
12
CumulativeVolume(mL)

45
45
72
76
80
84
88
99
111
130
189
201
220
232
251
263
275
287
Visitwindows:ScheduleVisitsB2A–B14withrespecttoVisitB2.VisitB2A(within10minofEOI);VisitsB2B,B2C(±10min);VisitB2D(-2hrs);VisitsB3,B4(±6hrs);VisitsB6,B7,B8,B9(±2
days);VisitsB10,B11,B12,B13,B14(±7days).VisitB5isnotapplicable.
1VisitB1Risthedayofenrollmentorre-assessmentforGroup7andmaybedoneonthesamedayasDay0.VB2/Day0isdayofproductadministrationandpreferablyscheduledwithin14daysafter
enrollmentatVisitB1Rbutmaybescheduledupto28daysafterVisitB1R.[X]isonlyrequiredforGroup7.
2Screeningincludesphysicalexam,vitalsigns(bloodpressure(BP),temperature,pulse,respiratoryrate(RR)),height,weight.Day0includesvitalsignsandweight(fororderingstudyproductdose).Atother
visits,performatargetedexamifmedicallyindicated,otherwiseonlyvitalsignsarerequired.
3Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.
4Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialbeforeproductadministration.UsePregPreventionCounselingFormwhenpregnancytestisdone.
5CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartateaminotransferase,totalbilirubin,calcium,total
protein.
6PKblooddraws,definedbytimeafteraninfusion,arerelativetotheexacttimeoftheendofinfusion(EOI).Recordtheexactstart/endtimesofproductadministrationandofblooddrawtoensureaccurate
PKanalysis.
7NotrequiredforPartAveteransinPartB†Anti-drugantibodies(ADA)assessedfromserumsamplesattimepointsasindicated.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page68of84

ScheduleofEvaluations:PartBSCGroup(Group6)
VisitNumber
01
1B1R
1B2
B2A
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
B14
TimeafterInfusion


Pre
EOI
24hr
48hr
72hr
Wk1
Wk2
Wk3
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24
DayofStudy -56to-1 -28to0
D0
D0
D1
D2
D3
D7
D14
D21
D28
D56
D84
D112
D140
D168
StudyProcedures
Tube
Screen
Enroll Dayofinjection

VRC500ScreeningConsent

X















VRC612InformedConsent,AoU


X














2PhysicalExam

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3MedicalHistory

X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
EKG

X















ConcomitantMedications

X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
ProductAdministration



X













Begin7-dayDiaryCard



X













4PregnancyPreventionCounseling

X
X
X





X




X

X
ClinicalEvaluations
4PregnancyTest(urineorserum)

X
X
X





X




X

X
CBCwithdifferential
EDTA
3

3

3


3
3

3

3



ALT,creatinine
GLT
X

X

4


4
4

4

4



5CMP
GLT
4

4













HIVAg/AbCombo
EDTA
3















SickleCellTest
EDTA
3















Troponin
GLT
4















SARS-CoV-2(PCR)
Swab
X















ResearchSamples
6PK
SST


4

4
4
4
4
4
4
4
4
4
4
4
4
PBMC
EDTA
20







40







Serum
SST
8

16†


8
8
8†
8
8
8†
8
8†
8
8
8†
DailyVolume(mL)

45
0
27
0
11
12
12
19
59
12
19
12
19
12
12
12
CumulativeVolume(mL)

45
45
72
72
83
95
107
126
185
197
216
228
247
259
271
283
Visitwindows:ScheduleVisitsB2A–B14withrespecttoVisitB2.VisitB2A(within10minofEOI);VisitsB3,B4,B5(±6hrs);VisitsB6,B7,B8,B9(±2days);VisitsB10,B11,B12,B13,B14(±7
days).
1VisitB1RisthedayofenrollmentandmaybedoneonthesamedayasDay0.VB2/Day0isdayofproductadministrationandpreferablyscheduledwithin14daysafterenrollmentatVisitB1Rbutmaybe
scheduledupto28daysafterVisitB1R.
2Screeningincludesphysicalexam,vitalsigns(BP,temperature,pulse,RR),height,weight.Day0includesvitalsignsandweight(fororderingstudyproductdose).Atothervisits,performatargetedexam
ifmedicallyindicated,otherwiseonlyvitalsignsarerequired.
3Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.
4Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialbeforeproductadministration.CompleteaPregnancyPreventionCounselingFormwhenpregnancytestisdone.
5CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartateaminotransferase,totalbilirubin,calcium,total
protein.
6PKblooddraws,definedbytimeafteraninfusion,arerelativetotheexacttimeoftheendofinfusion(EOI).Recordexactstart/endtimesofproductadministrationandofblooddrawtoensureaccurate
analysis.†ADAassessedfromserumsamplesattimepointsasindicated.


APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page69of84
ScheduleofEvaluations:PartBCHMIforGroups8and10
VisitNumber
01
1B1R
B1S
C1
C2
2C2A
2C2B
C3
C4
C5
C6
C7
C8
C9
C10
TimeAfterCHMI





24hr
72hr
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk2
CHMIDay -56to-1-56to-1 -5to-1
-1
D0
D1
D3
D7
D8
D9
D10
D11
D12
D13
D14
StudyProcedures
Tube
Screen Enroll


CHMI


ParasitemiaCheck(dailyuntiltreatmentcriteriamet)
VRC500ScreeningConsent

X














VRC612InformedConsent,AoU9


X













3PhysicalExam,VitalSigns

X
X
X
X
X


X
X
X
X
X
X
X
X
4MedicalHistory

X
X
X
X
X


X
X
X
X
X
X
X
X
EKG

X
[X]













CHMI





X










PhoneContact






X
X








5PregnancyPreventionCounseling

X
X

X











ClinicalEvaluations
5PregnancyTest(urineorserum)

X
X

X











CBCwithdifferential
EDTA
3
[X]

3



3







ALT,creatinine
GLT
X
[X]

4











6CMP
GLT
4
[X]













HIVAb/AgCombo
EDTA
3
[X]













SickleCellTest
EDTA
39














Troponin
GLT
4
[X]













SARS-CoV-2(PCR)
Swab
X

X












7ParasitemiaEvaluation(PCR)
EDTA







3
[3]
[3]
[3]
[3]
[3]
[3]
[3]
ResearchSamples
8PK
SST



4



4






4
PBMC
EDTA
20






40






**60
Serum
SST
8






16






**16
DailyVolume(mL)

45
0
0
11
0
0
0
66
3
3
3
3
3
3
83
CumulativeVolume(mL)

45
45
45
56
56
56
56
122
125
128
131
134
137
140
223
1VisitB1Risthedayofre-assessmentforGroup8,andforGroup10inthecaseofPartAGroup5veteransubjects.[X]isonlyrequiredforGroup8andveteranGroup10
2AfterCHMI,scheduleVisitC2AonDay1or2,VisitC2BonDay3or4.
3Screeningincludesphysicalexam,vitalsigns(BP,temperature,pulse,RR),height,weight.OnD0,performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsignsarerequired.
4Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.
5Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialwithin2dayspriortoCHMI.UsePregPreventionCounselingFormwhentestingforpregnancy.
6CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartateaminotransferase,totalbilirubin,calcium,totalprotein.
7ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.ApositiveresultpriortoDay21isrequiredforinitiationof
antimalarialtreatment.
8PKdrawisforGroup8only;doesnotapplytoGroup10.
9NotrequiredforPartAveteransinPartB
**Researchbloodwillbedrawnat14dayspost-CHMI(VisitC10)fromALLsubjects.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page70of84
ScheduleofEvaluations:PartBCHMIforGroups8and10(continued)
VisitNumber
C11
C12
C13
C14
1C15
C16
C17
2C20
TimeafterCHMI
Wk2
Wk2
Wk2
Wk2
Wk3
Wk3
Wk4
Wk7
CHMIDay
D15
D16
D17
D18
D21
D23
D28
D49
StudyProcedures
Tube
ParasitemiaCheck
(dailyuntiltreatmentcriteriamet)




3PhysicalExam,VitalSigns

X
X
X
X
X
X

[X]
InterimMedicalHistory

X
X
X
X
X
X

[X]
PhoneContact







X
[X]
ClinicalEvaluations
CBCwithdifferential
EDTA




*3
*3

[3]
ALT,creatinine
SST




*4
*4

[4]
4ParasitemiaEvaluation(PCR)
EDTA
[3]
[3]
[3]
[3]
[3]


[3]
Anti-MalarialTreatment





[X]
[X]


ResearchSamples
5PK
SST




4


[4]
PBMC
EDTA







[60]
Serum
SST




8


[16]
DailyVolume(mL)

3
3
3
3
22
7
0
90
CumulativeVolume(mL)

