Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against Plasmodium Falciparum, in an Age De-Escalation, Dose-Escalation Trial and a Randomized, Placebo-Controlled, Double-Blind Trial of Children in Western Kenya
Phase: PHASE2
Conditions: Plasmodium Falciparum Infection, Malaria
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Abbreviated Title: Anti-malaria MAb in Kenyan children 
Protocol #: 4413 
Version 6.0 Date: 2 Apr 2024 
 
 
Title: Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against Plasmodium falciparum, in 
an Age De-Escalation, Dose-Escalation Trial and a Randomized, Placebo-Controlled, Double-Blind Trial 
of Children in Western Kenya 
 
Study Identifiers: 
 
KEMRI SSC#4413 
NIH  
 
 
 
 
 
 
 
 
 
Co-Principal Investigators:  
Titus Kwambai, MD, PhD, Epidemiologist Centers for Disease Control and Prevention Kenya Malaria 
Program Phone: +254 722207281 Email: qbb5@cdc.gov 
Laura Steinhardt, PhD, MPH Malaria Branch, US CDC 1600 Clifton Rd., Atlanta, GA 30329 Phone: 
+1-404-718-4794 Email: LSteinhardt@cdc.gov 
Peter D. Crompton, MD, MPH, Chief, Malaria Infection Biology and Immunity Section Laboratory of 
Immunogenetics (LIG), National Institute of Allergy and Infectious Diseases (NIAID), National 
Institutes of Health (NIH), Phone: 240-383-7640 Email: pcrompton@niaid.nih.gov 
Co-Investigators: 
NIH: 
Robert A. Seder, MD, NIH Protocol Chair: Chief, Cellular Immunology Section, Vaccine Research 
Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), NIH, Phone: 301-594-
8483, Email: rseder@mail.nih.gov 
CDC: 

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Julie Gutman, MD, MS, Malaria Branch US CDC,1600 Clifton Rd., Atlanta, GA 30329 Phone: 404-
718-4730, Email: fff2@cdc.gov Role(s): D, F, G 
Peter McElroy, PhD, MPH,Malaria Branch US CDC,1600 Clifton Rd., Atlanta, GA 30329 Phone: 404-
718-4724, Email : pgm9@cdc.gov, Role (s): F, G 
LSTM: 
Feiko ter Kuile, MD, PhD, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 
5QA, UK, Mobile: +44 (0)7846 377 369 (UK), +254 (0)708 739 228 (Kenya) Email: 
feiko.terkuile@lstmed.ac.uk,  Role(s): B, E, F  
KEMRI: 
Eunice Ouma, MD, KEMRI Center for Global Health Research (CGHR) P.O. Box: 1578 - 40100, 
Kisumu, Kenya , Phone: +254722324496, E-mail: eunice.ouma@lstmed.ac.uk, Role(s): A, B, C, D, E, 
F, G  
Martina Oneko, MD, KEMRI CGHR,P.O. Box: 1578 - 40100, Kisumu, Kenya, Phone: +254-717-747-
279, Email: tinaoneko@gmail.com, Role(s): A, B, C, D, E, F, G 
Simon Kariuki, PhD,KEMRI CGHR,Phone: +254 725 389 246, Email: skariuki1578@gmail.com, 
Role(s): A, B, E, F, G 
Ruth Njoroge, BPharm,KEMRI CGHR,P.O. Box: 1578 - 40100, Kisumu, Kenya 
Phone: +254 702 964 102,Email: ruthwambuinjoroge1@gmail.com, Role(s): A, B, E, F, G 
Kephas Otieno, MSc,KEMRI CGHR, P.O. Box: 1578 - 40100, Kisumu, Kenya 
Phone: +254 721 405 643,Email: kotieno72@yahoo.com, Role(s): B, E, F, G 
Collaborators: 
Sean C. Murphy, MD, PhD,University of Washington,Department of Laboratory Medicine, 
NW120,Box 357110,1959 Pacific St.,Seattle, WA 98195–7110,Phone: 206-685-6162 Email: 
murphysc@uw.edu  
Role(s): F 
Daniel Neafsey, PhD,Harvard T.H. Chan School of Public Health,665 Huntington Avenue, Building 1, 
Room 711,Boston, MA 02115,Phone: 617-432-5404 Email: neafsey@hsph.harvard.edu 
Role(s): F 
Edmund Capparelli, PharmD,University of California, San Diego 9500 Gilman Drive La Jolla, CA 
92093 Phone: +1-858-246-0009 Email: ecapparelli@ucsd.edu, 
Role(s): F 

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Investigational Agent: 
Drug Name 
L9LS 
Investigational New 
Drug (IND) Number 
160213 
Manufacturer 
Vaccine Research Center (VRC), NIAID, NIH 
Sponsor: OCRPRO, NIH 
 
 
Office of The Clinical Research Policy and Regulatory 
Operations, NIH  
 
 
Revision chronology: 
Date 
Protocol 
Version 
Details 
of 
Changes 
Authors 
Signature 
Principal 
Investigator 
10 Feb 2022 
1.0 
Original Laura Steinhardt 
 
 
 
 
Titus Kwambai 
 
22 March 2022 
2.0 
Revised 
Laura Steinhardt 
 
 
 
 
Titus Kwambai 
 
29 July 2022 
3.0 
Revised 
Laura Steinhardt 
 
 
 
 
Titus Kwambai 
 
23 Nov 2022 
4.0 
Revised 
Laura Steinhardt 
 
 
 
 
Titus Kwambai 
 
12 Sep 2023 
5.0 
Revised 
Laura Steinhardt 
 
 
 
Revised 
Titus Kwambai 
 
2 Apr 2024 
6.0 
Revised 
Laura Steinhardt 
 
 
 
 
Titus Kwambai 
 
 

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Confidentiality Statement: This document contains confidential information that must not be disclosed to 
anyone other than the sponsor, the investigator team, host institution, relevant ethics committee and 
regulatory authorities 
 
 
Data and Safety Monitoring Board (DSMB): NIAID Intramural DSMB 
 
 
STUDY STAFF ROSTER 
CDC Investigators: 
CDC investigators are involved in study design, implementation, analysis of coded samples and 
data, and writing and dissemination of reports of study results. The CDC Co-Principal 
Investigators will have access to identifiable data. 
 
The research activities of the United States (US) CDC investigators will be reviewed by:  
Scientific and Ethics Review Unit (SERU) 
Kenya Medical Research Institute (KEMRI) 
P.O. Box 54840 00200 Off Mbagathi Road.  
Nairobi, Kenya. 
Tel : +254 722205901 
Email : kemriseru18@gmail.com 
 
CDC Principal Investigator: Laura Steinhardt, PhD, MPH 
Malaria Branch, US CDC 
1600 Clifton Rd., Atlanta, GA 30329 
Phone: +1-404-718-4794 
Email: LSteinhardt@cdc.gov 
CITI Expiration: December 24, 2024 
Role(s): B, E, F, G 
 
CDC Kenya Principal 
Investigator: 
Titus Kwambai, MD PhD 
US CDC, Kenya Malaria Program 
Address: P.O. Box: 1578 - 40100  
Kisumu, Kenya 
Phone: +254 722207281 
Email: qbb5@cdc.gov 
CITI Expiration: March 10, 2023 
Role(s): A, B, C, D, E, F, G 
 

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CDC Co-Investigators: Julie Gutman, MD, MS  
Malaria Branch US CDC 
1600 Clifton Rd., Atlanta, GA 30329 
Phone: 404-718-4730 
Email: fff2@cdc.gov 
CITI Expiration: July 17, 2025 
Role(s): D, F, G 
 
Peter McElroy, PhD, MPH 
Malaria Branch US CDC 
1600 Clifton Rd., Atlanta, GA 30329 
Phone: 404-718-4724 
Email : pgm9@cdc.gov 
CITI Expiration: May 25, 2025 
Role (s) : F, G 
 
 
KEMRI Investigators: 
The research activities of the KEMRI investigators will be reviewed by:  
SERU Ethics Committee 
Kenya Medical Research Institute 
P.O. Box 54840 00200 Off Mbagathi Road.  
Nairobi, Kenya. 
Tel : +254 722205901 
Email : kemriseru18@gmail.com 
 
KEMRI Co-Investigators: Eunice Ouma, MD 
KEMRI Center for Global Health Research (CGHR) 
P.O. Box: 1578 - 40100, Kisumu, Kenya Phone:  
E-mail: eunice.ouma@lstmed.ac.uk 
Role(s): A, B, C, D, E, F, G  
 
Martina Oneko, MD  
KEMRI CGHR 
P.O. Box: 1578 - 40100, Kisumu, Kenya 
Phone: +254-717-747-279 

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Email: tinaoneko@gmail.com 
Role(s): A, B, C, D, E, F, G 
 
Simon Kariuki, PhD 
KEMRI CGHR 
Phone: +254 725 389 246 
Email: skariuki1578@gmail.com 
Role(s): A, B, E, F, G 
 
Ruth Njoroge, BPharm 
KEMRI CGHR 
P.O. Box: 1578 - 40100, Kisumu, Kenya 
Phone: +254 702 964 102 
Email: ruthwambuinjoroge1@gmail.com  
Role(s): A, B, E, F, G 
 
Kephas Otieno, MSc 
KEMRI CGHR 
P.O. Box: 1578 - 40100, Kisumu, Kenya 
Phone: +254 721 405 643 
Email: kotieno72@yahoo.com 
Role(s): B, E, F, G 
 
NIH, LSTM and other non-CDC U.S. Investigators: 
NIH, LSTM and other non-CDC U.S. Investigators are involved in study design, 
implementation, analysis of coded samples and data, and writing and dissemination of reports of 
study results. Although they may support KEMRI and CDC investigators in 
monitoring/oversight capacities, NIH, LSTM, and other non-CDC U.S. investigators will not be 
engaged in human subjects research.  
 
NIH Protocol Chair: Robert A. Seder, MD 
Chief, Cellular Immunology Section 
VRC, NIAID, NIH 
Phone: 301-594-8483 
Email: rseder@mail.nih.gov 
Role(s): F 
 
NIH Principal Investigator and 
Referral Contact: 
Peter D. Crompton, MD, MPH 
Laboratory of Immunogenetics (LIG), NIAID, NIH 
5625 Fishers Lane Room 4N07D 

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Rockville, MD 20852 
Phone: 240-383-7640 
Email: pcrompton@niaid.nih.gov  
Role(s): F 
 
Statistician:  Zonghui Hu, PhD 
Biostatistics Research Branch, NIAID, NIH 
Phone: 240-669-5240 
Email: huzo@niaid.nih.gov 
Role(s): F 
 
LSTM Co-investigator 
 
 
 
 
 
 
 
Collaborators: 
 
Feiko ter Kuile, MD, PhD  
Liverpool School of Tropical Medicine, Pembroke Place, 
Liverpool L3 5QA, UK,  
Mobile: +44 (0)7846 377 369 (UK), +254 (0)708 739 228 
(Kenya) 
Role(s): B, E, F 
 
 
Sean C. Murphy, MD, PhD 
University of Washington 
Department of Laboratory Medicine, NW120 
Box 357110 
1959 Pacific St. 
Seattle, WA 98195–7110 
Phone: 206-685-6162  
Email : murphysc@uw.edu 
Role (s) : F 
 
Daniel Neafsey, PhD 
Harvard T.H. Chan School of Public Health 
665 Huntington Avenue 
Building 1, Room 711 
Boston, MA 02115 
Phone : 617-432-5404 
Email : neafsey@hsph.harvard.edu 
Role (s) : F 
 
Edmund Capparelli, PharmD 
University of California, San Diego 

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9500 Gilman Drive 
La Jolla, CA 92093 
Phone : +1-858-246-0009 
Email : ecapparelli@ucsd.edu 
Role (s) : F 
 
Role definitions:  
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about 
living individuals 
C. Obtaining the voluntary informed consent of 
individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable 
private information or data/specimens for research 
purposes 
F. Studying, interpreting, or analyzing coded (linked) 
data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
Study Site: 
KEMRI CGHR 
Siaya Clinical Research Centre 
Siaya County Referral Hospital, Siaya County 
Kenya 
 
Kogelo Dispensary, Siaya County 
Kenya 
 
Sponsor Medical Monitor (SMM):  Saran Wells, MD (Contractor) 
Leidos Biomedical Research, Inc. 
In support of NIAID, NIH 
Phone 240-529-4337 
Email: saran.wells@nih.gov 
 
Independent Safety Monitor (ISM): Dr. Janet Oyieko, MD 
KEMRI CCR, Po Box 54 -40100 Kisumu.  

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Email : janet.oyieko@gmail.com.  
Tel +254721996988  
US Office of Managaement and Budget/Paperwork Reduction Act (OMB/PRA) 
Information  
This study is being sponsored by the Office of Clinical Research Policy and Regulatory 
Operations (OCRPRO) within the National Institute of Allergies and Infectious Diseases 
(NIAID) within the US National Institutes of Health (NIH). The data collection in western 
Kenya is being carried out by KEMRI, which will initiate, direct, collect and own the data 
arising from this study. Data will be shared with CDC, LSTM, and NIH at KEMRI’s discretion. 
CDC and NIH staff are providing technical assistance for protocol development, training of staff, 
collection of data, data analysis, laboratory analyses, and preparation of scientific manuscripts.  
 
Funding for this study is being provided the Bill and Melinda Gates Foundation (BMGF), Grant 
ID# INV-035091. Funding from BMGF is provided to the CDC via a gift from the Centers for 
Diseases Control and Prevention (CDC) Foundation. CDC is providing funding to LSTM via a 
Cooperative Agreement (#GH002290) and LSTM (Federalwide Assurance Number: 
FWA00001877) is providing funding to KEMRI (Federalwide Assurance Number: 
FWA00002066) in a subagreement. The Vaccine Research Center (VRC) of NIAID 
(Federalwide Assurance Number: FWA00005897) is providing the investigational product for 
this trial. 
 
 

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TABLE OF CONTENTS  
STUDY STAFF ROSTER ................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................... 10 
List of Figures ..................................................................................................................................... 12 
List of Tables ...................................................................................................................................... 13 
ABBREVIATIONS ............................................................................................................................ 14 
STATEMENT OF COMPLIANCE .................................................................................................. 17 
1 
PROTOCOL SUMMARY ......................................................................................................... 18 
 
Abstract ................................................................................................................................ 18 
 
Schema ................................................................................................................................. 27 
 
Schedule of Activities (SOA) ............................................................................................. 31 
 
Part 1 Study Schedule ................................................................................................ 31 
 
Part 2 Study Schedule ................................................................................................ 33 
 
Part 1b Study Schedule.............................................................................................. 37 
 
Part 2 Extension Study Schedule .............................................................................. 40 
2 
INTRODUCTION ...................................................................................................................... 43 
 
Study Rationale.................................................................................................................... 43 
 
Background .......................................................................................................................... 43 
 
Study Agent: L9LS .................................................................................................... 45 
 
Laboratory Assessments of L9LS ............................................................................. 49 
 
Repeat Dosing: ADA, PK ......................................................................................... 51 
 
Risk/Benefit Assessment..................................................................................................... 52 
 
Known Potential Risks .............................................................................................. 52 
 
Known Potential Benefits.......................................................................................... 56 
 
Assessment of Potential Risks and Benefits ............................................................ 56 
3 
OBJECTIVES AND ENDPOINTS........................................................................................... 56 
4 
STUDY DESIGN ....................................................................................................................... 61 
 
Overall Design ..................................................................................................................... 61 
 
Year 2 Follow-on Study (Safety and Extension) ..................................................... 64 
 
Scientific Rationale for Study Design ................................................................................ 65 
 
Year 2 Follow-on Study (Safety and Extension) ..................................................... 66 
 
Justification for Dose ................................................................................................. 66 
5 
STUDY POPULATION ............................................................................................................ 67 
 
Inclusion Criteria ................................................................................................................. 67 
 
Year 2 Extension Inclusion Criteria ......................................................................... 67 
 
Exclusion Criteria ................................................................................................................ 68 
 
Inclusion of Vulnerable Participants .................................................................................. 70 
 
Inclusion of Pregnant Women, Fetuses or Neonates......................................................... 71 
 
Lifestyle Considerations ..................................................................................................... 71 
 
Screen Failures..................................................................................................................... 71 
 
Strategies for Recruitment and Retention .......................................................................... 71 
 
Costs ........................................................................................................................... 72 
 
Compensation ............................................................................................................ 72 
 
COVID-19 Risk Mitigation ................................................................................................ 72 
6 
STUDY INTERVENTION........................................................................................................ 73 
 
Study Interventions(s) Administration ............................................................................... 73 

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Study Intervention Description ................................................................................. 73 
 
Dosing and Administration. ...................................................................................... 73 
 
Preparation/Handling/Storage/Accountability ................................................................... 75 
 
Acquisition and Accountability ................................................................................ 75 
 
Formulation, Appearance, Packaging, and Labeling............................................... 76 
 
Product Storage and Stability.................................................................................... 76 
 
Preparation ................................................................................................................. 77 
 
Measures to Minimize Bias: Randomization and Blinding .............................................. 78 
 
Randomization ........................................................................................................... 78 
 
Blinding ...................................................................................................................... 78 
 
Study Intervention Compliance .......................................................................................... 79 
 
Concomitant Therapy .......................................................................................................... 79 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................................... 80 
 
Discontinuation of Study Intervention ............................................................................... 80 
 
Participant Discontinuation/Withdrawal from the Study .................................................. 80 
 
Lost to Follow-up ................................................................................................................ 80 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................... 81 
 
Screening and Pre-Enrollment Procedures ........................................................................ 81 
 
Efficacy Assessments .......................................................................................................... 83 
 
Clinical Evaluations ................................................................................................... 83 
 
Biospecimen Evaluations .......................................................................................... 84 
 
Correlative Studies for Research/Pharmacokinetic Studies .................................... 84 
 
Samples for Genomic Analysis................................................................................. 85 
 
Safety and Other Assessments ............................................................................................ 86 
 
Safety Definitions, Management, and Sponsor Reporting................................................ 86 
 
Definitions .................................................................................................................. 86 
 
Documenting, Assessing, Recording, and Reporting Events.................................. 89 
 
Withdrawal Criteria for an Individual Subject......................................................... 95 
 
Additional Safety Oversight...................................................................................... 96 
 
Pausing Rules ............................................................................................................. 97 
 
Halting Rules for the Protocol .................................................................................. 98 
 
Unanticipated Problems ...................................................................................................... 99 
 
Definition of Unanticipated Problems ...................................................................... 99 
 
Unanticipated Problem Reporting .......................................................................... 100 
 
ADDITIONAL REPORTING REQUIREMENTS ......................................................... 100 
 
Protocol Deviation Reporting ................................................................................. 100 
 
Reporting Protocol Deviations that Result from the COVID-19 Pandemic ........ 101 
9 
STATISTICAL CONSIDERATIONS .................................................................................... 101 
 
Statistical Hypothesis ........................................................................................................ 101 
 
Sample Size Determination .............................................................................................. 102 
 
Sample Size Considerations for the Dose-Escalation Study ................................. 102 
 
Sample Size Considerations for the Efficacy Study .............................................. 103 
 
Sample Size Considerations for the Year 2 Extension Study ......................................... 106 
 
Populations for Analyses .................................................................................................. 108 
 
Evaluable for toxicity .............................................................................................. 108 

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Evaluable for objective response ............................................................................ 108 
 
Evaluable Non-Target Disease Response .............................................................. 108 
 
Statistical Analyses............................................................................................................ 108 
 
General Approach .................................................................................................... 108 
 
Analysis of the Primary Endpoints ......................................................................... 109 
 
Analysis of the Secondary Endpoint(s) .................................................................. 109 
 
Efficacy Analyses .................................................................................................... 109 
 
Safety Analyses........................................................................................................ 111 
 
Pharmacokinetics Analysis ..................................................................................... 111 
 
Baseline Descriptive Statistics ................................................................................ 112 
 
Planned Interim Analyses........................................................................................ 112 
 
Sub-Group Analyses ................................................................................................ 113 
 
Tabulation of individual Participant Data .............................................................. 113 
 
Exploratory Analyses .............................................................................................. 113 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS .......................................... 113 
 
Informed Consent Process ............................................................................................ 113 
 
Consent/Assent Procedures and Documentation ................................................... 113 
 
Study Discontinuation and Closure .............................................................................. 114 
 
Confidentiality and Privacy .......................................................................................... 114 
 
Future use of Stored Specimens and Data ................................................................... 115 
 
Safety Oversight ............................................................................................................ 116 
 
Clinical Monitoring ....................................................................................................... 116 
 
Quality Assurance and Quality Control ....................................................................... 116 
 
Data Handling and Record Keeping ............................................................................. 117 
 
Data Collection and Management Responsibilities ............................................... 117 
 
Study Records Retention ......................................................................................... 117 
 
Protocol Deviations and Non-Compliance .................................................................. 117 
 
NIH Definition of Protocol Deviation .................................................................... 117 
 
Publication and Data Sharing Policy ............................................................................ 118 
 
Human Data Sharing Plan ....................................................................................... 118 
 
Genomic Data Sharing Compliance ....................................................................... 118 
 
Collaborative Agreements............................................................................................. 118 
 
Agreement Type ...................................................................................................... 118 
 
Conflict of Interest Policy ............................................................................................. 118 
 
Budget ............................................................................................................................ 119 
12 REFERENCES ......................................................................................................................... 121 
APPENDIX A: KENYA NATIONAL IMMUNIZATION SCHEDULE .................................... 124 
APPENDIX B: KENYA ADVERSE EVENT GRADING SCALE ............................................. 125 
PART 1 AND 1B: ............................................................................................................................. 125 
PART 2 AND THE EXTENSION PHASE: ................................................................................... 126 
 