226
229
232
235
257
264
264
354
1VisitC15isonlyrequiredforCHMIparticipantsnotpreviouslydiagnosedwithmalariaparasitemiatoruleoutadelayedcase.AtVisitC15(Day21),anysubjectnot
alreadyonantimalarialtreatmentwillbegivenDOT.SubjectsmustreturnforDOTfor2moredaysafterinitiation.Brackets[X]indicateoptionalasneededper
subjecttreatmentstatus.
2VisitC20isonlyrequiredforsubjectswhohadapositivePCRorbloodsmeartodocumenttestofcure.Itisscheduledtooccur26±5daysafterDOTcompletionandis
shownatDay49forconvenience.VisitC20maybecompletedviaphoneforsubjectswhoremainmalarianegative,brackets[X]indicateoptionalasneededper
subjectinfectionstatus.
3Performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsigns(BP,temperature,pulse,RR)arerequired.
4ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.Apositiveresult
priortoDay21isrequiredforinitiationofantimalarialDOT.Otherwise,initiateDOTatDay21.
5PKdrawisforGroup8only;doesnotapplytoGroup10.
*BloodforCBC,ALTandcreatininewillbedrawnatonsetofDOTandatabout2dayslater;shownatvisitsC15andC16toaccountforblooddraw.Parasitemia
evaluationsarenotperformedduringtreatmentthroughtotestofcure.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page71of84
ScheduleofEvaluations:PartBCHMIforGroups6,7,9
VisitNumber
B1S
C1
C2
1C2A
1C2B
C3
C4
C5
C6
C7
C8
C9
C10
TimeafterCHMI



24hr
72hr
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk2
CHMIDay -5to-1
-1
D0
D1
D3
D7
D8
D9
D10
D11
D12
D13
D14
StudyProcedures
Tube


CHMI


ParasitemiaCheck(dailychecksuntiltreatmentcriteriamet)
2PhysicalExam,VitalSigns

X
X
X


X
X
X
X
X
X
X
X
InterimMedicalHistory

X
X
X


X
X
X
X
X
X
X
X
CHMI



X










PhoneContact




X
X








PregnancyPreventionCounseling


X











ClinicalEvaluations
3PregnancyTest(urineorserum)


X











CBCwithdifferential
EDTA

3



3







ALT,creatinine
GLT

4











SARS-CoV-2(PCR)
Swab
X












4ParasitemiaEvaluation(PCR)
EDTA





3
3
[3]
[3]
[3]
[3]
[3]
[3]
ResearchSamples
PK
SST

4



4






4
PBMC
EDTA





40






**60
Serum
SST





16†






**16
DailyVolume(mL)

0
11
0
0
0
66
3
3
3
3
3
3
83
CumulativeVolume(mL)

0
11
11
11
11
77
80
83
86
89
92
95
178
1AfterCHMI,scheduleVisitC2AonDay1or2,VisitC2BonDay3or4
2Performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsigns(BP,temperature,pulse,RR)arerequired.
3Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialwithin2dayspriortoCHMI.CompleteaPregnancyPreventionCounselingForm
whenpregnancytestisdone.
4ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.Apositive
resultpriortoDay21isrequiredforinitiationofantimalarialdirectlyobservedtherapy(DOT).
**Researchbloodwillbedrawnat14dayspost-CHMI(VisitC10)fromALLsubjects.
†ADAassessedfromserumsamplesattimepointsasindicated.


APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page72of84
ScheduleofEvaluations:PartBCHMIforGroups6,7,9(continued)
1VisitNumber
C11
C12
C13
C14
1C15
C16
C17
2C20
TimeafterCHMI
Wk2
Wk2
Wk2
Wk2
Wk3
Wk3
Wk4
Wk7
CHMIDay
D15
D16
D17
D18
D21
D23
D28
D49
StudyProcedures
Tube
ParasitemiaCheck
(dailyuntiltreatmentcriteriamet)




3PhysicalExam,VitalSigns

X
X
X
X
X
X

[X]
InterimMedicalHistory

X
X
X
X
X
X

[X]
PhoneContact







X
[X]
ClinicalEvaluations
CBCwithdifferential
EDTA




*3
*3

[3]
ALT,creatinine
SST




*4
*4

[4]
4ParasitemiaEvaluation(PCR)
EDTA
[3]
[3]
[3]
[3]
[3]


[3]
Anti-MalarialTreatment





[X]
[X]


ResearchSamples
PK
SST




4


[4]
PBMC
EDTA







[60]
Serum
SST




8†


[16]
DailyVolume(mL)

3
3
3
3
22
7
0
90
CumulativeVolume(mL)