LIST OF FIGURES 
Figure 1. Enrollment and study flow schematics for part 1. ............................................................ 27 
Figure 2. Study flow schematic for part 2. ........................................................................................ 29 
Figure 3. Study flow schematic for part 1b (additional safety study) ............................................. 30 

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Figure 4. Study flow scheme for part 2 extension study .................................................................. 30 
  
 
LIST OF TABLES 
Table 1. Study agent assignment and dosing by age group/arm ...................................................... 73 
Table 2. Dosing of L9LS (10 to 20 mg/kg) by weight of child for part 2....................................... 77 
Table 3. Dosing schedule for dihydroartemisinin piperaquine ........................................................ 83 
Table 4. Standard event recording, assessment, and reporting timeframes. ................................... 90 
Table 5. Probability of events for different safety scenarios within an arm (n=9). ...................... 102 
Table 6. Sample size calculations based on secondary 12-month endpoint, to achieve 80% power 
to detect efficacy of 70% at 6 months and 60% at 12 months, assuming 35% of the control group 
are infected by 6 months and 45% by 12 months. .......................................................................... 104 
Table 7. The minimum detectable difference in event rate between L9LS arm and placebo arm
............................................................................................................................................................ 106 
Table 8.The comparison power with 108 participants per arm and a lost to follow up rate of 20%
............................................................................................................................................................ 107 
Table 9. The comparison power between two  L9LS arms  with 108 participants per arm and a 
lost to follow up rate of 20% ............................................................................................................ 107 
 
 

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ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AL 
Artemether-Lumefantrine 
ALT 
Alanine Transaminase 
AR 
Adverse Reaction 
AUC 
Area Under the Concentrations vs. Time Curve 
Cave 
Average Concentrations 
CDC 
Centers for Disease Control and Prevention 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CGHR 
Center for Global Health Research 
cGMP 
Current Good Manufacturing Practices 
CHMI 
Controlled Human Malaria Infection 
CL 
Clearance 
Cmax 
Maximum Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
Cr 
Creatinine 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CSO 
Clinical Safety Office 
CTM 
Clinical Trials Management 
DCR 
Division of Clinical Research 
DNA 
Deoxyribonucleic Acid 
DP 
Dihydroartemisinin-piperaquine 
DS 
Drug Substance 
DSMB 
Data and Safety Monitoring Board 
EC 
Effective Concentration 
ED 
Effective Dose 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council on Harmonisation  
IND 
Investigational New Drug Application 
IPC 
Infection Prevention and Control 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 

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IV 
Intravenous(ly) 
KEMRI 
Kenya Medical Research Institute 
KPPB 
Kenya Pharmacy and Poisons Board 
KSh 
Kenyan Shilling 
LIG 
Laboratory of Immunogenetics 
MAb 
Monoclonal Antibody 
MITT 
Modified Intention-To-Treat 
MoH 
Ministry of Health 
NC 
Non-Compartmental 
NCT 
National Clinical Trial 
NHP 
Non-Human Primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH  
National Institutes of Health 
NOAEL 
No Observed Adverse Effect Level 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
Pf 
Plasmodium falciparum 
PfCSP 
Plasmodium falciparum Circumsporozoite Protein 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
Q 
Intercompartmental Clearance 
QL 
Quantitative Limit 
RDT 
Rapid Diagnostic Test 
REDCap 
Research Electronic Data Capture 
REF 
Reportable Event Form 
RNA 
Ribonucleic Acid 
rRNA 
Ribosomal Ribonucleic Acid 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SC 
Subcutaneous 
SD 
Standard Deviation(s) 
SERF 
Safety Expedited Report Form 
SERU 
Scientific and Ethics Review Unit 
SMM 
Sponsor Medical Monitor 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 

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SRCP 
Safety Review and Communication Plan 
TCR 
Tissue Cross-Reactivity 
Tmax 
Maximal Concentration 
UP 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 
US 
United States 
VCMP 
Vaccine Clinical Materials Program 
Vd 
Volume of Distribution 
Vdss 
Volume of Distribution at Steady-State 
VE 
Vaccine Efficacy 
VRC 
Vaccine Research Center 
WHO 
World Health Organization 
 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation (ICH) 
Good Clinical Practice (GCP) and the following:  
• 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).  
 
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 and informed consent/assent forms will be submitted to the Kenya Medical 
Research Institute’s Scientific and Ethics Review Unit (SERU) and to the Kenya Pharmacy and 
Poisons Board (KPPB) as well as National Commission for Science, Technology and Innovation 
(NACOSTI) for review and approval. These review boards are collectively referred to as 
institutional review boards (IRBs) throughout this protocol. Approval of both the protocol and 
the consent/assent forms must be obtained before any subject is enrolled. Any amendment to the 
protocol will require review and approval by the IRBs before the changes are implemented to the 
study. In addition, all changes to the consent/assent forms will be IRB-approved; a determination 
will be made regarding whether a new consent/assent needs to be obtained from subjects who 
provided consent/assent using a previously approved form. 
 
 

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1 
PROTOCOL SUMMARY 
 
Abstract 
Title: 
Safety and Efficacy of L9LS, a Human Monoclonal Antibody 
Against Plasmodium falciparum, in an Age De-Escalation, 
Dose-Escalation Trial and a Randomized, Placebo-Controlled, 
Double-Blind Trial of Children in Western Kenya 
Study Description: 
A three-part, phase 2 trial evaluating the safety and 
tolerability of one-time subcutaneous (SC) administration of 
monoclonal antibody (MAb) L9LS in healthy Kenyan 
children aged 5 months to 10 years, as well as the safety and 
protective efficacy of up to four doses of L9LS against 
naturally occurring Plasmodium falciparum (Pf) infection 
among Kenyan children aged 5 to 59 months at enrollment, in 
a setting of perennial high transmission, plus the safety and 
continued efficacy of a third and fourth dose of L9LS in a 
second year of follow-up. The primary study hypotheses are 
that L9LS will be safe and will produce protection against 
malaria infection. Before study agent administration, all 
subjects will be given dihydro-artemisinin-piperaquine (DP) 
to clear any preexisting Pf blood-stage infection. 
 
Part 1: Age de-escalation and dose-escalation study 
In a stepwise fashion, children aged 5-10 years will receive 5 
mg/kg of L9LS or placebo and be followed for 3 months to 
assess tolerability and safety. If acceptable tolerability and 
safety profiles are met at 1-week post-injection, we will 
administer the 5-mg/kg dose of L9LS or placebo to children 
aged 5-59 months while enrolling another cohort of children 
aged 5-10 years at a dose of 10 mg/kg of L9LS or placebo. If 
after 1 week, the 10-mg/kg dose is found to be safe in 
children aged 5-10 years and the 5-mg/kg dose is found to be 
safe in children aged 5-59 months, we will then administer a 
20-mg/kg dose of L9LS or placebo to children aged 5-10 
years and a 10-mg/kg dose of L9LS or placebo to children 
aged 5-59 months. If these doses are found safe after 1 week, 
we will administer a 20-mg/kg dose of L9LS or placebo to 
children aged 5-59 months. Should tolerability and safety of 
all doses be acceptable in children aged 5-59 months, we will 

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move to part 2 of the trial. Dosing in part 1 of the study will 
be weight-based and all doses will be administered SC in a 
double-blinded fashion. We will enroll 12 participants in each 
age-dose group in a 3:1 ratio of L9LS to placebo, for a total of 
72 participants, and all participants will be followed for a total 
of 3 months. 
 
Part 1b: Age de-escalation and dose-escalation addition 
Based on data from Mali suggesting that doses higher than 
20mg/kg are needed to protect for 12 months, we propose to 
assess the safety of an additional two doses: 30 mg/kg and 40 
mg/kg in a similar fashion. This extension of part 1 will 
include an additional 24 children, and will utilize a similar 
design to before, with 12 participants in each age-dose group 
in a 3:1 ratio of L9LS to placebo; all participants will be 
followed for a total of 3 months. However, given that it 
appears that the younger children are clearing the product 
more quickly than older people, we will include only children 
aged 5-71 months, as these are the ages of the children to be 
included in the part 2 extension. As before, we will ensure 
safety out to 7 days before proceeding to dose additional 
subjects. 
 
Part 2: Efficacy study 
A total of 324 children 5-59 months of age will be 
randomized to receive a 10-20 mg/kg dose of L9LS or 
placebo by SC administration. There will be two L9LS 
cohorts, one 5-17 months of age and another 18-59 months of 
age, which will constitute one L9LS arm. A placebo arm will 
be composed of children 5–59 months of age. They will be 
followed over 12 months with monthly blood smear 
microscopy and polymerase chain reaction (PCR) and twice-
monthly symptomatology and care-seeking behavior 
questionnaires. Dosing will be based on three weight bands; 
all doses will be administered SC with fixed doses of 75 mg 
L9LS, 150 mg L9LS, or 225 mg L9LS, resulting in a range of 
10-20 mg/kg in a double-blinded fashion. Blood will be 
drawn to assess antibody titers at baseline, and at three 
additional time points over 12 months to establish 
pharmacokinetics (PK). Participants in the L9LS arm will be 

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randomized 1:1 at baseline to receive either a second L9LS 
injection or a placebo injection to evaluate the additional 
efficacy of a second dose administered 6 months after the first 
dose. (Those in the placebo arm will receive a second 
injection of placebo.) Participants will be followed for an 
additional 6 months after the second injection with monthly 
blood smear microscopy and PCR, and a blood draw at month 
11 to assess L9LS PK. 
 
Part 2 extension: Assuming there are no safety signals from 
the day 7 review following dosing children with 30 and 40 
mg/kg of product, and prior to the last study visit of the 
original protocol described above (September 2022 to June 
2024), study participants who remain enrolled in the part 2 
efficacy study will be invited to participate in a 12-month 
extension of the study. A separate written consent process 
will take place. Enrolled children will continue in the same 
study groups as in part 2: 1 dose L9LS, 2 doses L9LS, or 
placebo. A dose (of L9LS or placebo) will be given at the 
start of the extension and again after six months. Those 
receiving L9LS will receive a dose between 20 and 40 mg/kg, 
still in a double-blinded fashion. The monthly visit and 
sample collection schedule will mirror that in part 2. 
 
Objectives: 
 
Primary Objectives: 
Part 1: 
1. Safety: To evaluate the safety and tolerability of L9LS 
administered at doses of 5 mg/kg, 10 mg/kg, and 20 
mg/kg by SC administration to healthy Kenyan 
children. 
Part 1b: 
1. Safety: To evaluate the safety and tolerability of L9LS 
administered at doses of 30 mg/kg and 40 mg/kg by 
SC administration to healthy Kenyan children 
Part 2: 
1. Safety: To evaluate the safety and tolerability of L9LS 
administered at doses of 10-20 mg/kg by SC 
administration to healthy Kenyan children. 

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2. Efficacy: To assess the efficacy of two doses of L9LS 
at a concentration of 10-20 mg/kg, administered SC to 
participants aged 5-59 months of age against first/only 
Pf malaria infection diagnosed by blood smear 
microscopy (irrespective of fever) over 12 months 
compared to placebo. 
 
Secondary Objectives: 
1. To assess the efficacy of one dose of L9LS at 10-20 
mg/kg against first/only Pf malaria infection 
diagnosed by blood smear microscopy over 3 and 6 
months compared to placebo. 
2. To assess the efficacy of one dose of L9LS at 10-20 
mg/kg against first/only Pf malaria infection 
diagnosed by blood smear microscopy over 12 months 
compared to placebo. 
3. To evaluate the efficacy of L9LS at 10-20 mg/kg 
against first/only Pf malaria infection as detected by 
PCR over 3, 6 and 12 months compared to placebo. 
4. To assess protection of L9LS at 10-20 mg/kg against 
clinical malaria (first/only and all episodes) at 3, 6 and 
12 months compared to a placebo. 
5. To assess the primary objective and secondary 
objectives 1-4 among children 5-17 months of age. 
6. To assess the primary objective and secondary 
objectives 1-4 among children 18-59 months of age. 
7. To evaluate the PK of L9LS throughout the study at 
weight-based dose levels of 5 mg/kg, 10 mg/kg, and 
20 mg/kg (part 1) and fixed doses of 10-20 mg/kg 
(part 2) in healthy Kenyan children, and 
a. To correlate L9LS serum concentration with Pf 
infection risk. 
b. To correlate L9LS serum concentration with 
clinical malaria risk. 
Part 2 Extension Primary Objectives 
1. To evaluate the safety and tolerability of a third and 
fourth SC dose of L9LS at 20–40 mg/kg (compared to 
placebo) in healthy Kenyan children. 

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2. To evaluate the PK of L9LS throughout the follow-up 
phase at 20–40 mg/kg in healthy Kenyan children. 
3. To determine if ADAs to L9LS can be detected in sera 
of recipients at specific timepoints throughout the 
study and to correlate the occurrence of ADAs with 
L9LS PK. 
Part 2 Extension Exploratory Objectives (see Figure 4 for 
study arm definitions): 
1. To assess the efficacy of a third and fourth SC dose of 
L9LS over one year at 20–40 mg/kg in mediating 
protection against Pf infection and clinical malaria in 
healthy Kenyan children during a second year of 
follow-up compared to those who received placebo 
only (arms 1 vs. 3; arms 2 vs. 3) and in those receiving 
two L9LS doses in the extension versus one (arms 1 
vs. 2) 
2. To evaluate the PK of L9LS throughout the study and 
to correlate L9LS serum concentration with Pf 
infection risk and clinical malaria risk 
3. To evaluate the effect of a third and fourth dose of 
L9LS on development of acquired immunity (measured 
by antimalarial antibodies) 

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Endpoints: 
Primary Endpoints: 
1. Part 1, part 1b, and part 2: Incidence and severity of 
local and systemic adverse events (AEs) occurring 
within 7 days after the administration of L9LS, and 
incidence of serious adverse events (SAEs) throughout 
the study period. 
2. Part 2: Pf blood-stage infection as detected by 
microscopic examination of thick blood smear for 52 
weeks after administration of L9LS or placebo. 
 
Secondary Endpoints: 
Data from one or both parts of this study will be used to 
assess the following endpoints: 
1. Pf blood-stage infection as detected by microscopic 
examination of thick blood smear for 12 and 24 weeks 
after administration of L9LS or placebo. 
2. Pf blood-stage infection as detected by RT-PCR for 
12, 24 and 52 weeks after administration of L9LS or 
placebo. 
3. Incidence of clinical malaria (definition 1, see section 
2.2.2.3) for 12, 24 and 52 weeks after administration 
of L9LS or placebo. 
4. Incidence of clinical malaria (definition 2, see section 
2.2.2.3) for 12, 24 and 52 weeks after administration 
of L9LS or placebo. 
5. Measurement of L9LS in sera of recipients (parts 1 
and 2). 
6. PK analysis of L9LS and the association of L9LS 
concentration with Pf infection risk. 
 
 
Part 2 Extension Primary Endpoints: 
1. Incidence and severity of local and systemic AEs 
occurring within 7 days after the administration of 
L9LS and incidence of serious adverse events (SAEs) 
throughout the study period. 
2. Measurement of L9LS in sera of recipients. 
3. Measurement of ADA in sera of recipients. 

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Part 2 Extension Exploratory Endpoints: 
1. Pf blood-stage infection as detected by microscopic 
examination of thick blood smears obtained between 1 
week and 52 weeks after administration of a third dose 
of L9LS or placebo. 
2. Pf blood-stage infection as detected by RT-PCR from 
dried blood spots obtained between 1 week and 52 
weeks after administration of a third dose of L9LS or 
placebo. 
3. Incidence of clinical malaria (see section 2.2.2.3) 
between 1 week and 52 weeks after administration of a 
third dose of L9LS or placebo. 
4. PK analysis of L9LS and the association of L9LS 
concentration with Pf infection risk. 
5. PK analysis of L9LS and the association of L9LS 
concentration with clinical malaria risk. 
6. Levels of naturally occurring antimalarial antibodies in 
participant blood at selected time points 
 
Study Population: 
We will enroll a total of 396 healthy Kenyan children, 
including 72 ages 5 months to 10 years residing in western 
Kenya for part 1 and 324 ages 5-59 months for part 2.  
The year 2 follow-on study will enroll an additional 24 
children into an initial safety study (part 1b) and then 
participants who are currently enrolled in part 2 of the study 
and agree to continue in the extension phase will be followed 
for an additional year. 
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
Study activities will take place at the KEMRI clinical trials 
unit based in the Siaya County Referral Hospital, which is the 
largest hospital in Siaya County, western Kenya. In part 2 and 
the extension phase, study activities will also take place at 
Kogelo Dispensary, located approximately 12 km from Siaya 
County Referral Hospital. 

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Description of Study 
Intervention: 
Participants in part 1 of this study will receive one or two SC 
injections for a total dose of 5, 10, or 20 mg/kg of L9LS or 
placebo. Participants in part 1b will receive one or two SC 
injections for a total dose of 30 or 40 mg/kg.  
 
Participants in part 2 of this study will receive 10-20 mg/kg of 
L9LS or placebo as a single dose, given in 1 or 2 SC 
injections, depending on the total dose required. At 6 months 
after the initial injection, participants who received an initial 
dose of L9LS will either receive a second L9LS SC injection 
or a placebo injection. (Those in the placebo arm will receive 
a second injection of placebo.)  
In the part 2 extension study, the investigational product will 
be administered as two SC injection(s) of either L9LS at a 
dose of 20–40 mg/kg or matching placebo at the beginning of 
year 2 extension and after 6 months. 
 
Study Duration: 
36 months (including extension phase). 
Participant Duration: 
3 months (part 1or 1b) or 13 months (part 2) or 26 months 
(part 2 plus extension phase). 
 
 
 
Lay Summary 
 
Malaria is a disease that affects many people in the world, more so in sub-Saharan Africa. It is 
caused by parasites carried by mosquitoes. When the mosquitoes bite people, the parasites can 
pass into their blood and cause illness, which if not treated in a timely manner or sufficiently, can 
cause severe illness or even death. In effect, despite there being medicines to cure malaria, it is 
still responsible for a huge number of admissions and deaths, especially in Africa. This informs 
the need to come up with new ways to reduce the impact of malaria, for example, through 
preventing people from getting malaria in the first place.  
 
This is a research study to test an experimental drug, called L9LS, for malaria. L9LS is a type of 
drug called a monoclonal antibody. Antibodies are natural products made by the human body to 
fight infection by blocking germs such as bacteria and parasites. Monoclonal means that all the 
antibodies in the drug are exactly the same. The study drug stays in the blood for several months 
and blocks the parasite that causes malaria. We hope that, if enough of the drug is in the blood, it 
will prevent people from getting malaria. 
 

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The study aims to find out how safe the drug is and whether it prevents malaria and if so, to what 
extent. This study will be conducted in two parts. In the first part, involving 72 participants, the 
study will investigate how safe and well tolerated three different increasing doses of the study 
drug are by administering each dose to older children first (5-10 years of age) then to younger 
children (5-59 months of age) 1 week after each different dose, if it is well tolerated and safe in 
the older age group. The study will proceed to part 2 if the doses are safe and well tolerated in 
the younger age group, as determined by a data safety and monitoring board. The second part of 
the study will investigate whether the drug prevents malaria, and if so, to what extent. It will 
enroll an equal number of children aged between 5-17 months and those aged 18-59 months, 
totaling to about 324 participants. Each age category will further have 3 groups of children 
assigned by chance to each group. The first group will receive two doses of the study drug 6 
months apart, the 2nd group will receive the study drug then placebo (saltwater/an inactive 
substance similar to study drug) 6 months after, and the 3rd group will receive two doses of the 
placebo 6 months part.  
 
Other objectives which will be explored by the study include comparing the study drug level 
with the possibility of getting a malaria infection or detecting malaria parasites in the blood. 
 
The study will take place at Siaya County Referral Hospital and Kogelo Dispensary, both in 
Siaya County, western Kenya. The study duration will be approximately 24 months, with a 
participant in Part 1 of the study taking 4-5 months and a participant in Part 2 of the study taking 
13-14 months. 
 
The study procedures in Part 1 will entail assessing participant eligibility, getting consent and 
enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial 
followed by the study drug or placebo after 2 weeks. They will then have another 10 study visits 
within a 3 months period to monitor various safety measures. The study procedures in Part 2 will 
entail assessing participant eligibility, getting consent and enrollment into the study. On 
enrollment, participants will receive a standard dose of antimalarial followed by the study drug 
or placebo after 2 weeks. They will then have a study visit every month up to end of month 6 
when they will receive the 2nd dose of either the study drug or placebo. Other follow up visits 
will be conducted monthly until end of 12 months from the date of initial study drug or placebo 
dose. These follow-up visits will assess both safety and efficacy measures.  
 
Given new data showing that a higher dose might be needed to prevent malaria, a follow-on 
study will be done with consenting participants currently enrolled in part 2 who will receive an 
additional one or two doses of the study drug at a higher dose. Prior to this, a follow-on safety 
study will be done to look at these higher doses of L9LS to ensure they are safe and well 
tolerated. As part of the safety study, 24 children will be randomized to receive L9LS or placebo. 
They will then have another 10 study visits within a 3 months period to monitor various safety 

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measures. If no safety signals are noted, then participants finishing part 2 will be consented for 
the follow-on study.  
 
For the follow-on study, participants who consent will be enrolled once they complete 12 months 
of follow-up for part 2. They will receive another antimalarial treatment course and two weeks 
later they will receive their third dose of either L9LS or placebo; six months later, they will 
receive a  fourth dose of L9LS or placebo. Participants will get the same product (L9LS or 
placebo) that they received in part 2. They will continue to have monthly study visits until the 
end of the study (12 months following dose 3). These follow-up visits will assess both safety and 
efficacy measures. 
 
The study will provide information on the safety and usefulness of L9LS as a therapy used in  
the prevention of malaria. 
 