181
184
187
190
212
219
219
309
1VisitC15isonlyrequiredforCHMIparticipantsnotpreviouslydiagnosedwithmalariaparasitemiatoruleoutadelayedcase.AtVisitC15(Day21),any
subjectwhohasnotalreadystartedantimalarialtreatmentwillbegivendefinitiveDOT.SubjectsmustreturnforDOTfor2moredaysafterinitiation.
Brackets[X]indicateoptionalasneededpersubjecttreatmentstatus.
2VisitC20isonlyrequiredforsubjectswhohadapositivePCRorbloodsmeartodocumenttestofcure.Itisscheduledtooccur26±5daysafterDOT
completionandisshownatDay49forconvenience.VisitC20maybecompletedviaphoneforsubjectswhoremainmalarianegative,brackets[X]indicate
optionalasneededpersubjectinfectionstatus.
3Performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsigns(BP,temperature,pulse,RR)arerequired.
4ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.Apositive
resultpriortoDay21isrequiredforinitiationofantimalarialDOT.Otherwise,initiateDOTatC15.
*BloodforCBC,ALT,andcreatininewillbedrawnatonsetofDOTandabout2dayslater;shownatvisitsC15andC16toaccountforblooddraw.Parasitemia
evaluationsarenotperformedduringtreatmentthroughtotestofcure.
†ADAassessedfromserumsamplesattimepointsasindicated.



APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page73of84
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PARTCSCHEDULES



APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page74of84
ScheduleofEvaluations:PartCIVGroups(Groups11,12,14)
VisitNumber
01
1D1R
1D2
D2A
D2B
D2C
D2D
D3
D4
D6
D7
D8
D9
D10
D11
D12
D13
D14
TimeAfterInfusion


Pre
EOI
1hr
3h
6h
24hr
48hr
Wk1 Wk2 Wk3 Wk4 Wk8 Wk12 Wk16 Wk20 Wk24
DayofStudy -56to-1 -28to0
D0
D0
D0
D0
D0
D1
D2
D7
D14
D21
D28
D56
D84 D112 D140 D168
StudyProcedures
Tube*
Screen
Enroll
Dayofinfusion











VRC500ScreeningConsent

X

















VRC612InformedConsent,AoU


X
















2PhysicalExam

X
X
X
X



X
X
X
X
X
X
X
X
X
X
X
3MedicalHistory

X
X
X




X
X
X
X
X
X
X
X
X
X
X
EKG

X

















ConcomitantMedications

X
X
X




X
X
X
X
X
X
X
X
X
X
X
ProductAdministration



X















Begin7-dayDiaryCard



X















4PregnancyPreventionCounseling

X
X
X







X




X

X
ClinicalEvaluations
4PregnancyTest(urineorserum)

X
X
X







X




X

X
CBCwithdifferential
EDTA
3

3




3

3
3

3

3



ALT,creatinine
GLT
X

X




4

4
4

4

4



5CMP
GLT
4

4















HIVAg/AbCombo
EDTA
3

















SickleCellTest
EDTA
3

















Troponin
GLT
4

















ResearchSamples
6PK
SST


4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMC
EDTA
20









40







Serum
SST
8

16†





8
8†
8
8
8†
8
8†
8
8
8†
DailyVolume(mL)

45
0
27
4
4
4
4
11
12
19
59
12
19
12
19
12
12
12
CumulativeVolume(mL)

45
45
72
76
80
84
88
99
111
130
189
201
220
232
251
263
275
287
Visitwindows:ScheduleVisitsD2A–D14withrespecttoVisitD2.VisitD2A(within10minofEOI);VisitsD2B,D2C(±10min);VisitD2D(-2hrs);
VisitsD3,D4(±6hrs);VisitsD6,D7,D8,D9(±2days);VisitsD10,D11,D12,D13,D14(±7days).VisitD5isnotapplicabletothisschedule.
Footnotes(continuetonextpage):
1VisitD1RisthedayofenrollmentandmaybedoneonthesamedayasDay0.VisitD2/Day0isdayofproductadministrationandpreferablyscheduled
within14daysafterenrollmentatVisitD1Rbutmaybescheduledupto28daysafterVisitD1R.
2Screeningincludesphysicalexam,vitalsigns(bloodpressure(BP),temperature,pulse,respiratoryrate(RR)),height,weight.Day0includesvitalsignsand
weight(fororderingstudyproductdose).Atothervisits,performatargetedexamifmedicallyindicated,otherwiseonlyvitalsignsarerequired.
3Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page75of84
4Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialbeforeproductadministration.CompletePregnancyPreventionCounselingForm
whenpregnancytestisdone.
5CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartate
aminotransferase,totalbilirubin,calcium,totalprotein
6PKblooddraws,definedbytimeafteraninfusion,arerelativetotheexacttimeoftheendofinfusion(EOI).Recordtheexactstart/endtimesofproduct
administrationandofblooddrawtoensureaccuratePKanalysis.
†Anti-drugantibodies(ADA)assessedfromserumsamplesattimepointsasindicated.
*Tubetypes/volumesareshowntoestimatebloodvolumesinmL.Differenttubesforclinicalevaluationsmaybeusedtomeetsiterequirementsbutresearch
sampletubesmustbeusedasshownorasinstructedbytheINDSponsor.



APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page76of84
ScheduleofEvaluations:PartCSCGroup(Groups13and15)
VisitNumber
01
1D1R
1D2
D2A
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
TimeafterInfusion


Pre
EOI
24hr
48hr
72hr
Wk1
Wk2
Wk3
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24
StudyDay
-56to-1 -28to0
D0
D0
D1
D2
D3
D7
D14
D21
D28
D56
D84
D112
D140
D168
StudyProcedures
Tube*
Screen
Enroll Dayofinjection












VRC500ScreeningConsent

X















VRC612InformedConsent,AoU


X














2PhysicalExam

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3MedicalHistory

X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
EKG

X















ConcomitantMedications

X
X
X

X
X
X
X
X
X
X
X
X
X
X
X
ProductAdministration



X













Begin7-dayDiaryCard



X













4PregnancyPreventionCounseling

X
X
X





X




X

X
ClinicalEvaluations
4PregnancyTest(urineorserum)

X
X
X





X




X

X
CBCwithdifferential
EDTA
3

3

3


3
3

3

3



ALT,creatinine
GLT
X

X

4


4
4

4

4



5CMP
GLT
4

4













HIVAg/AbCombo
EDTA
3















SickleCellTest
EDTA
3















Troponin
GLT
4















ResearchSamples
6PK
SST


4

4
4
4
4
4
4
4
4
4
4
4
4
PBMC
EDTA
20







40







Serum
SST
8

16†


8
8
8†
8
8
8†
8
8†
8
8
8†
DailyVolume(mL)

45
0
27
0
11
12
12
19
59
12
19
12
19
12
12
12
CumulativeVolume(mL)

45
45
72
72
83
95
107
126
185
197
216
228
247
259
271
283
Visitwindows:ScheduleVisitsD2A–D14withrespecttoVisitD2.VisitD2A(within10minofEOI);VisitsD3,D4,D5(±6hrs);VisitsD6,D7,D8,D9
(±2days);VisitsD10–D14(±7days).
Footnotes(continuetonextpage):
1VisitD1RisthedayofenrollmentandmaybedoneonthesamedayasDay0.VisitD2/Day0isdayofproductadministrationandpreferablyscheduledwithin
14daysafterenrollmentatVisitD1Rbutmaybescheduledupto28daysafterVisitD1R.
2Screeningincludesphysicalexam,vitalsigns(BP,temperature,pulse,RR),height,weight.Day0includesvitalsignsandweight(fororderingstudyproduct
dose).Atothervisits,performatargetedexamifmedicallyindicated,otherwiseonlyvitalsignsarerequired.
3Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page77of84
4Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialbeforeproductadministration.CompletePregnancyPreventionCounselingForm
whenpregnancytestisdone.
5CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartate
aminotransferase,totalbilirubin,calcium,totalprotein
6PKblooddraws,definedbytimeafterinfusion,arerelativetotheexacttimeoftheendofinfusion(EOI).Recordexactstart/endtimesofproductadministration
andofblooddrawtoensureaccurateanalysis.
†ADAassessedfromserumsamplesattimepointsasindicated.
*Tubetypes/volumesareshowntoestimatebloodvolumesinmL.Differenttubesforclinicalevaluationsmaybeusedtomeetsiterequirementsbutresearchsample
tubesmustbeusedasshownorasinstructedbytheINDSponsor.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page78of84
ScheduleofEvaluations:PartCCHMICIS43LSGroups(Groups11,12,13,14,15)
VisitNumber

C1
C2
1C2A
1C2B
C3
C4
C5
C6
C7
C8
C9
C10
TimeafterCHMI



24hr
72hr
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk2
CHMIDay

-1
D0
D1
D3
D7
D8
D9
D10
D11
D12
D13
D14
StudyProcedures
Tube*


CHMI


ParasitemiaCheck(dailychecksuntiltreatmentcriteriamet)
2PhysicalExam,VitalSigns


X
X


X
X
X
X
X
X
X
X
InterimMedicalHistory


X
X


X
X
X
X
X
X
X
X
CHMI



X










PhoneContact




X
X








PregnancyPreventionCounseling


X











ClinicalEvaluations
3PregnancyTest(urineorserum)