 
Schema 
Figure 1. Enrollment and study flow schematics for part 1. 
Figure 1a. Age de-escalation, dose-escalation enrollment schematic for part 1. a 
Time Period 
Age group 
Dose 
Week 1  
Week 2 
Week 3 
Week 4 
Week 5  
Week 6 
5 - 10 years 
5 mg/kg 
  
  
  
5 - 10 years 
10 mg/kg 
  
  
  
5 - 10 years 
20 mg/kg 
  
  
  
  
  
  
  
  
  
5 - 59 months 
5 mg/kg 
  
  
  
5 - 59 months 
10 mg/kg 
  
  
  
5 - 59 months 
20 mg/kg 
  
  
  
  
  
  
  
  
  
  
  
  
Note: n=12 per age/dose group (3 placebo, 9 L9LS) 
a The table illustrates 1.5-week assessment periods prior to decision to proceed with enrollment into the next cohort; 
this allows all participants in the age/dose cohort to have their day 7 evaluation. All participants will be followed 
with safety assessments for a total of 3 months (see Figure 1b below). 
 

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Figure 1b. Study flow schematic for individual participants in part 1.
 
 
 
Screening (day -56 to -14): Assess eligibility; obtain informed consent, assign study 
identification number, and document medical history.  
Day 0:  
• Baseline assessments. 
• L9LS or placebo SC administration (3:1) and monitoring. 
Follow-up at days 1, 3, 7, 14, 21, 28, and month 2. 
Final assessments at month 3. 
Pre-Enrollment (day -21 to -14): Conduct physical exam and other screening. Upon 
confirmation of eligibility, administer first dose of DP. Subjects enrolled into age/dose 
group, as described in Figure 1a above. Total N=72. 
 
Age group: 5-10 years 
Age group: 5-59 months 

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Figure 2. Study flow schematic for part 2. 
 
 
Day 0: 
Baseline assessments. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded study agent administration (assigned by arm) and post-administration monitoring. 
Screening (day -56 to -14): Assess eligibility; obtain informed consent, assign 
study identification number, and document medical history.  
Age group: 18-59 months (n=162). 
Assigned 2:1 to L9LS:placebo. 
Follow-up: 
Monthly follow-up for safety and efficacy assessments through month 12. 
Participants in the L9LS arm will receive either a second L9LS injection or a 
placebo injection at 6 months and then be followed until 12 months. (Those in the 
placebo arm will receive a second placebo injection at 6 months and be followed 
until 12 months.)  
[Unscheduled visits as needed due to malaria or other symptoms.] 
Final study assessments at month 12. 
 
Age group: 5-17 months (n=162). 
Assigned 2:1 to L9LS:placebo. 
Randomize 
 
Subjects will be divided into age groups and then 
randomized 2:1 to 10-20 mg/kg L9LS or placebo. 
 
Placebo (n=108) 
L9LS (n=108) 
L9LS (n=108) 
Pre-Enrollment (day -21 to -14): Perform physical exam and other screening . 
Upon confirmation of eligibility, administer first dose of dihydroartemisinin-
piperaquine. Total N=324. 

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Figure 3. Study flow schematic for part 1b (additional safety study) 
 
Age group 
Dose 
Week 1  
Week 2 
Week 3 
5 - 71 months 
30 mg/kg 
  
  
  
 
5 - 71months 
40 mg/kg 
  
  
  
  
 
 
Figure 4. Study flow scheme for part 2 extension study 
 
 
 

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Schedule of Activities (SOA) 
 
Part 1 Study Schedule 
Study Timepoint 
Screen 0 
Pre-
Enrollme
nt 0 
Enrolm
ent (D0) 
D1 1 
D3 1 
D7 
D14 
D21 
D28 
D56 
D84 
Unscheduled 
Visit 2 
Window (days) 
-56 
to -14 
-21 to -14 
- 
+1 
±1 
±2 
±3 
±3 
±7 
±7 
±7 
Clinical Procedures/Evaluations 
Study comprehension exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam 3 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
 
 
X 
 
Vital signs (temperature and 
pulse) 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Medical history 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dihydroartemisinin-
piperaquine administration 
 
X 4 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
X 5 
 
 
 
 
 
 
 
 
 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Evaluations 
Test 
Tube 
 
(Blood volume in mL) 
HIV screen 6 
SST 
 
0.2 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
EDTA 
 
0.1 
 
 
 
0.1 
0.1 
 
0.1 
 
0.1 
 
Hemoglobin type 
EDTA 
 
0.5 7 
 
 
 
 
 
 
 
 
 
 

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Study Timepoint 
Screen 0 
Pre-
Enrollme
nt 0 
Enrolm
ent (D0) 
D1 1 
D3 1 
D7 
D14 
D21 
D28 
D56 
D84 
Unscheduled 
Visit 2 
Window (days) 
-56 
to -14 
-21 to -14 
- 
+1 
±1 
±2 
±3 
±3 
±7 
±7 
±7 
ALT, Cr 
SST 
 
0.2 
 
 
 
0.2 
0.2 
 
0.2 
 
0.2 
 
Blood smear and 
dried blood spot 
for Pf RT-PCR  
- 
 
0.4 
0.4 
 
 
0.4  
0.4 
0.4 
0.4  
0.4 
0.4 
0.4 
PK studies 
SST 
 
3.1 8 
 
 
 
3.1 
 
 
3.1 9 
 
3.1 9 
 
Serum storage 
SST 
 
(X) 
 
 
 
(X) 
 
 
(X) 
 
(X) 
 
ADA 
SST 
 
(X) 
 
 
 
(X) 
 
 
(X) 
 
(X) 
 
Daily volume (mL) 
- 
4.5 
0.4 
- 
- 
3.8 
0.7 
0.4 
3.8 
0.4 
3.8 9 
 
Cumulative volume (mL) 
- 
4.5 
4.9 
4.9 
4.9 
8.7 
9.4 
9.8 
13.6 
14.0 
14.7 9  
- 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; Cr, creatinine; D, day; EDTA, ethylenediaminetetraacetic acid; 
ELISA, enzyme-linked immunosorbent assay; HIV, human immunodeficiency virus; M, month; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum 
separating tube; RT-PCR, reverse transcription polymerase chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from the tube shown in the preceding row. 
 
Footnotes: 
0 Screening and pre-enrolment visits may be combined. Screening activities may be performed and/or repeated at pre-enrolment visit to ensure they are completed within 
the allowable window as described in section 8.1 (14 to 21 days prior to D0). As long as physical exam, height and weight measurement, vital signs, medical history, and 
concomitant medications are done at the pre-enrolment visit, they do not necessarily need to be done at the screening visit, if the two are separate visits. 
1 Days 1 and 3 will be home visits, with a phone call assessment if child is not able to be seen after 2 attempts.  
2 At any time during the study, the subject may have an unscheduled illness visit if experiencing malaria symptoms or other symptoms. The subject may be referred for 
standard care according to Kenya Ministry of Health treatment guidelines. 
3 Complete/comprehensive at screening; targeted/interim at other visits. 
4 The first dose of dihydroartemisinin-piperaquine will be directly observed in the clinic if possible, but might be given in the participant’s home. The subsequent 2 doses 
given over the following 2 days will be observed by study staff in the subject’s home or at the clinic. All dihydroartemisinin-piperaquine doses will be completed prior to 
day 0 and will be initiated between 21 and 14 days prior to D0. 
5 L9LS or placebo. All other study procedures must be completed prior to study agent administration. Each subject will be monitored for at least 60 minutes after study 
agent administration and vital signs will be recorded 1 hour after study agent administration. Prior to discharge, subject will be assessed for local reactogenicity (including 
pain/tenderness, swelling, redness, bruising, and pruritus at the site of injection) and systemic reactogenicity (including fever, feeling unusually tired or unwell, muscle 
aches, headache, chills, nausea, and joint pain). If the subject is assessed as being unwell or has ongoing reactogenicity symptoms, he or she will be asked to remain in the 
clinic until evaluation and discharge by a study clinician. Clinicians will follow any solicited symptoms that are ongoing until they have resolved. 

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6 Viral screenings will be performed according to Kenyan MoH guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus DNA PCR if the RDTs are 
discordant; subject will be referred for medical care for 2 positive RDTs or a positive PCR. Pre- and post-test HIV counseling will be provided. 
7 EDTA tube will be stored at screening, and hemoglobin typing will be performed; in the rare case that hemoglobin typing detects sickle cell disease, the participant will 
be considered a late screening failure; sickle cell trait is not an exclusion criterion. 
8 For PK, 3.5 mL serum will be collected prior to malaria treatment administration. 
9 Half of the participants will have this blood draw on Day 28 and the other half will have it at Day 84. Accordingly, the total cumulative volume reflects a PK blood 
volume for Day 28 or Day 84, but not both.  
 
Part 2 Study Schedule 
Study Timepoint 
Screen 0 
Pre-
Enrollment 0 
Enrolment 
(D0)
D1 1 
D3 1 
D7 
D28 (Wk 4) 
D56 (Wk 8) 
D84 (Wk 12) 
D112 (Wk 16) 
D140 (Wk 20) 
D168 (Wk 24)* 
D169 1 
D171 1 
D175 
D196 (Wk 28) 
D224 (Wk 32) 
D252 (Wk 36) 
D280 (Wk 40) 
D308 (Wk 44) 
D336 (Wk 48) 
D364 (Wk 52) 
Unscheduled 
Visit 2
Window (days) 
-56 to -14 
-21 to -14 
- 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Clinical Procedures/Evaluations 
Study comprehension 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
identity, age, and 
residency 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 3 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Vital signs 
(temperature and 
pulse) 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Anti-malaria Mab in Kenyan Children  
 
 
 
 
 
Version 6.0 Date XX Mar 2024 
Study Timepoint 
Screen 0 
Pre-
Enrollment 0 
Enrolment 
(D0)
D1 1 
D3 1 
D7 
D28 (Wk 4) 
D56 (Wk 8) 
D84 (Wk 12) 
D112 (Wk 16) 
D140 (Wk 20) 
D168 (Wk 24)* 
D169 1 
D171 1 
D175 
D196 (Wk 28) 
D224 (Wk 32) 
D252 (Wk 36) 
D280 (Wk 40) 
D308 (Wk 44) 
D336 (Wk 48) 
D364 (Wk 52) 
Unscheduled 
Visit 2
Window (days) 
-56 to -14 
-21 to -14 
- 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Concomitant 
medications 3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dihydroartemisinin-
piperaquine 
administration 
 
X 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study agent 
administration 
 
 
X 5 
 
 
 
 
 
 
 
 
X 5 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Evaluations 
Test 
Tube 
 
(Blood volume in mL) 
HIV 6 
SST 
 
0.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
EDT
A 
 
0.1 
0.1 
 
 
0.1 
0.1 
 
 
 
 
0.1 
 
 
0.1 
 
 
 
 
 
0.1 
 
 
Hemoglobin 
type 
EDT
A 
 
0.5 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT, Cr 
SST 
 
0.2 
0.2 
 
 
0.2 
0.2 
 
 
 
 
0.2 
 
 
0.2 
 
 
 
 
 
0.2 
 
 
Blood smear 
and dried 
blood spot for 
Pf RT-PCR  
- 
 
0.4 
0.48  
 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
 
 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
PK studies 
SST 
 
3.1 9 
 
 
 
 
3.1 
 
 
 
 
 
 
 
 
3.1 
 
 
 
 
3.1 
 
 

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Version 6.0 Date XX Mar 2024 
Study Timepoint 
Screen 0 
Pre-
Enrollment 0 
Enrolment 
(D0)
D1 1 
D3 1 
D7 
D28 (Wk 4) 
D56 (Wk 8) 
D84 (Wk 12) 
D112 (Wk 16) 
D140 (Wk 20) 
D168 (Wk 24)* 
D169 1 
D171 1 
D175 
D196 (Wk 28) 
D224 (Wk 32) 
D252 (Wk 36) 
D280 (Wk 40) 
D308 (Wk 44) 
D336 (Wk 48) 
D364 (Wk 52) 
Unscheduled 
Visit 2
Window (days) 
-56 to -14 
-21 to -14 
- 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Serum 
storage 
SST 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
(X)  
 
 
 
(X) 
 
 
ADA 
SST 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
(X)  
 
 
 
(X) 
 
 
Daily volume (mL) 
- 
4.5 
0.7 
- 
- 
0.7 
3.8 
0.4 
0.4 
0.4 
0.4 
0.7 
- 
- 
0.7 
3.5 
0.4 
0.4 
0.4 
0.4 
3.8 
0.4 
 
Cumulative volume 
(mL) 
- 
4.5 
5.2 
5.2 
5.2 
5.9 
9.7 
10.1 10.5 
10.9 11.3 
12.0 
12.0 12.0 12.7 16.2 16.6 
17.0 17.4 
17.8 
21.6 
22.0 - 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; Cr, creatinine; D, day; EDTA, ethylenediaminetetraacetic acid; HIV, 
human immunodeficiency virus; M, month; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum-separating tube; RT-PCR, reverse transcription polymerase 
chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from the tube shown in the preceding row. 
 
Footnotes: 
0 Screening and pre-enrolment visits may be combined. Screening activities may be performed and/or repeated at pre-enrolment visit to ensure they are completed within 
the allowable window as described in section 8.1 (14 to 21 days prior to D0). As long as physical exam, height and weight measurement, vital signs, medical history, and 
concomitant medications are done at the pre-enrolment visit, they do not necessarily need to be done at the screening visit, if the two are separate visits. 
1 Home-based visits. 
2 At any time during the study, the subject may have an unscheduled illness visit if experiencing malaria symptoms or other symptoms. The subject may be referred for 
standard care according to local guidelines. 
3 Complete/comprehensive at screening; targeted/interim at other visits. 
4 The first dose of dihydroartemisinin-piperaquine will be directly observed in the clinic if possible, but might be given in the participant’s home. The subsequent 2 doses 
given over the following 2 days will be observed by guides in the subject’s home or at the clinic. All dihydroartemisinin-piperaquine doses will be completed prior to day 
0 and will be initiated between 21 and 14 days prior to D0. 
5 L9LS or placebo. All other study procedures must be completed prior to study agent administration. Subjects who received L9LS at day 0 will receive L9LS or placebo 
at month 6; those in the placebo arm will receive a second placebo injection at 6 months. Each subject will be monitored for at least 60 minutes after study agent 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Version 6.0 Date XX Mar 2024 
administration and vital signs will be recorded 1 hour after study agent administration. Prior to discharge, subject will be assessed for local reactogenicity (including 
pain/tenderness, swelling, redness, bruising, and pruritus at the site of injection) and systemic reactogenicity (including fever, feeling unusually tired or unwell, muscle 
aches, headache, chills, nausea, and joint pain). If the subject is assessed as being unwell or has ongoing reactogenicity symptoms, he or she will be asked to remain in the 
clinic until evaluation and discharge by a study clinician. Clinicians will follow any solicited symptoms that are ongoing until they have resolved. 
6 Viral screenings will be performed according to international guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus DNA PCR if the RDTs are discordant; 
subject will be referred for medical care for 2 positive RDTs or a positive PCR. Pre- and post-test HIV counseling will be provided.  
7 EDTA tube will be stored at screening, and hemoglobin typing will be performed; in the rare case that hemoglobin typing detects sickle cell disease, the participant will 
be considered a late screening failure; sickle cell trait is not an exclusion criterion. 
8 Collected prior to study agent administration. Other indicated tests may be performed after study agent administration. 
9 For PK, 3.5 mL serum will be collected prior to malaria treatment administration.  
* The timing of all visits subsequent to Day 168 (administration of dose 2) will be in relation to the Day 168 visit, whenever that occurs; for example, if the Day 168 visit 
occurs on Day 161, the first day of the window, the Days 169 and 171 home visits will occur 1 and 3 days later (so on days 162 and 164 in relation to dose 1). 
 
 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Anti-malaria Mab in Kenyan Children  
 
 
 
 
 
Version 6.0 Date XX Mar 2024 
 
Part 1b Study Schedule  
Study Timepoint 
Screen 0 
Pre-
Enrollme
nt 0 
Enrolm
ent (D0) 
D1 1 
D3 1 
D7 
D14 
D21 
D28 
D56 
D84 
Unscheduled 
Visit 2 
Window (days) 
-56 
to -14 
-21 to -14 
- 
+1 
±1 
±2 
±3 
±3 
±7 
±7 
±7 
Clinical Procedures/Evaluations 
Study comprehension exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam 3 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
 
 
X 
 
Vital signs (temperature and 
pulse) 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Medical history 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dihydroartemisinin-
piperaquine administration 
 
X 4 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
X 5 
 
 
 
 
 
 
 
 
 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Evaluations 
Test 
Tube 
 
(Blood volume in mL) 
HIV screen 6 
SST 
 
0.2 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
EDTA 
 
0.1 
 
 
 
0.1 
0.1 
 
0.1 
 
0.1 
 
Hemoglobin type 
EDTA 
 
0.5 7 
 
 
 
 
 
 
 
 
 
 
ALT, Cr 
SST 
 
0.2 
 
 
 
0.2 
0.2 
 
0.2 
 
0.2 
 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Anti-malaria Mab in Kenyan Children  
 
 
 
 
 
Version 6.0 Date XX Mar 2024 
Study Timepoint 
Screen 0 
Pre-
Enrollme
nt 0 
Enrolm
ent (D0) 
D1 1 
D3 1 
D7 
D14 
D21 
D28 
D56 
D84 
Unscheduled 
Visit 2 
Window (days) 
-56 
to -14 
-21 to -14 
- 
+1 
±1 
±2 
±3 
±3 
±7 
±7 
±7 
Blood smear and 
dried blood spot 
for Pf RT-PCR  
- 
 
0.4 
0.4 
 
 
0.4  
0.4 
0.4 
0.4  
0.4 
0.4 
0.4 
PK studies 
SST 
 
3.1 8 
 
 
 
3.1 
 
 
3.1 9 
 
3.1 9 
 
Serum storage 
SST 
 
(X) 
 
 
 
(X) 
 
 
(X) 
 
(X) 
 
ADA 
SST 
 
(X) 
 
 
 
(X) 
 
 
(X) 
 
(X) 
 
Daily volume (mL) 
- 
4.5 
0.4 
- 
- 
3.8 
0.7 
0.4 
3.8 
0.4 
3.8 9 
 
Cumulative volume (mL) 
- 
4.5 
4.9 
4.9 
4.9 
8.7 
9.4 
9.8 
13.6 
14.0 
14.7 9  
- 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; Cr, creatinine; D, day; EDTA, ethylenediaminetetraacetic acid; 
ELISA, enzyme-linked immunosorbent assay; HIV, human immunodeficiency virus; M, month; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum 
separating tube; RT-PCR, reverse transcription polymerase chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from the tube shown in the preceding row. 
 
Footnotes: 
0 Screening and pre-enrolment visits may be combined. Screening activities may be performed and/or repeated at pre-enrolment visit to ensure they are completed within 
the allowable window as described in section 8.1 (14 to 21 days prior to D0). As long as physical exam, height and weight measurement, vital signs, medical history, and 
concomitant medications are done at the pre-enrolment visit, they do not necessarily need to be done at the screening visit, if the two are separate visits. 
1 Days 1 and 3 will be home visits, with a phone call assessment if child is not able to be seen after 2 attempts.  
2 At any time during the study, the subject may have an unscheduled illness visit if experiencing malaria symptoms or other symptoms. The subject may be referred for 
standard care according to Kenya Ministry of Health treatment guidelines. 
3 Complete/comprehensive at screening; targeted/interim at other visits. 
4 The first dose of dihydroartemisinin-piperaquine will be directly observed in the clinic if possible, but might be given in the participant’s home. The subsequent 2 doses 
given over the following 2 days will be observed by study staff in the subject’s home or at the clinic. All dihydroartemisinin-piperaquine doses will be completed prior to 
day 0 and will be initiated between 21 and 14 days prior to D0. 
5 L9LS or placebo. All other study procedures must be completed prior to study agent administration. Each subject will be monitored for at least 60 minutes after study 
agent administration and vital signs will be recorded 1 hour after study agent administration. Prior to discharge, subject will be assessed for local reactogenicity (including 
pain/tenderness, swelling, redness, bruising, and pruritus at the site of injection) and systemic reactogenicity (including fever, feeling unusually tired or unwell, muscle 
aches, headache, chills, nausea, and joint pain). If the subject is assessed as being unwell or has ongoing reactogenicity symptoms, he or she will be asked to remain in the 
clinic until evaluation and discharge by a study clinician. Clinicians will follow any solicited symptoms that are ongoing until they have resolved. 
6 Viral screenings will be performed according to Kenyan MoH guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus DNA PCR if the RDTs are 
discordant; subject will be referred for medical care for 2 positive RDTs or a positive PCR. Pre- and post-test HIV counseling will be provided. 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Version 6.0 Date XX Mar 2024 
7 EDTA tube will be stored at screening, and hemoglobin typing will be performed; in the rare case that hemoglobin typing detects sickle cell disease, the participant will 
be considered a late screening failure; sickle cell trait is not an exclusion criterion. 
8 For PK, 3.5 mL serum will be collected prior to malaria treatment administration. 
9 Half of the participants will have this blood draw on Day 28 and the other half will have it at Day 84. Accordingly, the total cumulative volume reflects a PK blood 
volume for Day 28 or Day 84, but not both.  
 
 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Part 2 Extension Study Schedule 
Study Timepoint 
Consent for 
Extension Phase0 
Pre-Enrolment 
Enrolment (D0) 
Y2D1 1 
Y2D3 1 
Y2D7 
Y2D28 (Wk 4) 
Y2D56 (Wk 8) 
Y2D84 (Wk 12) 
Y2D112 (Wk 16) 
Y2D140 (Wk 20) 
Y2D168 (Wk 
24)* 
Y2D169 1 
Y2D171 1 
Y2D175 
Y2D196 (Wk 28) 
Y2D224 (Wk 32) 
Y2D252 (Wk 36) 
Y2D280 (Wk 40) 
Y2D308 (Wk 44) 
Y2D336 (Wk 48) 
Y2D364 (Wk 52) 
Unscheduled 
Visit 2
Window (days) 
Before Parasit 
Clearance 0 
-21 to -14 
- 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Clinical Procedures/Evaluations 
Study comprehension 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
identity, age, and 
residency 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Vital signs 
(temperature, pulse) 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dihydroartemisinin-
piperaquine 
administration 
 
X 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Anti-malaria Mab in Kenyan Children  
 
 
 
 
 
Version 6.0 Date XX Mar 2024 
Study Timepoint 
Consent for 
Extension Phase0 
Pre-Enrolment 
Enrolment (D0) 
Y2D1 1 
Y2D3 1 
Y2D7 
Y2D28 (Wk 4) 
Y2D56 (Wk 8) 
Y2D84 (Wk 12) 
Y2D112 (Wk 16) 
Y2D140 (Wk 20) 
Y2D168 (Wk 
24)* 
Y2D169 1 
Y2D171 1 
Y2D175 
Y2D196 (Wk 28) 
Y2D224 (Wk 32) 
Y2D252 (Wk 36) 
Y2D280 (Wk 40) 
Y2D308 (Wk 44) 
Y2D336 (Wk 48) 
Y2D364 (Wk 52) 
Unscheduled 
Visit 2
Window (days) 
Before Parasit 
Clearance 0 
-21 to -14 
- 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
+1 
±1 
±1 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Study agent 
administration 
 
 
X 5  
 
 
 
 
 
 
 
X 5 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Evaluations 
Test 
Tube 
 
(Blood volume in mL) 
CBC with 
differential 
EDTA  
0.1 
0.1  
 
0.1 
0.1 
 
 
 
 
0.1 
 
 
0.1 
 
 
 
 
 
0.1 
 
 
ALT, Cr 
SST 
 
0.2 
0.2  
 
0.2 
0.2 
 
 
 
 
0.2 
 
 
0.2 
 
 
 
 
 
0.2 
 
 
Blood smear 
and dried 
blood spot for 
Pf RT-PCR  
- 
 
0.4 
0.4
8 
 
 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
 
 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
PK studies 
SST 
 
3.1 9  
 
 
 
3.1 
 
 
 
 
 
 
 
 
3.1 
 
 
 
 
3.1 
 
 
Serum 
storage 
SST 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
(X)  
 
 
 
(X) 
 
 
ADA 
SST 
 
(X) 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
(X)  
 
 
 
(X) 
 
 
Daily volume (mL) 
- 
3.8 
0.7 - 
- 
0.7 
3.8 
0.4 
0.4 
0.4 
0.4 
0.7 
- 
- 
0.7 
3.5 
0.4 
0.4 
0.4 
0.4 
3.8 
0.4 
 
Cumulative volume 
(mL) 
- 
3.8 
4.5 4.5 4.5 
5.2 
9.0 
9.4 
9.8 
10.2 10.6 
11.3 
11.3 11.3 12.0 15.5 15.9 
16.3 16.7 
17.1 
20.9 
21.3 - 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
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Version 6.0 Date XX Mar 2024 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; Cr, creatinine; D, day; EDTA, ethylenediaminetetraacetic acid; HIV, 
human immunodeficiency virus; M, month; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum-separating tube; RT-PCR, reverse transcription polymerase 
chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from the tube shown in the preceding row. 
 
Footnotes: 
0 The Consent for the extension phase visit can take place during the Day 364 close-out visit for part 2 or thereafter anytime before the extension phase parasite clearance 
visit. The extension phase pre-enrolment visit must take place within 3 months of the (year 1) Day 364 visit. 
1 Home-based visits. 
2 At any time during the study, the subject may have an unscheduled illness visit if experiencing malaria symptoms or other symptoms. The subject may be referred for 
standard care according to local guidelines. 
4 The first dose of dihydroartemisinin-piperaquine will be directly observed in the clinic if possible, but might be given in the participant’s home. The subsequent 2 doses 
given over the following 2 days will be observed by guides in the subject’s home or at the clinic. All dihydroartemisinin-piperaquine doses will be completed prior to day 
0 and will be initiated between 21 and 14 days prior to D0. 
5 L9LS or placebo. All other study procedures must be completed prior to study agent administration. Subjects who received L9LS at day 0 will receive L9LS at month 6; 
those in the placebo arm will receive a second placebo injection at 6 months (if a two-dose regimen is used). Each subject will be monitored for at least 60 minutes after 
study agent administration and vital signs will be recorded 1 hour after study agent administration. Prior to discharge, subject will be assessed for local reactogenicity 
(including pain/tenderness, swelling, redness, bruising, and pruritus at the site of injection) and systemic reactogenicity (including fever, feeling unusually tired or unwell, 
muscle aches, headache, chills, nausea, and joint pain). If the subject is assessed as being unwell or has ongoing reactogenicity symptoms, he or she will be asked to 
remain in the clinic until evaluation and discharge by a study clinician. Clinicians will follow any solicited symptoms that are ongoing until they have resolved. 
8 Collected prior to study agent administration. Other indicated tests may be performed after study agent administration. 
9 For PK, 3.5 mL serum will be collected prior to malaria treatment administration.  
* The timing of all visits subsequent to Day 168 (administration of dose 2) will be in relation to the Day 168 visit, whenever that occurs; for example, if the Day 168 visit 
occurs on Day 161, the first day of the window, the Days 169 and 171 home visits will occur 1 and 3 days later (so on days 162 and 164 in relation to dose 1). 
 
 

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2 
INTRODUCTION 
 
Study Rationale 
Malaria is a mosquito-borne disease caused by a protozoan belonging to the genus Plasmodium 
that affected approximately 229 million people and killed approximately 409,000 individuals in 
2019, with an enormous economic impact in the developing world, especially sub-Saharan 
Africa.1111 1 1 11 The 5 recognized species of Plasmodium that cause human malaria infection are 
Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Among these, P. 
falciparum (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. RTS,S/AS01 is currently being evaluated in an ongoing 
pilot immunization program in sub-Saharan Africa despite having been found to provide partial 
protection against malaria to children and infants.2,3 Based on results from the ongoing pilot 
program, the World Health Organization (WHO) recently recommended widespread use of 
RTS,S/AS01 in a schedule of 4 doses in infants from 5 months of age in sub-Saharan Africa and 
in other regions with moderate to high Pf malaria transmission.4 Therefore, based on the ~40% 
efficacy of RTS,S/AS01 after 4 years, there is an urgent need for the development of safe and 
more effective malaria vaccines and other novel interventions. Importantly, the use of 
monoclonal antibodies (MAbs) offers a new modality for mediating prevention of malaria to 
limit the morbidity and mortality in infants and young children.  
 
Background  
The WHO has set a target for the development of a malaria vaccine efficacy (VE) with at least 
75% VE against clinical malaria by 2030. Currently, RTS,S/AS01 is the only malaria vaccine for 
which phase 3 trials have been completed. It was found to have VE in children aged 5-17 months 
against clinical malaria (36.3%) and severe malaria (32.2%) after 4 years of follow-up;2 the 
vaccine had 60.1% efficacy against all episodes of clinical malaria after 6 months of follow-up.5 
More recently, in a Phase 2 trial, the R21/MM vaccine had 77% vaccine efficacy against the 
first/only episode of clinical malaria at 6 months. The efficacy remained at this level over 1 year; 
however, there were very few cases of malaria after 6 months in this study given the highly 
seasonal malaria transmission in Burkina Faso, so it remains unclear whether this vaccine would 
achieve the targeted level of protection over longer periods of time or in settings of perennial 
transmission. RTS,S/AS01 has been recently recommended for widespread use in infants as a 

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first step toward reducing clinical infection. Importantly, there is now focus on second-
generation vaccines or other immune interventions that may enhance protective efficacy. An 
intervention that could prevent malaria in children for a full 12 months in settings of perennial 
malaria transmission, such as Kenya, holds potential to reduce malaria morbidity and mortality 
substantially in this population at risk for severe malaria and death. If one year of protection can 
be achieved with a single dose of MAb, this has important implications for feasibility, 
acceptability, and cost of the intervention.6,7 In addition, children discharged after hospitalization 
with severe anemia have been shown to have high rates of subsequent morbidity and mortality in 
the immediate post-discharge period; administering a dose of MAb prior to discharge could help 
prevent poor outcomes in these children, possibly with better outcomes than was recently 
obtained with chemoprophylaxis.8888 8 8 88 Another group to consider would be children with 
sickle cell disease as a replacement for their ongoing malaria chemoprophylaxis. 
 
Recent evidence has shown that a non-vaccine biologic MAb, specifically CIS43, against a 
conserved region on the Pf circumsporozoite protein (PfCSP) which covers the infecting 
sporozoite, can prevent malaria infection.9,10 A phase 1 trial in US adults showed that CIS43LS, 
a version of CIS43 modified to extend half-life, was safe, well tolerated, and conferred complete 
protection against controlled human malaria infection (CHMI) by mosquito bite in all nine 
participants.111111 11 11 1111 It was notable that 2 of the participants were protected 9 months after 
receiving CIS43LS following CHMI. These data provided the first proof-of-concept that MAbs 
can be used to prevent malaria infection with a single administration. Based on these promising 
findings in terms of safety and efficacy, an ongoing placebo-controlled phase 2 study of 
CIS43LS mAb in a total of 330 adult volunteers in Mali is assessing its safety and efficacy 
against high-level transmission during the rainy season. That study in Mali will assess 2 doses of 
CIS43LS administered intravenously (IV) compared to placebo and should provide the first 
evidence of efficacy in the field against natural exposure.  
 
MAbs have a number of potential advantages over malaria vaccines: 1) MAb provide a 
consistent concentration of a highly potent antibody against a conserved site on the major 
sporozoite protein (PfCSP), independent of host/parasite factors that could alter vaccine immune 
responses, 2) they could confer protection against malaria after a single dose by preventing 
infection, while all malaria vaccines to date have required a minimum of 3 doses to limit clinical 
malaria; 3) MAbs are hypothesized to provide higher efficacy compared to malaria vaccines 
(26% of the children vaccinated with R21/MM were infected after 6 months); and 4) they are 
likely to be better tolerated, as MAbs do not contain adjuvants and are not meant to stimulate an 
immune response.  
 
An important aspect of using a MAb for prevention of malaria is the potency and durability. 
Improving the potency will be critical for improving protection, reducing cost as well as allow 
for sub-cutaneous (SC) dosing across all ages. Accordingly, a second-generation MAb, L9, was 

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recently discovered.122122 12 12 1212 L9 binds to a different region of the sporozoite than CIS43 and 
is approximately 2- to 3-fold more potent for mediating protection in 2 mouse models of malaria 
infection. L9 mediates protection through a distinct mechanism from CIS43. Thus, clinical 
development of L9LS was initiated as described below. As part of this development, we propose 
a 3-part study of L9LS in children in western Kenya to assess safety and efficacy in a phase 2 
trial. 
 
Study Agent: L9LS 
2.2.1.1 
Development 
The Vaccine Research Center (VRC) of the National Institute for Allergies and Infectious 
Diseases (NIAID), NIH, has developed a MAb called L9LS as a possible preventive therapeutic 
against Pf infection. L9LS represents a second-generation anti-malaria MAb that follows 
CIS43LS, which was also developed by the VRC. As described above, CIS43LS was shown to 
be safe and conferred complete protection against controlled Pf infection in a phase 1 study,111111 
11 11 1111 and is currently being evaluated in an ongoing phase 2 study in Mali (ClinicalTrials.gov 
Identifier: NCT04329104; FMOS/FAPH Protocol Number: 2020/32/CE/FMOS/FAPH).  
 
L9, the wild-type parent of L9LS, was isolated by sorting the PfCSP-reactive memory B cells 
obtained from a subject immunized with a radiation-attenuated Pf whole-sporozoite malaria 
vaccine in the VRC 314 clinical trial (NCT02015091) using a junctional epitope mimic probe 
designed to select for “CIS43-like” MAbs. Epitope mapping showed L9 bound to the sporozoite 
NPNV motifs associated with NVDP minor repeats of PfCSP and this defined a new site of 
neutralization on PfCSP. When compared to a published large panel of the most protective 
human PfCSP MAbs, L9 protected mice against intravenous (IV) and mosquito bite sporozoite 
challenge, and demonstrated the lowest effective dose (ED)80 and effective concentration 
(EC)80 values (325.7 µg and 145.1 µg/mL, respectively) of any human PfCSP MAbs evaluated, 
including CIS43LS (685.92 µg and 363.93 µg/mL, respectively).122122 12 12 1212 The unique 
preference of L9 for NPNV motifs was further underscored by the fact that all four NVDP 
tetrapeptide motifs had to be mutated to NANP to disrupt the recognition of L9 for the NPNV 
motifs found in recombinant PfCSP. As 100% of known Pf field isolates have one or more 
NVDP motifs, these data suggest that L9 should bind all circulating strains of Pf malaria.122122 12 
12 1212 
 
Half-life extension of L9 was accomplished by modifying the L9 Fc heavy chain to include an 
LS mutation (L9LS). The LS mutation is a methionine to leucine (L) and asparagine to serine (S) 
(M432L/N434S, collectively, LS) replacement, and changes have been reported to increase 
antibody Fc region binding affinity to FcRn, resulting in the extended recirculation of functional 
IgG and consequent longer antibody serum half-life. Other than these two amino acid sequences 
in the heavy chain Fc, the sequences of L9LS and L9 are identical. Immune protection and half-
life data acquired with L9 and L9LS identify L9LS as a promising clinical candidate for passive 

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malaria prophylaxis. Of note, LS mutations have been used for half-life extension of a large 
number of HIV MAbs tested in humans, and 2 complement-inhibitor MAbs that contain LS 
mutations are approved for human use for the treatment of patients with paroxysmal nocturnal 
hemoglobinuria to reduce hemolysis and patients with atypical hemolytic uremic syndrome to 
inhibit complement-mediated thrombotic microangiopathy, as well as other indications.13,14 
Thus, in all published studies, LS mutations have been safe and well tolerated. 
2.2.1.2 
Preclinical Experience 
To assess L9LS as a candidate for clinical trials, research-grade MAb was evaluated for in vitro 
functional activity including binding properties, auto-reactivity, and PK, and in mouse models of 
in vivo protection following challenge. In addition, PK studies in non-human primates (NHPs) 
were performed. In mice, L9 was more potent than CIS43, and both L9LS and L9 mediated the 
same potency following challenge. In NHP PK studies, L9LS exhibited significantly longer half-
life in blood as compared to the parental L9 MAb without the LS mutation. 
 
Two preclinical toxicology studies were conducted with a process-representative developmental 
batch of L9LS. An in vitro tissue cross-reactivity (TCR) assay to screen for potential cross-
reactivity and an in vivo rat toxicity study to demonstrate safety both were conducted in 
compliance with 21 CFR 58 Good Laboratory Practice (GLP) for Nonclinical Laboratory 
Studies. 
2.2.1.2.1 TCR Study 
The TCR assay screened a standard panel of normal human tissues (three donors per tissue) and 
Sprague Dawley rat tissues (two rats per tissue). Mammalian cells transfected to express CSP 
were used as a tissue-positive control. Two concentrations of L9LS were tested: 1.15 µg/mL 
(selected as the concentration which saturated the positive control tissue), and 11.5 µg/mL (10-
fold excess). A negative control IgG1κ antibody (GR338422-1, no mammalian target antigen) 
was tested at the same two concentrations. L9LS exhibited scattered specific membrane binding 
in 3/3 human salivary gland tissue samples and localized to the epithelial cells lining the ducts 
and acini. Binding was rare (1-5% of these epithelial cells) at 1.15 µg/mL, and rare to occasional 
(5-25% of these epithelial cells) at 11.5 µg/mL. The cause of the salivary epithelial cell 
membrane binding has not been identified. Specific membrane binding to salivary gland tissue 
was not observed for the negative control antibody. L9LS did not bind to rat salivary epithelium. 
No specific membrane binding to other human tissues was observed. 
2.2.1.2.2 Rat Toxicity Study 
Sprague Dawley rats were dosed with L9LS to evaluate toxicity and toxicokinetics. Rats 
received 0, 40, or 400 mg/kg by IV bolus injection twice (Day 1 and Day 11). Female rats were 
dosed with 10 mg/kg by SC injection once (D1); male rats were dosed with 10 mg/kg SC twice 
(D1 and D11); both male and female rats were dosed with 100 mg/kg SC twice (Day 1 and Day 

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11). For all dose levels, the main group was necropsied at Day 12 to evaluate potential 
immediate effects, and recovery animals were necropsied at Day 46, to evaluate the potential for 
delayed effects and recovery. Treated rats exhibited a transient increase in body temperature 
post-dose (up to + 0.5oC, considered a non-adverse response). Serum clinical chemistry tests 
detected slightly increased globulin, consistent with the administration of L9LS, an IgG MAb. 
For IV dosing, the no observed adverse effect level (NOAEL) was the high dose, 400 mg/kg IV 
x2. For SC dosing, the NOAEL was the high-dose, 100 mg/kg SC x2. SC injection of L9LS did 
not cause reactogenicity (edema, erythema, eschar) in any rat. Histopathology evaluation of the 
skin at the SC injection site reported minimal to moderate SC mixed cell infiltration, considered 
treatment related and predictive for human volunteers. One treated rat (in the 100 mg/kg SC 
group) was found dead; this event was attributed to a procedural error the previous day and is not 
considered treatment related. One treated female (in the 100 mg/kg SC recovery group) had 
grossly visible heart enlargement (2-fold increase in both heart weight and heart-body weight 
compared to the control means), with normal heart histology. Spontaneous cardiomyopathies are 
occasionally observed for the Sprague Dawley strain of rat. Based on the singular incidence, this 
observation is not considered treatment related. 
 
With reference to the US Food and Drug Administration (FDA) Center for Drug Evaluation and 
Research 2005 Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers, scaling based on body weight is 
appropriate for a MAb expected to distribute mainly in the vascular space. The rat IV NOAEL of 
400 mg/kg x2 supports the IV clinical high dose with a 20-fold dose margin. The rat SC NOAEL 
of 100 mg/kg x2 supports the SC clinical dose with a 20-fold dose margin. 
 
The FDA provides guidance on “the nonclinical safety studies recommended to support human 
clinical trials” in the Guidances for Industry ICH M3(R2) Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and ICH S6 
Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. Taken 
together, the L9LS TCR and rat toxicity study results meet the safety standard set in these 
guidances and support proceeding with L9LS clinical trials. 
2.2.1.3 
Clinical Experience 
L9LS was evaluated in a phase 1, dose-escalation, open-label clinical trial with experimental 
CHMI to evaluate safety and protective efficacy of L9LS in healthy, malaria-naive adults at the 
VRC. The phase 1 trial at the VRC was a two-part, dose-escalation, adaptive-design study 
evaluating the safety, tolerability, PK, and protective efficacy of L9LS.  
 
Doses evaluated ranged from 1 to 20 mg/kg delivered via IV administration, and 5 mg/kg 
delivered via SC administration. No safety concerns were identified. A total of 17 L9LS 
recipients and 6 control participants underwent CHMI. Of the 17 participants who received a 

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single dose of L9LS, 15 (88%) were protected after CHMI. Parasitemia did not develop in any of 
the participants who received 5 or 20 mg/kg of IV L9LS. Parasitemia developed in 1 of 5 
participants who received 1 mg/kg IV, 1 of 5 participants who received 5 mg/kg SC, and all 6 
control participants through 21 days after CHMI. Protection conferred by L9LS was seen at 
serum concentrations as low as 9.2 μg/mL. Thus, in this small phase 1 trial, L9LS administered 
IV or SC protected recipients against malaria after controlled infection, without evident safety 
concerns, and all IV and SC administrations were well tolerated.15  
 
For the first proof-of-concept study with CIS43LS in Malian adults, CIS43LS was administered 
by the IV route at doses of 40 mg/kg and 10 mg/kg. The first generation anti-malaria MAb 
CIS43LS was shown to be safe and conferred complete protection against controlled Pf infection 
in a phase 1 study in healthy adult volunteers at the VRC.11  CIS43LS was evaluated in a 
completed phase 2 study of adults in Mali (ClinicalTrials.gov Identifier: NCT04329104). For the 
first proof-of-concept study with CIS43LS in Malian adults against intense seasonal 
transmission, CIS43LS was administered by the IV route at doses of 40 mg/kg and 10 mg/kg. No 
significant safety concerns were noted. By time-to-event analysis, compared to placebo at 6 
months, CIS43LS efficacy was 88.2% (adjusted 95% CI, 79.3 to 93.3; P<0.0001) for 40 mg/kg, 
and 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.0001) for 10 mg/kg 16 Together, the phase 1 and 
2 trials of CIS43LS provide proof of concept that a MAb with an extended half-life can safely 
confer protection against Pf infection. 
 