X











CBCwithdifferential
EDTA

3



3







ALT,creatinine
GLT

4











4ParasitemiaEvaluation(PCR)
EDTA





3
3
[3]
[3]
[3]
[3]
[3]
[3]
ResearchSamples
PK
SST

4



54






54
PBMC
EDTA





540






5**60
Serum
SST





516†






5**16
DailyVolume(mL)


11
0
0
0
66
3
3
3
3
3
3
83
CumulativeVolume(mL)


11
11
11
11
77
80
83
86
89
92
95
178
1AfterCHMI,scheduleVisitC2AonDay1or2,VisitC2BonDay3or4
2Performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsigns(BP,temperature,pulse,RR)arerequired.
3Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialwithin2dayspriortoCHMI.CompleteaPregnancyPrevention
CounselingFormwhenpregnancytestisdone.
4ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.
ApositiveresultpriortoDay21isrequiredforinitiationofantimalarialdirectlyobservedtherapy(DOT).
5ResearchsamplesforVisitsC3andC10maybecollectedateitherVisitC3orC4,oratVisitC9,C10,orC11,respectively.
*Tubetypes/volumesareshowntoestimatebloodvolumesinmL.Differenttubesforclinicalevaluationsmaybeusedtomeetsiterequirementsbut
researchsampletubesmustbeusedasshownorasinstructedbytheINDSponsor.
**Researchbloodwillbedrawnat14dayspost-CHMI(VisitC10)fromALLsubjects.
†ADAassessedfromserumsamplesattimepointsasindicated.



APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
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ScheduleofEvaluations:PartCCHMICIS43LSGroups(Groups11,12,13,14,15)
1VisitNumber
C11
C12
C13
C14
1C15
C16
C17
2C20
TimeafterCHMI
Wk2
Wk2
Wk2
Wk2
Wk3
Wk3
Wk4
Wk7
CHMIDay
D15
D16
D17
D18
D21
D23
D28
D49
StudyProcedures
Tube*
ParasitemiaCheck
(dailyuntiltreatmentcriteriamet)




3PhysicalExam,VitalSigns

X
X
X
X
X
X

[X]
InterimMedicalHistory

X
X
X
X
X
X

[X]
PhoneContact







X
[X]
ClinicalEvaluations
CBCwithdifferential
EDTA




**3
**3

[3]
ALT,creatinine
SST




**4
**4

[4]
4ParasitemiaEvaluation(PCR)
EDTA
[3]
[3]
[3]
[3]
[3]


[3]
Anti-MalarialTreatment





[X]
[X]


ResearchSamples
PK
SST




4


[4]
PBMC
EDTA







[60]
Serum
SST




8†


[16]
DailyVolume(mL)

3
3
3
3
22
7
0
90
CumulativeVolume(mL)

181
184
187
190
212
219
219
309
1VisitC15isonlyrequiredforCHMIparticipantsnotpreviouslydiagnosedwithmalariaparasitemiatoruleoutadelayedcase.AtVisitC15(Day21),any
subjectwhohasnotalreadystartedantimalarialtreatmentwillbegivendefinitiveDOT.SubjectsmustreturnforDOTfor2moredaysafterinitiation;
Day2ofDOT(Day22)visitwillbeassigned“C15S”.Brackets[X]indicateoptionalasneededpersubjecttreatmentstatus.
2VisitC20isonlyrequiredforsubjectswhohadapositivePCRorbloodsmeartodocumenttestofcure.Itisscheduledtooccur26±5daysafterDOT
completionandisshownatDay49forconvenience.VisitC20maybecompletedviaphoneforsubjectswhoremainmalarianegative,brackets[X]
indicateoptionalasneededpersubjectinfectionstatus.
3Performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsigns(BP,temperature,pulse,RR)arerequired.
4ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.A
positiveresultpriortoDay21isrequiredforinitiationofantimalarialDOT.Otherwise,initiateDOTatC15.
*Tubetypes/volumesareshowntoestimatebloodvolumesinmL.Differenttubesforclinicalevaluationsmaybeusedtomeetsiterequirementsbutresearch
sampletubesmustbeusedasshownorasinstructedbytheINDSponsor.
**BloodforCBC,ALT,andcreatininewillbedrawnatonsetofDOTandabout2dayslater;shownatvisitsC15andC16toaccountforblooddraw.
Parasitemiaevaluationsarenotperformedduringtreatmentthroughtotestofcure.
†ADAassessedfromserumsamplesattimepointsasindicated.



APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page80of84
ScheduleofEvaluations:PartCCHMIforControlGroup16
VisitNumber
01
1D1R

C1
C2
2C2A
2C2B
C3
C4
C5
C6
C7
C8
C9
C10
TimeAfterCHMI





24hr
72hr
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk1
Wk2
CHMIDay -56to-1-56to-1

-1
D0
D1
D3
D7
D8
D9
D10
D11
D12
D13
D14
StudyProcedures
Tube* Screen Enroll


CHMI


ParasitemiaCheck(dailyuntiltreatmentcriteriamet)
VRC500ScreeningConsent

X














VRC612InformedConsent,AoU


X













3PhysicalExam,VitalSigns

X
X

X
X


X
X
X
X
X
X
X
X
4MedicalHistory

X
X

X
X


X
X
X
X
X
X
X
X
EKG

X














CHMI





X










PhoneContact






X
X








5PregnancyPreventionCounseling

X
X

X











ClinicalEvaluations
5PregnancyTest(urineorserum)

X
X

X











CBCwithdifferential
EDTA
3


3



3







ALT,creatinine
GLT
X


4











6CMP
GLT
4














HIVAb/AgCombo
EDTA
3














SickleCellTest
EDTA
3














Troponin
GLT
4














7ParasitemiaEvaluation(PCR)
EDTA







3
[3]
[3]
[3]
[3]
[3]
[3]
[3]
ResearchSamples
PK
SST



4











PBMC
EDTA
20






840






8**60
Serum
SST
8






816






8**16
DailyVolume(mL)

45
0

11
0
0
0
66
3
3
3
3
3
3
83
CumulativeVolume(mL)

45
45

56
56
56
56
122
125
128
131
134
137
140
223
Footnotes(continuetonextpage):
1VisitD1RisthedayofenrollmentandmaybedoneonthesamedayasDayC1.
2AfterCHMI,scheduleVisitC2AonDay1or2,VisitC2BonDay3or4.
3Screeningincludesphysicalexam,vitalsigns(BP,temperature,pulse,RR),height,weight.OnD0,performatargetedphysicalexamifmedicallyindicated,
otherwiseonlyvitalsignsarerequired.
4Performfullmedicalhistoryatscreening.Atothervisits,performinterimmedicalhistory.
5Pregnancytestresultsmustbenegativeforwomenofreproductivepotentialwithin2dayspriortoCHMI.UsePregPreventionCounselingFormwhentesting
forpregnancy.
6CMPincludessodium,potassium,chloride,totalCO2,creatinine,glucose,ureanitrogen,albumin,alanineaminotransferase,alkalinephosphatase,aspartate
aminotransferase,totalbilirubin,calcium,totalprotein.

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page81of84
7ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.Apositive
resultpriortoDay21isrequiredforinitiationofantimalarialtreatment.
8ResearchsamplesforVisitsC3andC10maybecollectedateitherVisitC3orC4,oratVisitC9,C10,orC11,respectively.
*Tubetypes/volumesareshowntoestimatebloodvolumesinmL.Differenttubesforclinicalevaluationsmaybeusedtomeetsiterequirementsbutresearch
sampletubesmustbeusedasshownorasinstructedbytheINDSponsor.
**Researchbloodwillbedrawnat14dayspost-CHMI(VisitC10)fromALLsubjects.


APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page82of84
ScheduleofEvaluations:PartCCHMIforControlGroup16
VisitNumber
C11
C12
C13
C14
1C15
C16
C17
2C20
TimeafterCHMI
Wk2
Wk2
Wk2
Wk2
Wk3
Wk3
Wk4
Wk7
CHMIDay
D15
D16
D17
D18
D21
D23
D28
D49
StudyProcedures
Tube*
ParasitemiaCheck
(dailyuntiltreatmentcriteriamet)




3PhysicalExam,VitalSigns

X
X
X
X
X
X

[X]
InterimMedicalHistory

X
X
X
X
X
X

[X]
PhoneContact







X
[X]
ClinicalEvaluations
CBCwithdifferential
EDTA




**3
**3

[3]
ALT,creatinine
SST




**4
**4

[4]
4ParasitemiaEvaluation(PCR)
EDTA
[3]
[3]
[3]
[3]
[3]


[3]
Anti-MalarialTreatment





[X]
[X]


ResearchSamples
PK
SST








PBMC
EDTA







[60]
Serum
SST




8


[16]
DailyVolume(mL)

3
3
3
3
22
7
0
90
CumulativeVolume(mL)