As a follow-up to the VRC phase 1 L9LS study, we conducted a phase 2 trial in Mali to assess 
the safety and efficacy of a single subcutaneous injection of L9LS against P. falciparum 
infection in healthy children aged 6-10 years over a 6-month malaria season (ClinicalTrials.gov 
number, NCT05304611). In Part A, safety was assessed at three escalating dose levels in adults, 
followed by two escalating dose levels in children aged 6-10 years. In Part B, children aged 6-10 
years were randomly assigned (in a 1:1:1 ratio) to receive 150 mg of L9LS, 300 mg of L9LS, or 
placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. 
falciparum infection detected on blood-smear examination, which was performed at least every 2 
weeks for 24 weeks. A secondary efficacy end point, assessed in a time-to-event analysis, was 
the first episode of clinical malaria. At enrollment, all the participants received artemether–
lumefantrine to clear possible P. falciparum infection. In Part B, 225 children underwent 
randomization; 75 were assigned to each trial group. Subcutaneous injection of L9LS was well 
tolerated and there were no serious adverse events. At 6 months, the efficacy against P. 
falciparum infection of 300 mg of L9LS as compared with placebo was 69.9% (adjusted 95% 
confidence interval [CI], 50.1 to 81.9; P<0.001), and the efficacy of 150 mg of L9LS as 
compared with placebo was 66.0% (adjusted 95% CI, 45.0 to 79.0; P<0.001). At 6 months, the 
efficacy against clinical malaria of 300 mg of L9LS as compared with placebo was 77.4% 
(adjusted 95% confidence interval [CI], 55.0 to 88.7; P<0.001), and the efficacy of 150 mg of 
L9LS as compared with placebo was 67.0% (adjusted 95% CI, 39.0 to 82.0; P<0.001). In 

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summary, subcutaneous administration of L9LS to children was protective against P. falciparum 
infection and clinical malaria over a 6-month malaria season in Mali without evident safety 
concerns. 
 
Based on the increased potency of L9LS in pre-clinical models, its higher concentration (150 
mg/mL), and the lower weight of infants and children, we administered L9LS by the SC route, 
which is the optimal route for application in this age group. As a follow-up to the phase 1 VRC 
study, this protocol is designed to evaluate the safety and efficacy of L9LS administered SC in 
healthy children ages 5 months to 10 years in a setting of perennial high malaria transmission in 
western Kenya. Kenya is currently participating in the RTS,S/AS01 pilot scheduled to end in 
May 2023. The immediate catchment area of Siaya County Referral Hospital is a control area, so 
children are not receiving RTS,S/AS01 or any other malaria chemoprevention currently.  
 
Laboratory Assessments of L9LS 
Some laboratory assessments in this study are designed to characterize the investigational 
product. This includes PK analysis and evaluation for anti-drug antibody (ADA) development 
after product exposure. Other assays may also be completed from stored samples at a later date.  
The KEMRI laboratories at Siaya County Referral Hospital and at the Kisian campus in Kisumu 
will process blood and store coded samples and will either perform sample testing or ship coded 
samples to designated research laboratories at LIG/NIAID and VRC/NIAID or other approved 
collaborators for assays that cannot be performed in Kenya. The key to the code will remain at 
KEMRI. See section 0 for schedules, blood volumes, and tube types to be used for research 
sample collection. Research assays will be performed on samples from both study product 
recipients and placebo controls at baseline and throughout the study.  
 
Tube types for clinical labs are according to institutional requirements and are shown in section 0 
to estimate blood volumes. Different tubes for clinical evaluations may be used to meet site 
requirements. In some instances, coded samples may be transported directly by study staff to the 
laboratory of an approved collaborator. 
2.2.2.1 
PK Analysis 
Concentrations of L9LS will be measured by a Meso Scale Discovery LLC–based automation 
platform and similar methodology as previously described for other VRC MAb products.17 
2.2.2.2 
Detection of Anti-Drug Antibodies 
Assays for detection of ADA will be performed at specified timepoints following product 
administration and compared to baseline status using a similar methodology as previously 
described for other VRC MAb products.17 

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2.2.2.3 
Measures of MAb-Mediated Protection Against Pf infection and Clinical 
Malaria 
L9LS-mediated protection against naturally occurring Pf infection will be assessed and 
compared to control subjects. The endpoint defining MAb-mediated protection from Pf infection 
is the absence of Pf parasites in blood samples obtained from L9LS-recipients collected from day 
7 through week 52 (day 196) after study agent administration (and the same for the part 2 
extension). The criterion for a case of Pf infection is based on blood smear analysis.  
 
Giemsa-stained thick blood films will be prepared and examined by trained personnel following 
the standard operating procedure (SOP) based on the standard WHO protocol. Thick blood 
smears will be prepared from the blood remaining in the collection device, or (at timepoints 
when no blood collection is planned) from a finger prick sample. The smears will be examined 
microscopically.  
 
As secondary endpoints, L9LS-mediated protection against clinical malaria will be assessed and 
compared to control subjects from day 7 through week 24 (month 6) after study agent 
administration. The two definitions of clinical malaria in this protocol are 1) an illness 
accompanied by measured fever ≥37.5°C in the previous 24 hours, and Pf asexual parasitemia 
>5,000 parasites/µL as detected from microscopic examination of thick blood smear, and 2) an 
illness accompanied by measured fever ≥37.5°C, or history of fever (subjective or objective) in 
the previous 24 hours accompanied by any level of Pf asexual parasitemia as detected from 
microscopic examination of thick blood smear that requires administration of anti-malarial 
treatment.  
 
Clinical malaria will be assessed by both passive surveillance (unscheduled sick visits) and 
active surveillance (medical history, physical exam, and blood smear at all scheduled visits), but 
the blood smear will be read in an expedited manner, ideally within one hour, only if the medical 
history and/or physical exam are suggestive of clinical malaria. Otherwise, blood smears will be 
read within 48 hours by two independent microscopists. Children with a positive blood smear, 
regardless of symptoms, will be treated with artemether-lumefantrine (AL), the first-line 
antimalarial in Kenya. If the child has already departed the clinic, a treatment course of AL will 
be sent to the child’s home with a community interviewer (ideally within 72 hours of taking the 
blood smear), who will counsel the parent/guardian about treating the child with the full course. 
Thick and thin blood smears will be prepared from the blood remaining in the collection device, 
or from a venipuncture or finger prick sample when clinically indicated (or at timepoints when 
no other blood collection is planned). Giemsa-stained thick and thin blood films will be prepared 
and examined microscopically by trained personnel following the SOP based on the standard 
WHO protocol. Thick and thin blood smears will be used for diagnosis throughout the study. 
 

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Additionally, another secondary endpoint, Plasmodium 18S ribosomal ribonucleic acid (rRNA) 
RT-PCR, will be performed by Dr. Sean Murphy, University of Washington. The assay will be 
applied to dried blood spots using methods substantially equivalent to those reviewed extensively 
by the FDA for Biomarker Qualification of the 18S rRNA by the University of Washington for 
CHMI trials (Biomarker Qualification Letter DDTBMQ000044, Oct 12, 2018). The assay has 
been validated for use on dried blood spots. 
  
Research blood samples may also be used for Pf malaria parasite genome analysis that will be 
conducted by Dr. Daniel Neafsey, Harvard School of Public Health. 
 
Repeat Dosing: ADA, PK 
All MAbs are potentially immunogenic and can result in the formation of ADA, particularly with 
repeated dosing.18,17 An ADA response can result in diminished efficacy by altering the PK 
properties of the MAb, and can also promote adverse reactions to the MAb, including infusion 
reactions and local and systemic immune reactions.18,19 In the case of the widely used tumor 
necrosis factor (TNF)-alpha inhibitor MAbs, rates of ADA formation are generally higher in 
patients treated with chimeric anti-TNF constructs compared with fully human MAbs.20,19 
Formation of ADA to anti-TNF MAbs has also been linked to subtherapeutic serum MAb levels 
that may occur during intermittent dosing.21,20 Moreover, some studies suggest that intramuscular 
and subcutaneous administration of MAbs is more immunogenic than intravenous 
administration.21,20   
 
As described above, L9 is a fully human IgG1 MAb that was modified with the Fc region LS 
mutation (L9LS) to increase neonatal Fc receptor (FcRn) binding and consequent antibody half-
life. Other human IgG1 MAbs with LS mutations produced by the VRC that target HIV and 
Ebola have been tested in over 30 clinical trials, and ADA has not been observed to date, 
including in individuals who received up to five administrations of the same MAb. For example, 
VRC01 was found to be safe and well tolerated at doses ranging from 5-40 mg/kg administered 
IV and at 5 mg/kg SC in clinical trials that involved HIV-infected and non-infected adults.17,22-24 
In these studies, VRC01 retained its expected neutralizing activity in participants’ serum and no 
ADA responses were detected over the course of multiple administrations. ADA responses 
against the anti-malarial MAbs CIS43LS and L9LS have not yet been assessed in serum samples 
collected during the phase 1 US trials11,15 or the ongoing phase 2 trials in Mali. 
 
Regulatory authorities in the US and Europe request premarketing evaluations for 
immunogenicity (ADA testing) for all novel biologics.19,25 FDA recommends the following 
regarding the implementation of ADA testing in clinical trials: 
 
“FDA recommends that sponsors obtain pre-treatment samples from all subjects. Because there 
is the potential for pre-existing antibodies or confounding components in the matrix, 
understanding the degree of reactivity before treatment is essential. The sponsor should obtain 

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subsequent samples, with the timing depending on the frequency of dosing. Optimally, samples 
taken 7 to 14 days after the first exposure can help elucidate an early IgM response. Samples 
taken at 3 to 6 weeks after the first exposure are generally optimal for determining IgG 
responses. IgA responses may peak earlier than IgG responses, at around 2 to 3 weeks after 
antigen exposure (Schütz et al. 2013; Macpherson et al. 2008). For individuals receiving a 
single dose of a therapeutic protein product, these time frames may be adequate. However, for 
subjects receiving a therapeutic protein product at multiple times during the trial, the sponsor 
should obtain samples at appropriate intervals throughout the trial and obtain a sample 
approximately 30 days after the last exposure. For products with long half-lives, samples should 
be obtained approximately five half-lives after last exposure.” 
 
“Samples to determine serum concentrations of the therapeutic protein product should be 
obtained at the same time as immunogenicity samples. Testing such samples can provide 
information on whether the therapeutic protein product in the samples is interfering with ADA 
testing and whether ADA is altering the therapeutic protein product’s pharmacokinetics.”  
 
In addition to measuring ADA in the pre-MAb administration samples (already collected in the 
first year of the study), the protocol extension will follow FDA recommendations by collecting 
serum samples for PK and ADA testing before re-dosing of L9LS/placebo and periodically after 
re-dosing. The final assessment time point (Day 364) represents approximately 6.5 half-lives 
after the last exposure since the estimated half-life of L9LS was 56 days in the phase 1 US trial. 
 
 
Risk/Benefit Assessment 
 
Known Potential Risks 
Risks of L9LS: There have been no notable safety signals in the VRC 614 phase 1 trial (the first 
in human study of this product) to date, which includes 12 weeks of follow-up after initial 
administration and 8 weeks after CHMI. A similar malaria antibody, CIS43LS, was evaluated as 
safe and well tolerated in the VRC 612 study.11 Similarly, no significant safety concerns have 
arisen in the completed trial of CIS43LS in healthy Malian adults at 6 months after product 
administration.16 The study in Mali was done with a dose of 40 mg/kg IV (110 participants), 10 
mg/kg IV (110 participants), and placebo (110 participants). As described above (Section 
2.2.1.3), an ongoing phase 2 trial in Mali is assessing the safety and efficacy of subcutaneous 
injection of L9LS against P. falciparum infection in healthy children aged 6-10 years over a 6-
month malaria season (July-December). In Part A (initiated in March 2022), safety was first 
assessed at three escalating dose levels in adults (n=18), followed by two escalating dose levels 
in children aged 6-10 years (n=18). In Part B (initiated in July 2022), 225 children aged 6-10 
years were randomly assigned (in a 1:1:1 ratio) to receive 150 mg of L9LS, 300 mg of L9LS, or 
placebo. Before the second malaria season (starting in June 2023) approximately 90% of 
pediatriac participants were re-enrolled in a 1-year extension and were re-randomized within 
their original study arms and received placebo or L9LS at the dose they received in year 1 (150 
mg or 300 mg; or 150 mg for children who received placebo in year 1). Both the first and second 

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subcutaneous injections of L9LS were well tolerated and there have been no serious adverse 
events.  
 
In Part 1 of this study, safety was assessed at three escalating dose levels in older children 6 – 10 
years (n=36), and also at these same doses in children aged 5 – 59 months (n=36). From the 72 
participants, 54 received L9LS. The subcutaneous injections of L9LS were well tolerated and no 
serious adverse events were reported.  
 
In a preclinical TCR study, L9LS produced membrane and cytoplasmic binding in infrequent 
ductal and acinar epithelial cells in the human salivary gland which is of unclear clinical 
significance. Binding occurred in only 1-5% of cells and was scattered without evidence of 
clustering. Histopathology findings suggests the human salivary tissues were sourced from 
surgical excisions with evidence of pre-existing inflammation, which may have contributed to 
the observed binding. We suspect any effect on the salivary glands from L9LS, if present, would 
be transient due to the clearance of the passively transferred antibody and the rapid turnover of 
salivary gland epithelium. To address these findings, the trial will exclude any population at an 
increased risk for salivary gland dysfunction and will prospectively monitor for signs and 
symptoms that may be indicative of salivary gland hypofunction. Subject matter experts in 
salivary gland disorders at the National Institute of Dental and Craniofacial Research who are 
board-certified by the American Board of Oral and Maxillofacial Pathology have agreed to assist 
the protocol team by being available for consultation throughout the trial. In addition, L9LS is 
being evaluated in an ongoing phase 1 study in healthy adult volunteers at the VRC to assess 
safety, tolerability, PK, and protective efficacy, as described in section 2.2.1. Safety assessment 
in the phase 1 trial includes prospective monitoring for signs and symptoms that may be 
indicative of salivary gland hypofunction. Since September 13, 2021, 18 subjects have received 
L9LS either IV or SC, and there have been no SAEs and no safety pauses. All systemic 
symptoms were only mild to moderate and self-limited. Mild or moderate solicited systemic AEs 
were reported by 5 subjects (27.8%). Solicited systemic AEs include mild malaise (5 subjects), 
mild or moderate headache (4 subjects), mild chills (2 subjects), mild or moderate nausea (2 
subjects), and mild joint pain (1 subject). There were also 2 related unsolicited AEs that were 
reported (lymphadenopathy and elevated serum creatinine), both of which were grade 1. All IV 
and SC administrations were well tolerated. Of the 13 subjects who received L9LS IV, 4 
reported mild pain and 1 reported moderate bruising at the site of administration. Of the 5 
subjects who received L9LS SC, 2 reported mild pain, 1 reported mild pruritus and 1 reported 
mild redness at the site of administration. The protocol and consent will be updated if new 
information about risks and side effects becomes available from the ongoing phase 1 study.  
 
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 

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mouse MAbs that would have a risk of human anti-mouse antibodies.26 In this regard, because 
L9LS 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, pruritis) and systemic reactions such as 
fever, chills, rigors, nausea, vomiting, pain, headache, myalgia, arthralgia, dizziness, fatigue, 
shortness of breath, bronchospasm, hypotension, hypertension, pruritus, rash, urticaria, 
angioedema, diarrhea, tachycardia, or chest pain. Healthcare staff will be appropriately trained 
and necessary medical equipment will be readily available at the clinic where the study agent is 
administered. Clinical use of MAbs that are targeted to cytokines or antigens associated with 
human cells may be associated with an increased risk of infections;26 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 MAbs, such as a mouse MAb.26 Most administration-related events occur within the first 
24 hours after MAb administration. 
 
Published experience with human MAbs directed against cell surface targets on lymphocytes 
shows that administration of a MAb may be associated with cytokine release, causing a reaction 
known as cytokine release syndrome (CRS).27 CRS reactions commonly occur within the first 
few hours of administration and with the first MAb administration 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 administering histamine blockers.28  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.26 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 will be managed 
according to the principles of the American Academy of Allergy, Asthma, and Immunology 
guidelines.29 
 
Participation in this study may limit a subject’s eligibility for future MAb studies. 
 

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Risks of Placebo Administration: There are no risks of the placebo (normal saline) other than 
injection related events such as transient vasovagal-mediated hypotension or local site injection 
bruising, swelling, or infection, the risk of which will be minimized by using sterile techniques. 
 
Risks of Blood Drawing: Drawing blood by venipuncture or fingerprick/ heel prick may cause 
pain, bruising, and a feeling of lightheadedness or fainting. Rarely, an infection may develop at 
the site where blood is taken.  
 
Risks of DP Administration: Before study agent administration, all subjects will be given DP, 
the second-line antimalarial according to the Kenyan national guidelines, to clear any preexisting 
Pf blood-stage infection. DP is being selected over AL for logistic reasons, as it is administered 
only once daily for three days, simplifying the process of observing each administration and 
therefore improving compliance and ensuring parasite clearance prior to MAb administration. 
Clearance of preexisting Pf blood-stage infection is necessary to accurately assess the primary 
endpoint of Pf blood-stage infection as detected by microscopic examination of thick blood 
smear after administration of L9LS or placebo, since preexisting Pf blood-stage parasites cannot 
be reliably distinguished from newly transmitted Pf blood-stage parasites.  
 
Although there is some evidence to suggest that exposure to Pf blood-stage infection may 
interfere with the human immune response to malaria vaccine candidates, clearance of 
preexisting Pf blood-stage infection is not considered necessary for L9LS efficacy since it 
directly mediates its protective effect against sporozoites and does not depend on induction of 
any host immune response.12    
 
Adverse reactions (ARs) to DP are estimated to occur in 1.8% of patients, according to two 
studies included in a recent meta-analysis.30 Reactions typically do not require stopping 
treatment. In postmarketing experience, serious hypersensitivity reactions including anaphylaxis 
and serious skin reactions (bullous eruption) have been reported. Children receiving this 
medication should have a weight of at least 5 kilograms. Medication like macrolide antibiotics, 
quinolones, and certain antihistamines like astemizole will be avoided during the period of 
giving DP. Very common side effects (≥1 in 10) in children include pyrexia; common side 
effects (≥1 in 100 to <1 in 10) diarrhea, vomiting, abdominal pain, rashes, irregular heart rate, 
QT/QTc prolongation, leukopenia/neutropenia. Possible side effects will be communicated to the 
parent/guardian. Individuals with known sensitivity or contraindications to the antimalarials 
administered in this study are excluded from participation.  
 
In a recently completed therapeutic efficacy trial assessing AL and DP (ClinicalTrials.gov 
Identifier: NCT05060198), both drugs were well tolerated (<2% of children vomited the first 
dose of medication in both arms). Only one severe adverse event was recorded—a participant in 

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the AL arm hospitalized with severe dehydration due to a diarrheal illness; the child recovered 
fully. This event was deemed unrelated to the study drug. 
 
A complete list of side effects and contraindications is provided in the product Guide for 
Healthcare Professionals (insert).31  
 
Known Potential Benefits 
Subjects may not receive direct health benefit from study participation. Depending on whether 
L9LS confers protective efficacy, subjects receiving a sufficient dose of L9LS may experience 
some protection against Pf infection and clinical malaria.  
 
In the future, others may benefit from knowledge gained in this study that may aid in the 
development of malaria prevention. 
 
Assessment of Potential Risks and Benefits 
The study population lives in a setting of perennial high transmission and so is at significant risk 
of malarial infection and disease. As described above, it is possible that some subjects may 
benefit from study participation by receiving some protection from malaria. Therefore, the value 
of the information that will be gained from this study for developing malaria prevention 
strategies justifies the potential risks of study participation described above. Additionally, 
potential risks are minimized by careful design of subject eligibility criteria and monitoring after 
study product administration.  
3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
1. Part 1: Safety: To evaluate the 
safety and tolerability of 
L9LS administered at doses 
of 5 mg/kg, 10 mg/kg, and 20 
mg/kg by SC administration 
to healthy Kenyan children. 
2. Part 2: Safety: To evaluate the 
safety and tolerability of 
L9LS administered at doses 
of 10-20 mg/kg by SC 
administration to healthy 
Kenyan children 
1. Parts 1 & 2: Incidence and 
severity of local and 
systemic AEs occurring 
within 7 days after the 
administration of L9LS, 
and incidence of SAEs 
throughout the study 
period. 
2. Part 2: Pf blood-stage 
infection as detected by 
microscopic examination 
of thick blood smear for 
52 weeks after 
1. Assessment of AEs is 
a standard measure of 
study agent safety 
and tolerability. 
2. Blood smear is the 
gold standard for 
diagnosis of blood-
stage Pf infection. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
3. Part 2: Efficacy: To assess the 
efficacy of two doses of L9LS 
at a concentration of 10-20 
mg/kg, administered SC to 
participants aged 5-59 months 
of age against first/only Pf 
malaria infection diagnosed 
by blood smear microscopy 
(irrespective of fever) over 12 
months compared to placebo. 
administration of L9LS or 
placebo. 
 
Secondary 
1. To assess the efficacy of one 
dose of L9LS at 10-20 mg/kg 
against first/only Pf malaria 
infection diagnosed by blood 
smear microscopy over 3 and 
6 months compared to 
placebo. 
2. To assess the efficacy of one 
dose of L9LS at 10-20 mg/kg 
against first/only Pf malaria 
infection diagnosed by blood 
smear microscopy over 12 
months compared to placebo. 
3. To evaluate the efficacy of 
L9LS at 10-20 mg/kg against 
first/only Pf malaria infection 
as detected by PCR over 3, 6 
and 12 months compared to 
placebo. 
4. To assess protection of L9LS 
at 10-20 mg/kg against 
clinical malaria (first/only and 
all episodes) at 3, 6 and 12 
months compared to a 
placebo. 
5. To assess the primary 
objective and secondary 
1. Pf blood-stage infection as 
detected by microscopic 
examination of thick 
blood smear for 12 and 24 
weeks after administration 
of L9LS or placebo. 
2. Pf blood-stage infection as 
detected by microscopic 
examination of thick 
blood smear for 52 weeks 
after administration of 
L9LS or placebo. 
3. Pf blood-stage infection as 
detected by RT-PCR for 
12, 24 and 52 weeks after 
administration of L9LS or 
placebo. 
4. Incidence of clinical 
malaria (definitions 1 and 
2, see section 2.2.2.3) for 
12, 24 and 52 weeks after 
administration of L9LS or 
placebo. 
5. See 1 – 4 above 
6. See 1 – 4 above 
1. Blood smear is the 
gold standard for 
diagnosis of 
blood-stage Pf 
infection. 
2. See 1 above. 
3. RT-PCR is more 
sensitive than blood 
smear for detecting 
Pf blood-stage 
infection. 
4. 6–59-month-old 
children in Kenya are 
at high risk for 
clinical malaria. 
5. See 1 – 5 above 
6. See 1 – 5 above 
7. Concentrations of 
L9LS in blood will 
help assess durability 
of L9LS at each dose 
level and will allow 
for correlation with  
a. Pf infection  

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
objectives 1-4 among children 
5-17 months of age. 
6. To assess the primary 
objective and secondary 
objectives 1-4 among children 
18-59 months of age. 
7. To evaluate the PK of L9LS 
throughout the study at 
weight-based dose levels of 5 
mg/kg, 10 mg/kg, and 20 
mg/kg (part 1) and fixed 
doses of 10-20 mg/kg (part 2) 
in healthy Kenyan children, 
and 
a. To correlate L9LS 
serum concentration 
with Pf infection risk. 
b. To correlate L9LS 
serum concentration 
with clinical malaria 
risk. 
7. Measurement of L9LS in 
sera of recipients, 
including PK analysis of 
L9LS and the association 
of L9LS concentration 
with Pf infection risk and  
with clinical malaria risk. 
b. Clinical 
malaria risk. 
 
Tertiary/Exploratory 
1. To assess the impact of L9LS 
on hospitalizations with 
malaria 
2. To determine whether ADA 
to L9LS can be detected in 
sera of recipients at specific 
timepoints throughout the 
study. 
3. To assess for IgG1 allotypes 
and allotype specific effects 
on L9LS PK.  
4. To determine if the efficacy 
of L9LS is specific to certain 
1. Proportion of participants 
hospitalized with malaria 
2. Measurement of ADA to 
L9LS in sera of recipients. 
3. Assessment of IgG1 
allotypes and allotype-
specific effects on L9LS 
PK.  
4. CSP genotyping of 
parasites isolated from 
study subjects. 
5. Pre-existing parasitemia 
detected by microscopic 
examination of thick 
1. It is possible that 
L9LS might not 
prevent malaria but 
might prevent the 
progression to severe 
malaria. 
2. ADA to L9LS may 
impact the PK and 
activity of L9LS. 
3. Subject IgG1 allotype 
may impact the PK 
and activity of L9LS.  
4. L9LS efficacy may 
be specific to certain 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Pf parasite genotypes at the 
CSP locus. 
5. To explore the impact of 
pre-existing parasitemia on 
the protective efficacy and 
PK of L9LS.  
6. To explore the impact of 
pre-existing CSP antibodies 
on the protective efficacy and 
PK of L9LS. 
7. To assess the effect of L9LS 
on antibodies to measles in 
the younger age group. 
8. To compare the efficacy of 
one versus two doses of 
L9LS against Pf infection 
and clinical malaria over 12 
months. 
blood smears or RT-PCR 
before L9LS 
administration. 
6. Pre-existing CSP-specific 
antibodies measured in 
sera collected before 
L9LS administration. 
7. Measles virus-specific IgG 
antibodies among subjects 
<9 months of age at 
enrollment. 
8. Pf infection and clinical 
malaria over 12 months. 
Pf parasite genotypes 
at the CSP locus. 
5. Pre-existing 
parasitemia may 
impact the protective 
efficacy and PK of 
L9LS.  
6. Pre-existing 
CSP-specific 
antibodies may 
impact the protective 
efficacy and PK of 
L9LS. 
7. Address concerns that 
L9LS might impact 
immune response to 
measles vaccine. 
8. Pf infection and 
clinical malaria are 
our primary and 
secondary endpoints. 
Follow-on Study Primary Objectives 
Follow-on Safety (part 1b) 
1. To evaluate the safety and 
tolerability of L9LS 
administered at doses of 30  
mg/kg and 40 mg/kg by SC 
administration to healthy 
Kenyan children. 
Follow-on Part 2 Extension 
2. To evaluate the safety and 
tolerability of a third and 
fourth SC dose of L9LS at 
20–40 mg/kg (compared to 
placebo) in healthy Kenyan 
children. 
1. Incidence and severity of 
local and systemic AEs 
occurring within 7 days 
after the administration of 
L9LS and incidence of 
serious adverse events 
(SAEs) throughout the 
study period. 
2. Measurement of L9LS in 
sera of recipients. 
3. Measurement of ADA in 
sera of recipients. 
1. Assessment of AEs is a 
standard measure of 
study agent safety and 
tolerability. 
2. Concentrations of L9LS 
in blood will help 
assess durability of 
L9LS at each dose 
level. 
3. ADA to L9LS may 
impact the PK and 
activity of L9LS. 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
3. To evaluate the PK of L9LS 
throughout the follow-up 
phase at 20–40 mg/kg in 
healthy Kenyan children. 
4. To determine if ADAs to 
L9LS can be detected in sera 
of recipients at specific 
timepoints throughout the 
study and to correlate the 
occurrence of ADAs with 
L9LS PK. 
Extension Phase Exploratory Objectives (see Error! Reference source not found.4 for 
study arm definitions) 
1. To assess the efficacy of an 
additional one or two SC 
doses of L9LS over one year 
at 20–40 mg/kg in mediating 
protection against Pf infection 
and clinical malaria in healthy 
Kenyan children during a 
second year of follow-up 
compared to those who 
received placebo only (arms 1 
vs. 3; arms 2 vs. 3) and in 
those receiving two L9LS 
doses in the extension versus 
one (arms 1 vs. 2) 
2. To evaluate the PK of L9LS 
throughout the study and to 
correlate L9LS serum 
concentration with Pf 
infection risk and clinical 
malaria risk 
3. To evaluate the effect of a 
third (and fourth) dose of 
L9LS on development of 
acquired immunity (measured 
by antibodies) 
1. Pf blood-stage infection as 
detected by microscopic 
examination of thick 
blood smears obtained 
between 1 week and 52 
weeks after administration 
of L9LS or placebo. 
2. Pf blood-stage infection as 
detected by RT-PCR from 
dried blood spots obtained 
between 1 week and 52 
weeks after administration 
of L9LS or placebo. 
3. Incidence of clinical 
malaria (see section 
2.2.2.3) between 1 week 
and 52 weeks after 
administration of L9LS or 
placebo. 
4. PK analysis of L9LS and 
the association of L9LS 
concentration with Pf 
infection risk. 
5. PK analysis of L9LS and 
the association of L9LS 
1. Blood smear is the gold 
standard for diagnosis 
of blood stage Pf 
infection. 
2. RT-PCR is more 
sensitive than blood 
smear for detecting Pf 
blood-stage infection. 
3. Children <5 years of 
age in Kenya are at 
high risk for clinical 
malaria. 
4. Concentrations of L9LS 
in blood will help 
assess durability of 
L9LS and will allow for 
correlation with Pf 
infection risk. 
5. Concentrations of L9LS 
in blood will help 
assess durability of 
L9LS and will allow for 
correlation with clinical 
malaria risk. 
6. Concentrations of anti-
malaria antibodies will 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
concentration with clinical 
malaria risk. 
6. Levels of naturally 
occurring antimalaria 
antibodies in participant 
blood at selected time 
points 
 
help assess potential for 
rebound after L9LS 
4 
STUDY DESIGN 
 
Overall Design 
This is a three-part, phase 2 trial evaluating the safety and tolerability of SC administration of 
L9LS in healthy Kenyan children, as well as its protective efficacy against naturally occurring Pf 
infection over a 12-month period in healthy Kenyan children 5-59 months of age. The primary 
study hypotheses are that L9LS will be safe and will produce protection against malaria 
infection. Before study agent administration, all subjects will be given an antimalarial (in most 
cases, DP) to clear any preexisting Pf blood-stage infection.  
 
The target age group for this trial is children 5 to 59 months. Young children are notable for 
having substantial morbidity and mortality from malaria. For this reason, RTS,S/AS01 is now 
being routinely implemented in a large-scale pilot and as of 2023 as part of the routine 
immunization programme in western Kenya by the Kenya National Vaccines and Immunizations 
Program (NVIP) to children beginning at 6 months, with the second, third, and fourth doses 
occurring at 7, 9, and 24 months, respectively. RTS/S/AS01 confers ~ 36% protection against 
clinical infection after 4 years. Thus, an intervention that could provide high-level durable 
efficacy for 6 or 12 months (>70%) could have important implications for malaria control in 
perennial transmission settings, with advantages related to compliance and increased protection. 
Given the potential interest in MAbs as an alternative to malaria vaccines, we propose to increase 
the sample size in the 5- to 17-month-old age group to enable a comparison to efficacy of 
RTS,S/AS01 from data in this age group in the same region. A key feature of this study will be 
assessment of 1 of 3 fixed-dose regimens given by the SC route at 1 injection site (in infants and 
children up to 15 kg) or possibly 2 sites (children > 15 kg). (Children >15 kg would receive a 
greater dose administered in 1 or 2 sites to maintain a minimum dose concentration of 10 
mg/kg.) This fixed-dose regimen design is simple, easy for implementation by clinicians, and 
provides a “real” world setting for administration. 
  

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For the current study in western Kenya, we propose an age de-escalation approach to test the 
safety of L9LS first in older children (5-10 years of age) and then in the younger target age group 
for the trial (5-59 months of age), at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg administered via 
SC injection. The initial age de-escalation component will enroll 12 participants in each age-dose 
group in a 3:1 ratio of L9LS to placebo. The second part is a randomized, double-blind, placebo-
controlled trial to assess safety and protective efficacy of L9LS versus placebo in children ages 
5-59 months. In this part of the study, children will be randomized 2:1 to L9LS or placebo in an 
age-stratified manner so that there will be one L9LS cohort for younger children, aged 5-17 
months, and one L9LS cohort for older children, aged 18–59 months, which together will 
constitute one L9LS study arm. A placebo study arm will be composed of children aged 5–59 
months (composed of subjects from both age groups).  
 
Part 1: Double-blinded, age de-escalation, dose-escalation trial to assess tolerability and safety 
In a stepwise fashion, children aged 5-10 years will be screened, and those eligible will undergo 
a pre-enrolment process after obtaining informed consent. Two to three weeks after a treatment 
course with DP for parasite clearance, individuals will receive 5 mg/kg of L9LS or placebo via 
SC injection and will be followed for 3 months post-injection to assess tolerability and safety. If 
acceptable tolerability and safety profiles are met at 1 week post-injection, we will dose children 
ages 5-59 months with 5-mg/kg L9LS or placebo while dosing another cohort of children ages 5-
10 years with 10 mg/kg of L9LS or placebo. If after 1 week, L9LS at 10 mg/kg is found to be 
safe in children aged 5-10 years, and 5 mg/kg is found to be safe in children ages 5-59 months, 
we will then assess tolerability and safety of 20 mg/kg L9LS or placebo in children ages 5-10 
years, and 10 mg/kg L9LS or placebo among children ages 5-59 months, using the approach in 
Figure 1A above. Should tolerability and safety of all doses be acceptable in children ages 5-59 
months, we will move to part 2 of the trial. Dosing in part 1 of the study will be weight-based 
and all doses will be administered via SC injection. All participants in part 1 will be followed for 
a total of 3 months. 
 
See section 1.4.1 for a detailed schedule of assessments. 
 
Part 2: Evaluating efficacy of monoclonal antibodies 
This will be a phase 2, double-blind, randomized, controlled clinical trial to evaluate the efficacy 
of L9LS against malaria infection among children ages 5 to 59 months in a setting of perennial 
high transmission. Participants will be stratified by age group (5-17 months and 18-59 months) 
and within each age group randomly assigned in a 2:1 ratio to receive L9LS or placebo as an 
initial injection. The two age groups will be enrolled in parallel. Study arms are as follows: 
1. L9LS at 10-20 mg/kg (SC administration):  
a. 5-17 months of age 
i. L9LS dose 2 at 6 months 
ii. Placebo dose 2 at 6 months 

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b. 18 months to 59 months of age  
i. L9LS dose 2 at 6 months 
ii. Placebo dose 2 at 6 months 
2. Placebo arm: 
a. 5-17 months of age (with placebo dose 2 at 6 months)  
b. 18 months to 5 years of age (with placebo dose 2 at 6 months) 
 
After an initial screening, we will obtain informed consent from those eligible; for those 
consenting, we will conduct a more complete screening that includes a physical exam and blood 
draw to assess parasitemia, hematological and biochemistry values, antimalarial antibody and 
antigen titers, and other parameters; for those who remain eligible, we will administer a full, 
weight-based course of DP, the second-line antimalarial in Kenya, to clear parasites. (For 
children who have taken an antimalarial within the last 2–4 weeks, this antimalarial course will 
be deferred at least 7 days from the date of the last dose of AL or at least 4 weeks after the last 
dose of DP.) Between 14 and 21 days after the first dose of DP (considered day 1 for dosing 
window), children will return and then be randomized to receive a SC injection(s) of either 
placebo or L9LS, according to study arm. Children will be considered enrolled once they are 
randomized on the Day 0 dosing visit. We will use a ‘constrained’ fixed dosing approach that 
ensures each child receives a minimum of 10 mg/kg in a relatively simple dosing scheme. See 
section 6.2.4 for exact dosing information and the number of required injections of two syringe 
types for various participant weights. 
 
Children will be scheduled for monthly visits at the study health facility throughout the duration 
of the trial, and parents/guardians will be asked to bring their child to the study facility for 
unscheduled visits for assessment of any concerns or illness (free of charge). Starting after the 
first monthly visit after IP administration, study staff will contact parents/caregivers 2 weeks 
after scheduled visits (via home visits or telephone calls) to administer questionnaires about 
symptomatology and care-seeking behavior. If a child has fever or history of fever, they will be 
brought to the clinic for a finger prick for malaria testing. 
 
At monthly visits, a capillary blood draw will be conducted to collect a sample for blood smear 
microscopy and PCR. Questionnaires will be administered focusing on development of 
symptoms, care-seeking behavior and any medications taken. At key time points, venous blood 
will be collected to assess antibody titers. 
 
Benefit of a second dose at 6 months: Participants in the L9LS arm will be randomized to receive 
either a second dose of L9LS or placebo at 6 months to evaluate the additional efficacy of a 
second dose. (Those in the placebo arm will receive a second injection of placebo.) 
 
See section 1.4.2 for a detailed schedule of assessments. 

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Year 2 Follow-on Study (Safety and Extension) 
Part 1b. Follow-on Safety 
As part of the follow-on study, an initial dose escalation study will assess the safety and 
tolerability of 30 mg/kg L9LS and 40 mg/kg L9LS. An additional 12 children ages 5 – 71 
months will be randomized to receive L9LS at 30 mg/kg (weight-based dose) or placebo in a 3:1 
ratio. If no safety signals are seen after 7 days, an additional 12 children aged 5 – 71 months will 
be randomized to receive L9LS at 40 mg/kg (weight-based dose) or placebo in a 3:1 ratio. If no 
safety signals are seen then the follow-on extension will move forward, pending DSMB review 
of the data and approval to proceed. Children will be followed for a total of three months after 
dosing. Subjects will be followed at study visits 1, 3, 7, 14, 21, and 28 days after administration, 
and then at month 2 and month 3. 
 
Follow-on part 2 extension  
In the extension phase, all parents/guardians of participants who are currently enrolled in the part 
2 efficacy study will be invited to extend their child’s participation for approximately 13 months 
from the time of re-consenting. Parents/guardians of children can be consented to allow  
participation of their children in the extension phase at any time before their termination in part 2 
and up to 3 months after their part 2 close-out. Participants will remain in their same 
randomization groups from part 2. Those who received two doses of L9LS in part 2 will also 
receive two doses of L9LS, six months apart, in the extension phase. Those who received one 
dose of L9LS will receive one dose (plus a dose of placebo six months later), and those who 
received two doses of placebo will receive an additional two doses of placebo, six months apart. 
 
Before study agent administration, all subjects will be given dihydroartemisinin-piperaquine to 
clear any preexisting Pf blood-stage infection. Subjects will be followed at study visits 1, 3, 7, 
and 28 days after administration, and then will have alternating biweekly home visits and clinic 
visits, identical to the visit schedule during year one, up through 52 weeks after the initial follow-
on extension dose in year two. Primary study assessments include medical history, physical 
examination, and blood collection for pharmacokinetics (PK), anti-drug antibody (ADA) 
assessments, identification of Pf infection by microscopic examination of thick blood smears and 
RT-PCR, and other research laboratory evaluations. 
 
Safety outcomes will be evaluated within arms to assess the safety of a third and fourth L9LS 
dose vs. placebo in year 2 (1 vs. 3 and 2 vs. 3). Finally, safety outcomes of L9LS vs. placebo will 
be evaluated in aggregate (1 + 2 vs. 3).  
 
PK of L9LS will be evaluated throughout the study for those receiving various numbers of L9LS 
doses. The presence of ADA to L9LS will be assessed in sera of recipients at specific timepoints 
throughout the study and will be correlated with L9LS PK.  

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In exploratory analysis, L9LS serum concentration will be correlated with the risk of Pf infection 
(assessed by blood smear and RT-PCR) and clinical malaria. The protective efficacy of L9LS 
against P. falciparum infection (by blood smear and RT-PCR) and clinical malaria will be 
assessed by comparing: 1) arm 1 vs. arm 3 (over 12 months); 2) arm 2 vs. arm 3 (over 12 
months); arms 1+2 vs. arm 3 (over 6 months); and arm 1 vs. 2 (over 12 months). 
 
Study site 
The CDC has collaborated with KEMRI in western Kenya to evaluate tools for malaria 
transmission and burden reduction for over 40 years. The collaboration has a highly experienced 
clinical trials unit that includes two pediatricians, immunologists, medical officers, pharmacists, 
clinical officers, nurses, quality control and regulatory officers. This group has been involved in 
phase 2, 3, and 4 trials of RTS,S/AS01 and conducted the largest phase 2 trial of the PfSPZ 
Vaccine in 5- to 12-month-old infants as well as a number of pharmaceutical clinical trials. The 
clinical trials unit is based in Siaya County Referral Hospital, the largest hospital in Siaya 
County, western Kenya. Here, malaria transmission is perennial with seasonal peaks following 
the long and short rains in June/July and November/December, respectively. Clinical malaria 
incidence (any parasite density by microscopy in a child who reports fever within the previous 
24 hours) among children aged 5 to 17 months was 3.06 cases per year in 2019–2020. In the 
recent PfSPZ Vaccine trial among infants 5-12 months of age at the time of first vaccination 
(with a 3-dose series over 5 months), 66.7% of participants in the placebo arm had at least one Pf 
infection based on microscopy within 6 months after the last dose; in another trial among 5- to 
17-month-olds at the time of first vaccination (with a 3-dose series over 3 months), 46.8% had at 
least one clinical malaria episode (parasitemia >0 parasites/µL and fever/history of fever within 
24 hours) within 6 months after the last dose. Currently, the RTS,S/AS01 malaria vaccine is 
being rolled out by the Kenya Expanded Programme on Immunization in select sub-counties in 
western Kenya; the RTS,S/AS01 vaccine is not being implemented in Alego-Usonga sub-county 
(where the clinical research site is located). The current Malaria Vaccine Pilot Evaluation is 
scheduled to run until May 2023, so the earliest that RTS,S/AS01 vaccinations would be offered 
in Karemo, where the study site hospital is, would be June 2023. In part 2, staff will also recruit 
and follow up patients at Kogelo Dispensary, a satellite clinic referring patients to Siaya County 
Referral Hospital. 
 
Scientific Rationale for Study Design 
This two-part study was designed to test L9LS in the setting of naturally occurring Pf infection 
and in a population that could potentially benefit from a novel therapeutic for malaria prevention, 
with initial safety data collected from older children prior to proceeding with the enrollment of 
younger ages. 
 

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Both parts of the study will use randomization and a placebo control, and double-blinding to 
minimize bias in subject selection and study assessments. The placebo will be inactive (normal 
saline) rather than a comparator MAb, as currently there are no licensed anti-malaria MAbs 
available. 
 
Year 2 Follow-on Study (Safety and Extension) 
The protocol follow-on study was designed to evaluate the safety and PK of a third and fourth 
L9LS dose in the setting of naturally occurring Pf infection and in a population that could 
potentially benefit from a novel therapeutic for malaria prevention.  
 
The protocol extension will use a double-blind design in the cohorts of children to minimize bias 
in subject selection and study assessments. The placebo will be inactive (normal saline) rather 
than a comparator MAb, as currently there are no licensed anti-malaria MAbs available. 
 
 
Justification for Dose 
The doses used in this study were selected based on preclinical data and data generated in the 
phase 1 VRC study, which tested the dose range included in this protocol and showed that 4/5 
individuals that received 5 mg/kg SC were protected and 4/4 that received 20 mg/kg IV were 
protected following CHMI. This study will test fixed doses of L9LS in children to approximate 
the weight-based dosing used in the phase 1 VRC study. Compared to weight-based dosing, 
fixed dosing will provide a greater range of antibody concentrations in vivo for determining a 
protective L9LS titer. Fixed dosing is also simpler to administer, reduces the risk of medication 
errors, and is generally more cost effective—factors that are relevant to the potential use of L9LS 
in malaria-endemic regions.  
 
In Part 1, subjects aged 5 months to 10 years will receive weight-based doses of 5 mg/kg, 10 
mg/kg, and 20 mg/kg. Children weighing >30 kg will be excluded given that administration of 
20 mg/kg would entail more than 2 mL of L9LS at two different injection sites for heavier 
children. According to a recent study in the area, female children 10 years old had an average 
weight of 26.3 kg (SD = 5.4 kg) and male children 10 years old an average of 26.9 kg (SD = 5.1 
kg). 
 