226
229
232
235
257
264
264
354
1VisitC15isonlyrequiredforCHMIparticipantsnotpreviouslydiagnosedwithmalariaparasitemiatoruleoutadelayedcase.AtVisitC15(Day21),any
subjectnotalreadyonantimalarialtreatmentwillbegivenDOT;Day2ofDOT(Day22)visitwillbeassigned“C15S”.SubjectsmustreturnforDOTfor2
moredaysafterinitiation.Brackets[X]indicateoptionalasneededpersubjecttreatmentstatus.
2VisitC20isonlyrequiredforsubjectswhohadapositivePCRorbloodsmeartodocumenttestofcure.Itisscheduledtooccur26±5daysafterDOT
completionandisshownatDay49forconvenience.VisitC20maybecompletedviaphoneforsubjectswhoremainmalarianegative,brackets[X]indicate
optionalasneededpersubjectinfectionstatus.
3Performatargetedphysicalexamifmedicallyindicated,otherwiseonlyvitalsigns(BP,temperature,pulse,RR)arerequired.
4ParasitemiaevaluationsshouldcontinuedailyuntilasubjecthasonepositivePCRorbloodsmear;brackets[3]indicateoptionaldrawasneeded.Apositive
resultpriortoDay21isrequiredforinitiationofantimalarialDOT.Otherwise,initiateDOTatDay21.
*Tubetypes/volumesareshowntoestimatebloodvolumesinmL.Differenttubesforclinicalevaluationsmaybeusedtomeetsiterequirementsbutresearch
sampletubesmustbeusedasshownorasinstructedbytheINDSponsor.
**BloodforCBC,ALTandcreatininewillbedrawnatonsetofDOTandatabout2dayslater;shownatvisitsC15andC16toaccountforblooddraw.
Parasitemiaevaluationsarenotperformedduringtreatmentthroughtotestofcure.


APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page83of84
APPENDIXII:ASSESSMENTOFAERELATIONSHIPANDSEVERITY
GRADING

APhase1TrialtoEvaluateCIS43LSinHealthyAdults

VRC612,Version8.0

October26,2021
Page84of84
AssessmentofRelationshipofanAdverseEvent
TherelationshipbetweenanAEandthestudyproductorCHMIwillbeassessedbythe
investigatoronthebasisofclinicaljudgmentandthedefinitionsbelow.
• DefinitelyRelated:TheAEandadministrationofstudyproductand/orCHMIare
relatedintime,andadirectassociationcanbedemonstrated.
• ProbablyRelated:TheAEandadministrationofstudyproductand/orCHMIare
reasonablyrelatedintime,andtheAEismorelikelyexplainedbystudyagentorCHMI
thanothercauses.
• PossiblyRelated:TheAEandadministrationofstudyproductand/orCHMIare
reasonablyrelatedintime,buttheAEcanbeexplainedequallywellbycausesotherthan
studyagentorCHMI.
• NotRelated:TheAEisclearlyexplainedbyanothercausenotrelatedtothestudy
productorCHMI.
ForpurposesofpreparingsummarydatareportsinwhichAEattributionsaresimplifiedto
“Related”or“NotRelated”,inthisprotocol,the“Definitely,ProbablyandPossibly”attributions
abovewillbemappedtothe“Related”category,whilethe“Unlikely/ProbablyNotRelated”and
“NotRelated”attributionsabovewillbemappedtothe“NotRelated”category.Thedefinitions
thatapplywhenthesetwoattributioncategoriesaloneareusedareasfollows:
• Related:ThereisareasonablepossibilitythattheAEmayberelatedtothestudy
productorCHMI.
• NotRelated:ThereisnotareasonablepossibilitythattheAEisrelatedtothestudy
productorCHMI.

GradingtheSeverityofanAdverseEvent
TheDivisionofAIDS(DAIDS)TableforGradingtheSeverityofAdultandPediatricAdverse
Events,CorrectedVersion2.1[July2017]willbeusedtodeterminetheseveritygradesofAEs
inthisprotocolandisavailablefrom:https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables.

Severalmodificationsweremadetothetableasfollows:
• WeightlosswillberecordedasanAEonlyifitisconsidereddeleterioustothe
participant’shealth.
•
Forseveritygradingofthesolicitedbruisingparameterattheproductadministrationsite,
thedefinitionsbasedonsizeofthelargestdiameterandlistedforthe“InjectionSite
ErythemaorRedness”willbeused.Theseveritygradedefinitionfor“Bruising”
providedundertheDermatologicClinicalConditionswillbeusedonlyforunsolicited
AEsinvolvingbruisingatotherbodylocations.
• Creatininechangeswillbegradedonthebasisoftheupperlimitofnormalprovidedby
thegradingtableandnotchangefrombaseline.
• Creatinineclearancechangeswillbegradedaccordingtoml/minprovidedbythegrading
tableandnotchangefrombaseline.
• SubclinicalCMPresultsforsodium,potassium,chloride,bicarbonate,BUN,andglucose
willnotbeconsideredanAEunlessGrade2orhigher.