The doses used in the efficacy study will complement the data generated in the phase 1 VRC 
study. The doses used in the phase 1 VRC study were derived from 1) efficacy data from the 
challenge studies performed in mice showing that the protective concentration of antibody in 
vivo is between 5-100 μg/mL in 2 different mouse models of malaria infection;12 and 2) PK data 
from NHP studies with L9LS and prior clinical experience in healthy adults with human MAbs 
targeting HIV (i.e., VRC01, VRC01LS, and VRC07-523LS) and ebolavirus (MAb114) at the 
same dose.  

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In the ongoing phase 2 trial of L9LS in Mali involving healthy children aged 6-10 years, a pre-
specified exploratory analysis of the relationship between the weight-based dose of L9LS (mg of 
L9LS administered per kg of body weight) and protective efficacy suggested that ~12 mg/kg of 
L9LS corresponds to a protective efficacy against clinical malaria of approximately 75% over six 
months compared to placebo. In addition, preliminary PK analysis indicates that the average 
half-life of L9LS in Malian children is ~35 days, compared to ~55 days in Malian adults, and 
~65 days in U.S. adults. After receiving 10-20 mg/kg of L9LS, the average number of days 
required for the serum concentration of L9LS to fall below the lower limit of detection (0.61 
µg/mL) was 243 (95% CI 232–254). Therefore, we anticipate that a single dose of L9LS in the 
range of 10-20 mg/kg will not provide high-level protection (>75%) against malaria over 12 
months in healthy Kenyan children 5-59 months of age who are exposed to intense perennial 
malaria transmission. Therefore, the 1-year extension of the phase 2 Kenya trial will assess the 
safety and protective efficacy of L9LS at a dose range of 20-40 mg/kg. 
5 
STUDY POPULATION  
 
Inclusion Criteria 
Individuals must meet all of the following criteria to be eligible for study participation: 
1. Healthy children aged 5 months to 10 years (Part 1) or 5-59 months (Part 2). 
2. Weight ≥5 kg and weight ≤30 kg (Part 1) or weight ≥5 kg and ≤22.5 kg (Part 2) or weight 
≥5 kg and ≤20 kg (for 30 mg/kg group) or weight ≥5 kg and ≤15 kg (for 40 mg/kg 
group), to ensure a maximum volume of two 2-mL (Part 1b)  
3. Hemoglobin level ≥8 g/dL. 
4. Height and weight Z-scores >-2. 
5. Living within Alego-Usonga sub-county. 
6. Able to participate for the duration of the trial. 
7. Parent and/or guardian of participant able to provide informed consent. 
 
Year 2 Extension Inclusion Criteria 
Individuals must meet all of the following criteria to be eligible for participation: 
1. Participated in part 2 of the protocol.  
2. Able to participate for the duration of the extension period. 
3. Parent and/or guardian of participant able to provide informed consent. 
 

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Exclusion Criteria 
Individuals meeting any of the following criteria will be excluded from study participation: 
1. Taking long-term cotrimoxazole. 
2. Participation or planned participation in any other interventional trial with an 
investigational product prior to the last required protocol visit or receipt of an 
investigational product within the past 30 days. (Note: Past, current, or planned 
participation in observational studies is NOT exclusionary.) 
3. Received any doses of any malaria vaccine.  
4. Participation in part 1 of this study (for individuals being screened for enrollment into 
part 2) 
5. Age < 12 months at the time the RTS,S/AS01 vaccine is anticipated to become available 
in the whole of Siaya County  
6. Current significant medical condition (neurologic, cardiac, pulmonary, hepatic, 
endocrine, rheumatologic, autoimmune, renal, oncologic, or hematological) or evidence 
of any serious underlying medical condition identified by medical history, physical 
examination, or laboratory examination. 
a. Known sickle cell disease. (Note: Known sickle cell trait is NOT exclusionary.) 
b. White blood cell, absolute neutrophil, or platelet count outside the local 
laboratory-defined limits of normal. Subjects may be included at the 
investigator’s discretion for values that are not clinically significant (ie., do not 
require any repeat or follow-up). 
c. Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-
defined upper limit of normal. (Subjects may be included at the investigator’s 
discretion for values that are not clinically significant.) 
d. Infected with HIV. 
e. History of a severe allergic reaction or anaphylaxis. 
f. Severe asthma (defined as asthma that is unstable or required emergency care, 
urgent care, hospitalization, or intubation during the past 2 years, or that has 
required the use of oral or parenteral corticosteroids at any time during the past 2 
years). 
g. Pre-existing autoimmune or antibody-mediated diseases including but not limited 
to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, 
Sjogren’s syndrome, or autoimmune thrombocytopenia. 
h. Known immunodeficiency syndrome. 
i. Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at 
immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive 
drugs within 30 days of day 0. 
j. Known asplenia or functional asplenia. 

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k. Clinical signs of malnutrition.  
l. Receipt of immunoglobulins and/or blood products within the past 6 months. 
7. Any history of menses. 
8. Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects 
the ability of the subject to understand and comply with the study protocol. 
9. Parental/guardian study comprehension examination score of <80% correct or per 
investigator discretion. 
10. Receipt of a live vaccine or a killed vaccine within the past 2 weeks prior to study agent 
administration. 
11. Known allergies or contraindication to dihydroartemisinin-piperaquine. 
12. Use or known need at the time of pre-enrolment (DP administration) of concomitant 
prohibited medication, including:  
a. Antimicrobial agents of the following classes (systemic use only): 
i. Macrolides (e.g. erythromycin, clarithromycin, azithromycin, 
roxithromycin) 
ii. Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin) 
iii. Pentamidine 
b. Antiarrhythmic agents (e.g. amiodarone, sotalol) 
c. Antihistamines (e.g. promethazine) 
d. Antifungals (systemic): ketoconazole, fluconazole, itraconazole 
e. Antiretrovirals: Saquinavir 
f. Diuretics (e.g. hydrochlorothiazide, furosemide) 
g. Antipsychotics (neuroleptics): haloperidol, thioridazine 
h. Antidepressants: imipramin, citalopram, escitalopram 
i. Antiemetics: domperidone, chlorpromazine, ondansetron   
13. Increased risk of salivary gland hypofunction (dryness of the mouth, swelling under the 
tongue and/or below the ear, halitosis) 
14. History of any other illness or condition which, in the investigator's judgment, may 
substantially increase the risk associated with the subject’s participation in the protocol or 
compromise the scientific objectives, or other condition(s) that, in the opinion of the 
investigator, would jeopardize the safety or rights of a subject participating in the trial, 
interfere with the evaluation of the study objectives, or render the subject unable to 
comply with the protocol. 
If enrollment of subjects (minimum age of 5 months) is completed by November 2022, then 
there is no chance of overlap between subjects in the MAb trial and those potentially eligible for 
RTS,S/AS01 (who need to be 6–12 months of age), if the RTS,S/AS01 vaccine is introduced in 
the entirety of Siaya county in June 2023 (see section 4.1). Should the anticipated timeline for 
RTS,S/AS01 routine introduction in all of Siaya county shift earlier, we will re-evaluate 
eligibility of our MAb trial subjects, to ensure that participation in the MAb trial would not 

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prevent anyone from receiving RTS,S—see exclusion criterion number 6 above. For example, if 
RTS,S implementation were scheduled for March 2023, we would add an exclusion criterion that 
subjects need to be at least 12 months of age (and thus ineligible for RTS,S) by March 2023. If 
children <12 months of age are excluded from enrolment in part 2 of the trial, enrolment will no 
longer be stratified by age. 
 
Inclusion of Vulnerable Participants 
Children: L9LS was evaluated in a phase 1 clinical trial to evaluate safety and protective 
efficacy of L9LS in healthy, malaria-naive adults. The results showed that L9LS is highly 
protective at a low dose given by the SC route, is safe and well tolerated and has favorable PK 
(see summary of safety data in section 2.3.1).15 L9LS was also evaluated in an ongoing phase 2 
clinical trial in Mali to evalute the safety and protective efficacy of L9LS in healhy children aged 
6-10 years. As described in Section 2.2.1.3, the results of the first year of the Mali trial 
demonstrated that SC administration of L9LS to children was protective against P. falciparum 
infection and clinical malaria over a 6-month malaria season without evident safety concerns. As 
noted in Section 2.3.1, the Mali trial was extended a second year starting in June 2023. 
Approximately 90% of participants were re-enrolled in the extension and were re-randomized 
within their original study arms and received placebo or L9LS at the dose they received in year 1 
(150 mg or 300 mg; or 150 mg for children who received placebo in year 1). The second SC 
administration of L9LS was well tolerated and there have been no safety concerns to date. 
Children aged 5–59 months in Kenya are at high risk for malaria infection and clinical disease. 
Previous research in the study area has indicated that children aged 5 to 17 months had on 
average 3.06 malaria cases per year in 2019–2020.  
 
Children who have Z scores below -2 for weight-for-age (or BMI for older children) and/or for 
height-for-age will be excluded, as these children are likely to be malnourished and/or stunted. 
Children will also be excluded if they weigh <5 kg, which is the minimum weight for dosing 
with DP. For Part 1, children in the 5- to 10-years age group will be excluded if they weigh >30 
kg, as one of the dose groups will be 20 mg/kg; this will require 600 mg of L9LS to be given, up 
to 2 mL at each of 2 injection sites. Excluding children weighing >30 kg will allow us to avoid 
using more than 2 injection sites. In Part 2, children weighing >22.5 kg will be excluded, as they 
would receive less than the minimum desired 10 mg/kg with the proposed fixed dose of 225 mg. 
In the area surrounding the study site, according to recent survey data, 95% of children between 
4 and 5 years old weighed <20 kg.    
 
Illiterate Individuals: We anticipate that many individuals eligible for this study and their 
parents/guardians will be illiterate in English, so the study team will translate the consent into 
local languages when appropriate, as described in section 10.1. 

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Inclusion of Pregnant Women, Fetuses or Neonates 
Not applicable. 
 
Lifestyle Considerations 
Beyond the prohibited treatments and procedures listed in section 6.5, this study would not 
impact the lifestyle of the subjects.  
 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
pre-enrolled and dosed with DP. Late screen failures are those who are pre-enrolled and dosed 
with DP but do not get randomized to receive IP/placebo. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. 
 
Individuals who initially do not meet the criteria for participation in this trial (screen failure) 
because of an acute illness or a transient lab or other screening procedure findings 
(e.g., abnormal transient lab evaluation, has taken antimalarials within 2 weeks) may be 
rescreened or may repeat individual screening procedures at the investigator’s discretion. 
Rescreened subjects should be assigned the same subject number as for the initial screening. 
 
Strategies for Recruitment and Retention 
Study subjects will be selected based on the eligibility criteria described in sections 5.1 and 5.2. 
The total target sample size is 72 subjects for part 1 and 324 subjects in part 2. We expect to 
enroll all subjects for both parts of the study within the first 6 months of the study from August 
2022 through February 2023. Subject selection will not be limited based on sex, race, or 
ethnicity. 
 
As is customary for all studies conducted under the ongoing KEMRI and CDC collaboration, a 
series of community sensitization measures will be undertaken. Meetings will be coordinated 
with the local County Health Management Teams and among local community leaders (village 
chiefs/assistance chiefs) prior to training activities, in addition to the meetings with health 
facility and community health workers. Community meetings (barazas) will be held in the 
selected areas to explain the purpose of the study and what will happen as part of the study. 
During the meetings we will disseminate information about the purpose of the study and the 
procedures. After community sensitization, children will be recruited from the well child clinic 
or from communities surrounding the study clinic. Parents/guardians of children potentially 
eligible for inclusion will be approached and asked whether they would like to learn more about 

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the trial. Interested parents/guardians will have the trial explained, and if interested, the consent 
process will proceed as described in section 10.1.   
 
For the year 2 follow-on, 24 new participants will be recruited for the follow-on safety study 
(Part 1b) using the methods described above. For the part 2 extension, study participants who 
remain enrolled in the part 2 efficacy study will be invited to participate in the extension study 
before completing their last visit of the original study.    
 
Costs 
There are no costs associated with participation in this trial. 
 
Compensation 
Parents/guardians of participants will be reimbursed per visit for their travel expenses per 
KEMRI guidelines to minimize loss to follow-up and to prevent the family from incurring extra 
expenses in travel to and from the clinic for the purpose of participating in the study. Participants 
will receive 500 Kenyan shillings (KShs) per scheduled visit in part 1 and in part 2. In both part 
1 and 2, parents will also be provided with partial reimbursement (400 KShs) for sick visits, as it 
is important that we capture every malaria episode. If participants pre-enrolled at Kogelo 
Dispensary in part 2 come to Siaya for their IP adminsitration visits (Day 0 and/or Day 168), 
they will be reimbursed 700 KShs or offered free transport from Kogelo Dispensary. In addition, 
medication (typically essential drugs at outpatient facilities as listed in the pediatric guidelines) 
to treat illnesses during the course of the study will be provided to them free of charge by the 
study. 
 
In the year 2 follow-on study (both part 1b and the part 2 extension), participants will receive 
800 Kenyan shillings (KShs) per scheduled visit; parents will also be provided with partial 
reimbursement (600 KShs) for sick visits, given increased fuel prices in the study area. 
 
COVID-19 Risk Mitigation  
Given the ongoing risk posed by COVID-19 in Kenya, this trial will adopt mitigation measures 
put in place by other trials at the site. Measures have already been put in place to enable social 
distancing in the study clinic, including making a partition on the veranda of the clinic so that 
participants can be registered and reviewed in an open-air space. Only one participant will be 
seen at a given time in a study room. The emergency room has also been modified so that two 
children could be admitted for overnight observation or care, should the wards in the main 
hospital be overcrowded with potential COVID-19 patients.  
 
This study will be conducted while strictly adhering to the KEMRI-SERU guidelines (section 
3.2.5) on mitigation measures needed to minimize COVID-19 exposure to research participants, 
staff and the community.32 We will also adhere to any new Government, Kenya Ministry of 

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Health (MoH), or KEMRI-SERU directives on COVID-19 control measures which may come as 
new evidence emerges. All staff will be trained on infection prevention and control (IPC) for 
COVID-19 based on MoH and WHO guidelines. Study staff and participants will be screened for 
COVID-19 symptoms or possible exposure before conducting interviews or exams. Should the 
interviewer determine that a participant has potentially been exposed to or is infected with 
COVID-19, they will immediately alert the Hospital IPC team. During the conduct of study 
procedures IPC measures will be observed, including appropriate hand washing with soap and 
water or use of alcohol-based hand rubs/sanitizers, use of facemasks/gowns, and physical 
distancing of at least 1.5 meters in a well aerated room or in an open-air space. The study will 
provide all the necessary materials needed for effective IPC.  
 
6 
STUDY INTERVENTION 
 
Study Interventions(s) Administration 
 
Study Intervention Description 
The study intervention involves an initial administration of L9LS SC or placebo SC to all 
subjects. At six months, subjects in part 2 of the study will receive either a second dose of L9LS 
(half those in MAb groups) or placebo (other half of those in MAb groups and those in placebo 
group). During the part 2 extension, participants will receive 2 additional SC doses (either two of 
L9LS, one of L9LS and one of placebo, or two of placebo), 6 months apart, following their 
initial randomization.  
 
Dosing and Administration.  
Study agent and dosing will be dependent on the progress of the study and study arm assignment 
(Table 1). Total effective doses by subject weight for part 2 of the study are provided in Table 2 
(section 6.2.4). The dose escalation study dosing plan is described in section 0. Procedures for 
administration are described in section 6.1.2.4.  
 
Table 1. Study agent assignment and dosing by age group/arm 
Age group/arm 
Total 
Subjects 
Study Agent and Dose 
Part 1 
5 to 10 years 
12 
5 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
12 
10 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
12 
20 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
5 to 59 months 
12 
5 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
12 
10 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
12 
20 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 

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Part 1b 
5 to 71 months 
12 
30 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
12 
40 mg/kg L9LS SC (n=9) or placebo SC (normal saline; n=3) 
Part 2 
Arm 1 (5 to 17 
months of age) 
108 
10-20 mg/kg L9LS SC plus second dose of 10-20 mg/kg 
L9LS SC or second placebo dose at 6 months 
Arm 1 (18 to 59 
months of age) 
108 
10-20 mg/kg L9LS SC plus second dose of 10-20 mg/kg 
L9LS SC or second placebo dose at 6 months 
Arm 2 (5 to 59 
months of age) 
108 
Placebo (normal saline) SC plus second dose of placebo at 6 
months 
Part 2 Extension (year 2) 
Arm 1 (from part 
2 
108* 
20-40 mg/kg L9LS SC plus second dose of 20-40 mg/kg 
L9LS SC at 6 months 
Arm 2 (from part 
2 
108* 
20-40 mg/kg L9LS SC plus placebo dose at 6 months 
Arm 3 (from part 
2 
108* 
Placebo (normal saline) SC plus second dose of placebo at 6 
months 
*108 represents the maximum enrollment, as participants might already be lost to follow-up during part 2. 
6.1.2.1 
Dose Escalation 
In part 1 of the study, dose escalation will proceed in a stepwise fashion in each age-based 
cohort, with dosing in 5- to 59-month-olds proceeding only after confirmation of safety in the 
respective 5- to 10-year-old dosing group, as described in section 4.1 above. 
6.1.2.2 
Dose Limiting Toxicity 
Pausing and halting rules are provided in sections 8.4.5 and 8.4.6. 
6.1.2.3 
Dose Modifications 
Not applicable. 
6.1.2.4 
Drug Administration 
Prior to study agent administration on day 0, subjects will undergo vital signs measurement and a 
targeted physical examination (as needed based on signs, reported symptoms, or interim medical 
history). The assigned study agent will be administered as 1 or 2 SC injections, depending on 
total dose, in the upper inner thigh, abdomen, or triceps area (1 injection per arm/thigh when 2 
injections are required), using proper technique to ensure administration into SC fatty layer and a 
slow push to minimize discomfort or the excessive distention of overlying skin. The abdomen 

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may be used as an alternate injection site if the outer triceps area or inner thigh is not suitable. SC 
administration sites in the abdomen should be at least 2 inches apart from each other and at least 2 
inches away from the umbilicus. Because L9LS has a slight yellow tint, and the placebo (normal 
saline) is colorless, all syringes will be covered with transparent yellow tape by the study 
pharmacist prior to administration to maintain blinding. L9LS is more viscous than normal 
saline, so the study agents will only be administered to subjects by designated individuals who 
remain separate from the team of blinded investigators who conduct all subsequent follow-up 
study assessments. 
 
The first two subjects in each arm of the dose-escalation study in part 1 will be observed for at 
least 4 hours following completion of product administration, and subsequent subjects will be 
observed for at least 2 hours following completion of product administration. The first two 
subjects in each dose group in part 1b will be observed for two hours, and subsequent subjects 
will be observed for at least one hour following dosing. All subjects in the efficacy study and the 
part 2 extension will be observed for at least 60 minutes following completion of product 
administration. Prior to discharge from the clinic, vital signs will be recorded and subjects will 
be assessed for local reactogenicity (including pain/tenderness, swelling, redness, bruising, and 
pruritus at the site of injection) and systemic reactogenicity (including fever, feeling unusually 
tired or unwell, muscle aches, headache, chills, nausea, and joint pain). Any subject who is 
assessed as being unwell or has ongoing reactogenicity symptoms will be asked to remain in the 
clinic until evaluation and discharge by a study clinician. If necessary, the subject would be 
referred to the County hospital to evaluate for safety and possible treatment. Clinicians will 
follow any solicited adverse events that are ongoing until they have resolved. 
 
Preparation/Handling/Storage/Accountability  
 
Acquisition and Accountability 
Acquisition: L9LS and the normal saline placebo will be shipped from the US to the study site 
where administration will take place, in compliance with all FDA, US Department of 
Transportation, and United Nations transport guidelines for shipping biohazardous materials.  
 
Accountability: The study pharmacist will be responsible for maintaining an accurate record of 
the study arm codes, inventory, and an accountability record of study agent supplies. Electronic 
documentation as well as paper copies may be used. 
 
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 regulatory, 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 manufacturer in accordance with policies that apply 
to investigational agents. Partially used vials will not be administered to other subjects or used 

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for in vitro experimental studies. These vials will be disposed of in accordance with regulatory, 
institutional or pharmacy policy. 
 
Formulation, Appearance, Packaging, and Labeling 
L9LS 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. It is a sterile, aqueous, buffered solution that is filled into single -dose vials 
at 150 + 15 mg/mL to a target fill volume of 2.25 mL in a 3-mL vial. The formulation buffer is 
the same as the drug substance (DS). The drug product container closure system consists of Type 
I glass vials, chlorobutyl rubber stoppers, and seals purchased from approved manufacturers. 
Any diluent composition will be described in the IND. The placebo product will be sterile 
isotonic (0.9%) normal saline. The products will be prepared by an unblinded pharmacist and 
placed in a sterile syringe when preparing for SC administration. Because L9LS has a slight 
yellow tint, and the placebo (normal saline) is colorless, the pharmacist will cover all syringes 
with transparent yellow tape to maintain blinding. L9LS is more viscous than normal saline, so 
the study agents will only be administered to subjects SC by designated individuals who remain 
separate from the team of blinded investigators who conduct all subsequent follow-up study 
assessments.  
 
Vials of L9LS and placebo 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. 
 
Product Storage and Stability 
L9LS: L9LS vials should be stored frozen at −35°C to −15°C in a qualified, continuously 
monitored, temperature-controlled freezer.  The site pharmacist must promptly report any storage 
temperature excursions outside of the normal allowance for the storage device 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 VRCProductinquiries@nih.gov. 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 (VRCProductinquiries@nih.gov) 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. 
 

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Prior to preparation for SC administration, thaw and equilibrate vials for a minimum of 
90 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. 33  
 
After product preparation in a syringe, the prepared L9LS 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. 
Product may not be stored in direct sunlight. 33  
 
Placebo: Normal saline will be stored at room temperature in a controlled room per product 
standards. 
 
Preparation 
Study product will be prepared by an unblinded pharmacist. For Part 1, dosing will be weight-
based and the pharmacist will prepare one or two syringes to deliver doses of 5 mg/kg, 10 mg/kg, 
and 20 mg/kg. For those receiving 20 mg/kg L9LS, 2 mL syringes will be used so that a 
maximum of two injection sites will be used for those requiring up to 600 mg L9LS.  
 
For Part 2, three fixed doses of L9LS will be prepared depending on the participant’s weight 
band, as shown in Table 2. Because L9LS has a slight yellow tint, and the placebo (normal 
saline) is colorless, the pharmacist will cover all syringes with transparent yellow tape to 
maintain blinding. 
 
Table 2. Dosing of L9LS (10 to 20 mg/kg) by weight of child for part 2  
 
L9LS 10 to 20 mg/kg 
Subject 
weight (kg) 
Total dose, 
mg L9LS 
Effective dose 
in mg/kg 
5.00-7.50 
75 
10-15 
 
7.51-15.00 
150 
10-20 
 
15.01-22.50 
225 
10-15 
 
 
Weight data from a household survey in the study area indicated that the mean weight for 
children between 4 and 5 years = 15.7 kg (boys), with 95% of weights falling below 20 kg; thus, 
we do not anticipate any children <59 months will weigh >22 kg.  
 

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For the extension phase (year 2), dosing will be constrained to be within a 20–40 mg/kg range to 
test higher average doses for ADA and increase the chances for high efficacy, given the known 
dose-response relationship with mAbs. Depending on the child’s weight, one of three dosing 
bands will be selected, as shown in Table 3.  
 
Table 3. Dosing of L9LS (20 to 40 mg/kg) by weight of child for the extension phase  
L9LS Extension 20–40 mg/kgmg/kg 
Subject weight, 
kg 
Total dose 
Total volume, 
mL 
6 – 7.4 
225 
1.5 
7.5 – 14.9 
300 
2.0 
15 – 30  
600 
4.0 
Note: given current weights of part 2 participants, no child is expected to weigh more than 30 kg during the 
extension phase. 
 
For each injection order, the dose level and study arm code will be included in the pharmacy 
order. To prepare an injection, the pharmacist will follow the IP Preparation SOP. 
 
Measures to Minimize Bias: Randomization and Blinding 
 
Randomization 
Randomization lists for each randomized phase of the trial will be generated by the study 
statistician, and the randomization code lists will be maintained by a designated pharmacist at the 
study site where the study intervention will take place. 
 
Randomization is further described in section 9.5.1. 
 
Blinding 
Parts 1 and 2, as well as the follow-on (part 1 b and part 2 extension), of this trial will be 
conducted with a double blind. Because L9LS has a slight yellow tint, and the placebo (normal 
saline) is colorless, the pharmacy team will cover all syringes with transparent yellow tape to 
maintain blinding for all parts of the study. The subjects, the clinical staff, and the study team 
will be blinded to study treatment allocation, with the exception of designated individuals who 
administer the study agents and remain separate from the team of blinded investigators who 
conduct all subsequent follow-up study assessments. The study pharmacy team will be 
unblinded, and they are responsible for maintaining security of study treatment assignments. 

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Data will remain blinded until the last subject completes the final study visit for each phase of 
the study (part 1, part 1b, part 2, and the follow-on). Blinded subjects will then be informed 
about their study treatment assignment. 
 
Unscheduled unblinding, either intentional (e.g., in the case of a medical emergency in a subject) 
or unintentional, will be handled according to SOPs. Intentional and unintentional unscheduled 
unblinding will be documented in the appropriate source and/or research record and will include 
the reason for the unscheduled unblinding, the date it occurred, who approved the unblinding, 
who was unblinded, who was notified of the unblinding, and the plan for the subject.  
 
The principal investigator will report all cases of intentional and unintentional unscheduled 
unblinding to the DSMB in writing within 1 business day after site awareness via email to the 
DSMB mailbox (niaiddsmbia@niaid.nih.gov) outlining the reason for the unblinding and the 
date it occurred. The report will also be submitted to the IRBs. If an SAE has resulted in 
unblinding, this information will be included in the SAE Report. 
 
Study Intervention Compliance 
Study intervention administration will be documented by study staff.   
 
Concomitant Therapy 
All concomitant prescription and nonprescription (including over-the-counter, herbal, or 
traditional) medications taken during study participation will be recorded. For this protocol, a 
prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. 
 
Treatment with the following drugs and procedures will not be permitted unless discussed with 
and approved by the investigator: 
• Live or killed vaccines within 2 weeks of study agent administration. (In Kenya there are 
no routine vaccinations scheduled for 5- to 10-year-old children; see Appendix A) 
• Immunoglobulins for the duration of the study.  
• Receipt of any investigational product or co-enrollment in other clinical studies of 
investigational products. 
• Oral or IV corticosteroids at immunosuppressive doses (i.e., prednisone >10 mg/day for 6 
or more days) or immunosuppressive drugs for the duration of the study.  
 
Patients taking any of the following drugs at the time of enrolment will be excluded due to the 
potential for prolongation of the QT interval when used concomitantly with DP.  These drugs 
will not be prohibited at other time points in the follow-up period.  

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• Antimicrobial agents of the following classes (systemic use only): 
• Macrolides (e.g. erythromycin, clarithromycin, azithromycin, 
roxithromycin) 
• Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin) 
• Pentamidine 
• Antiarrhythmic agents (e.g. amiodarone, sotalol) 
• Antihistamines (e.g. promethazine) 
• Antifungals (systemic): ketoconazole, fluconazole, itraconazole 
• Antiretrovirals: Saquinavir 
• Diuretics (e.g. hydrochlorothiazide, furosemide) 
• Antipsychotics (neuroleptics): haloperidol, thioridazine 
• Antidepressants: imipramin, citalopram, escitalopram 
• Antiemetics: domperidone, chlorpromazine, ondansetron   
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
 
Discontinuation of Study Intervention 
Study intervention may be discontinued for a protocol-defined group or arm (in part 1) or an 
individual (in part 2) (i.e., pausing), or it may be discontinued for all subjects and enrollment 
suspended (i.e., halting). Pausing and halting are described in sections 8.4.5 and 8.4.6. Subjects 
who have already received the study agent at the time of a pause or halt will continue planned 
follow-up under the protocol. 
 
Participant Discontinuation/Withdrawal from the Study 
Plans for managing the involuntary withdrawal of a subject are provided in section 8.4.3. The 
reason for subject discontinuation or withdrawal from the study will be recorded on the case 
report form (CRF). 
 
Subjects who withdraw after receiving study agent but prior to study completion will be 
encouraged to attend an early termination visit, where they will complete as many of the 
procedures and evaluations indicated in the schedule of activities (section 0) as possible. 
 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
 

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The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the subject/parent/guardian and reschedule the missed 
visit within 7 days, counsel them on the importance of maintaining the assigned visit 
schedule, and ascertain if they wish to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject/parent/guardian (where possible, 3 telephone 
calls and/or home visits). These contact attempts should be documented in the subject’s 
medical record or study file.  
• Should the subject/parent/guardian continue to be unreachable, he or she will be 
considered to have withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
Screening and Pre-Enrollment Procedures 
At screening, the study staff will explain the study to prospective subjects’ parents/guardians, 
and complete a pre-screening process to determine whether children are eligible based on age, 
weight, and not taking prohibited medications. For potentially eligible children, study staff will 
take parents/guardians through the informed consent form and then administer them the study 
comprehension examination; if they pass and consent (section 10.1) to participate, study staff 
will further assess eligibility. Consent will be obtained before any study-related procedures are 
performed. Once a subject has consented a unique participant identification number (PID) will be 
assigned that will be used for the duration of the study. 
 
The following screening and pre-enrollment procedures and evaluations must be performed 
within 21 days of study intervention. Screening may take place over multiple visits if necessary 
or it could be combined with the pre-enrolment visit. As long as the physical exam, height and 
weight measurement, vital signs, medical history, and concomitant medications are done at the 
pre-enrolment visit, they do not necessarily need to be done at the screening visit, if the two are 
separate visits. 
• Confirmation of identity, age, and residency. 
• Complete review of medical history and medication use. 
• Complete physical examination, including height and weight. 
• Vital signs (temperature and pulse). 
• Blood collection via finger prick or venipuncture for screening evaluations: 
o HIV tests: 2 rapid diagnostic tests (RDTs), plus DNA PCR if the RDTs are 
discordant. A subject will be referred for medical care for 2 positive RDTs or a 

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positive PCR. If the PCR is negative, no further work-up will be done. Pre and 
post-test HIV counseling will be provided. 
o Hemoglobin typing. 
o Complete blood count (CBC) with differential. 
o ALT. 
o Cr. 
• Pre- and post-test HIV counseling. 
 
 For children who are still breastfeeding, their child health booklet will be checked for the 
mother’s HIV status. If the mother is HIV-positive and the child is not taking cotrimoxazole, the 
child will be referred for cotrimoxazole prophylaxis according to Kenyan MoH guidelines and 
excluded from the study. If the mother had a negative HIV test more than six months prior to the 
current date or no documented HIV test, the mother will be referred for HIV testing, per Kenyan 
MoH guidelines. If the mother refuses HIV testing, the child will still be enrolled. However, if 
study investigators subsequently become aware that the mother tested positive for HIV and the 
child is still breastfeeding (or was breastfeeding when the mother could have potentially 
transmitted the virus), the child will be referred for cotrimoxazole prophylaxis and followed for 
safety but no additional study products will be administered. 
 
A prospective subject who has any clinically significant abnormal finding and/or is diagnosed 
with a medical condition at screening or during the conduct of the study will be notified and 
referred for medical care. Per national requirements for reporting communicable diseases, 
positive test results for HIV will be reported to the local health department according to 
applicable laws and appropriate medical referrals initiated. The cost of initial and long-term 
treatment and care of medical conditions diagnosed during the screening process will not be 
reimbursed by the study but referrals to relevant specialist will be provided.  
 
Screening evaluations may be repeated as described in section 5.6, at the discretion of the 
investigator. If screening is completed outside the specified window, all screening procedures 
and evaluations must be repeated. If an individual screens and is enrolled into part 1 of the study 
but for any reason does not receive study agent, they may later consent to be screened and 
enrolled in part 2; otherwise, participation in part 1 is exclusionary for part 2. If the subject is 
still eligible at the end of the pre-enrolment visit, he/she will be given a three-day course of DP, 
directly observed each day, and a Day 0 (Enrolment) clinic appointment will be fixed for 14 to 
21 days after the first dose of DP. 
 
Enrollment: If the individual is eligible and agrees to participate, has completed a three-day 
course of DP, and returns 14 to 21 days after DP administration for their Day 0 (Enrolment) visit, 
he or she will be randomized to study product or placebo and will be considered enrolled. 

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Enrollment is defined as the time of randomization, immediately after which the subject will 
receive IP/placebo. The identification number will link subject samples and data collected 
throughout the study. 
 
Efficacy Assessments 
 
Clinical Evaluations 
The following clinical evaluations will be performed as efficacy assessments. 
 
Medical History and Medication Review: A complete review of all medical history and 
medications will be conducted at screening. Subsequent visits will include a targeted review of 
changes in medical history or medications since the last study visit. 
 
Physical Examination: A complete physical examination (including height and weight) will be 
done at screening. A targeted physical examination based on signs, reported symptoms, and 
medical history will be conducted at subsequent study visits. Weight will also be recorded on day 
0 prior to study agent administration. 
 
DP: At the end of the pre-enrollment visit, all subjects will be orally administered standard doses 
of DP presumptively to clear any possible Pf blood-stage infection prior to study agent 
administration. The dosing will be once per day and by weight as shown in Table 3. 
 
Table 3. Dosing schedule for dihydroartemisinin piperaquine 
Body Weight 
Dihydroartemisinin 
Piperaquine 
Number of 
tablets (160 
mg/20 mg) 
Number of 
tablets (320 
mg/40 mg) 
5 to <8 kg 
20 mg 
160 mg 
1 tablet 
½ tablet 
8 to <11 kg 
30 mg 
240 mg 
1.5 tablets 
¾ tablet  
11 to <17 kg 
40 mg 
320 mg 
2 tablets 
1 tablet 
17 to < 25 kg  
60 mg 
480 mg 
3 tablets 
1.5 tablets  
25 to <36 kg 
80 mg  
640 mg 
4 tablets 
2 tablets  
 
 
Randomization Procedures: Randomization is described in sections 6.3.1 and 9.4.1. 
 
Study Agent Administration and Monitoring: Study agent will be administered according to 
the assigned arm and monitoring will be performed as described in section 6.1. 
 
Illness Visit: A subject will be instructed to come in for an unscheduled visit if he or she has 
symptoms of malaria or other symptoms. The subject will be evaluated by the study team and 

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treated according to local guidelines. At an illness visit, the subject may undergo review of 
medical history and concomitant medications, a focused physical exam for symptoms of malaria 
or other diseases, vital sign measurement, and a fingerprick/heelprick blood collection for blood 
smear for malaria diagnosis as well as a dried blood spot for Pf RT-PCR for research purposes.  
 
Malaria Diagnosis and Management: If a subject has a malarial infection, we will share these 
results with the subject and provide standard treatment in accordance with the recommendations 
of the Kenyan Division of National Malaria Program guideline. RT-PCR is not commonly used 
for routine malaria diagnosis. 
 
Biospecimen Evaluations 
Blood will be collected under this protocol by the following methods: 
• Venipuncture will be performed with single-use needles. Venous blood samples will be 
used as follows: 
o Safety evaluations described in section 8.3. 
o Shipment to the research laboratories in Kenya and the US for evaluation 
(including assays described in section 8.2.3) and storage. 
o Blood smear and dried blood spot for Pf RT-PCR if unable to obtain ample 
sample from finger prick. 
• Finger or heel prick will be performed using single-use disposable lancets. Finger/ heel 
prick blood samples will be used as follows: 
o Blood smear and dried blood spot for Pf RT-PCR. 
o Biochemical and hematologic tests for safety described in section 8.3. 
 
The amount of blood drawn for research purposes will be within the limits allowed for research 
subjects by the NIH Clinical Center: no more than 5 mL/kg in a single day, and no more than 9.5 
mL/kg over any 8-week period. 
 
The collection schedule, volumes, and test tubes are presented in section 0. 
 
Correlative Studies for Research/Pharmacokinetic Studies 
The following evaluations will be performed according to the schedule presented in section 0. 
 
Blood smear: Thick and thin blood smears will be prepared and analyzed by the standard WHO 
method (section 2.2.2.3) to identify Pf infection for the primary endpoint and to identify clinical 
malaria for a secondary endpoint. This evaluation will be performed within 48 hours of 
collection, unless the subject is displaying signs or symptoms of clinical malaria in which case 
the blood smear will be analyzed at the time of the scheduled or unscheduled visit. For 

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asymptomatic participants with positive blood smears, a home visit will be conducted within 72 
hours of the blood draw to notify the family and provide treatment.  
 
Pf RT-PCR: RT-PCR will be performed to identify Pf infection as a secondary endpoint. This 
evaluation will be performed at the University of Washington in the US on coded dried blood 
spots. Real-time PCR might also be performed by KEMRI on the dried blood spots. 
 
PK studies: Blood L9LS concentrations will be measured by Meso Scale Discovery LLC-based 
automation platform. The concentration at the visit prior to the first Pf infection will be used to 
assess L9LS-mediated protection. This evaluation will be performed at the NIAID. 
 
ADA detection: Assays for detection of ADA will be performed at specified timepoints 
(section 0) following product administration and compared to baseline status. This evaluation 
will be performed at the NIAID. 
 
Parasite genotyping: For subjects who become infected during the study, coded blood samples 
collected around the time of the first infection will be used to perform a genotypic sieve analysis 
to analyze sequences of breakthrough parasites (section 9.5.11). This evaluation will be 
performed by Dr. Daniel Neafsey at the Harvard School of Public Health. 
 
Pf-specific antibodies: Levels of antibodies specific for pre-erythrocytic and blood-stage Pf 
antigens will be measured by NIH in stored serum samples collected at enrollment and at one of 
the subsequent blood draws to explore the impact of L9LS on naturally acquired humoral 
immunity to malaria.  
 
Samples for Genomic Analysis 
8.2.4.1 
Description of the Scope of Genomic Analysis 
Genetic testing performed in this protocol will be limited to analyzing the genetic material of 
infection-inducing parasites in blood samples. No human genetic analyses will be performed. 
8.2.4.2 
Description of How Privacy and Confidentiality of Medical 
Information/Biological Specimens Will Be Maximized 
Privacy and confidentiality of medical information and biological samples is described in section 
10.3. 
8.2.4.3 
Management of Results 
As no human genetic analyses will be performed in this protocol, no genetic results will be 
returned to subjects. 

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8.2.4.4 
Genetic Counseling 
Not applicable. 
 
Safety and Other Assessments 
The following study procedures and evaluations will be done according to the schedule in 
section 0 to monitor safety and support the understanding of the study intervention’s safety. The 
assessment and collection of safety events such as AEs are described in section 8.4.2. 
 
Physical Examination: As described in section 8.2.1, physical examination will also be 
performed for assessment of safety. 
 
Vital Signs: Vital signs (temperature and heart rate) will be collected at visits, including before 
and after study agent injection, as described in section 8.2.1. 
 
Safety Blood Laboratory Evaluations: The following safety laboratory evaluations will be 
performed at a frequency presented in section 0: 
• CBC with differential. 
• ALT, Cr. 
 
Safety Definitions, Management, and Sponsor Reporting 
 
Definitions 
Adverse Event: An 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 the research, whether or not 
considered related to the research. 
 
Adverse Reaction: An AR means any AE caused (see “Causality” below) by a study agent. ARs 
are a subset of all suspected adverse reactions (SARs; defined below) where there is reason to 
conclude that the study agent caused the event. 
 
Suspected Adverse Reaction: SAR means any AE for which there is a reasonable possibility 
that the study agent caused the AE. 
Per US FDA guidance:   
For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to 
suggest a causal (see “Causality” below) relationship between the study agent and the AE. A 
SAR implies a lesser degree of certainty about causality than an AR, which means any AE 
caused by a study agent. 
 

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SARs are the subset of all AEs for which there is a reasonable possibility that the study agent 
caused (see “Causality” below) the event. Inherent in this definition, and in the requirement 
to report SARs, is the need for the sponsor to evaluate the available evidence and make a 
judgment about the likelihood that the study agent actually caused the AE.  
 
The sponsor is responsible for making the causality judgment. 
 
Serious Adverse Event (SAE): 
• is an AE that results in death. 
• is an AE that is a life-threatening event (places the subject at immediate risk of death 
from the event as it occurred). 
• is an AE that requires inpatient hospitalization or prolongs an existing hospitalization. 
NOTE: 
o Hospitalization is considered required if outpatient treatment would generally be 
considered inappropriate. 
o Same-day surgical procedures that are required to address an AE are considered 
hospitalizations, even if they do not involve an overnight admission. 
o Hospitalization due to a condition that has not worsened and that pre-dates study 
participation (e.g., elective correction of an unchanged baseline skin lesion), or 
due to social circumstance (e.g., prolonged stay to arrange aftercare), or that is 
planned/required “per protocol” AND that proceeds without prolongation or 
complication, is NOT considered an SAE by this criterion. 
• is, or results in, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• is a medically important event. 
NOTE: Medical and scientific judgment should be exercised. Events that significantly 
jeopardize the subject and/or require intervention to prevent one of the SAE outcomes 
listed above are generally considered medically important, and are thus SAEs. 
 
Unexpected Adverse Event: An AE is unexpected if it is not listed in the investigator’s 
brochure or package insert (for marketed products) at the frequency, AND specificity, AND 
severity that has been observed. 
NOTE: 
• Such events should also be evaluated for possible reporting as unanticipated problems 
(UPs) (see section 8.4.2.3.3 below). 
• Unexpected, as used in this definition, also refers to AEs or SARs that are mentioned in 
the investigator’s brochure as occurring with a class of drugs/biologics, or as anticipated 

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from the pharmacological properties of the study agent but are not specifically mentioned 
as occurring with the particular study agent under investigation. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is an SAR 
(defined above) that is both serious and unexpected. 
 
Unanticipated Problem: A UP is any incident, experience, or outcome that meets all the 
following criteria: 
1. 
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 
2. 
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 
3. 
Suggests 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. 
NOTE: 
o Per the sponsor, an SAE always meets this “greater risk” criterion. 
o An incident, experience, or outcome that meets the definition of a UP generally 
will warrant consideration of changes to the protocol or informed consent form, or 
to study procedures (e.g., the manual of procedures for the study), in order to 
protect the safety, welfare, or rights of participants or others. Some UPs may 
warrant a corrective and preventive action plan at the discretion of the sponsor or 
other oversight entities. 
 
Unanticipated Problem that is not an Adverse Event (UPnonAE): A UPnonAE belongs to a 
subset of UPs that: 
• meets the definition of a UP, AND 
• does NOT fit the definition of an AE or an SAE. 
NOTE: Examples of UPnonAEs include, but are not limited to: 
o a breach of confidentiality 
o subject departure from an isolation unit prior to meeting all discharge criteria 
o accidental destruction of study records 
o unaccounted-for study agent 

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o overdosage, underdosage, or other significant error in administration or use of 
study agent or intervention, even if there is no AE/SAE 
o development of an actual or possible concern for study agent purity, sterility, 
potency, dosage, etc. 
NOTE: A decision to temporarily quarantine, or to permanently not use all or 
part of study agent supply due to an unexpected finding or event (e.g., 
particulate, cloudiness, temperature excursion), even if there is no known or 
proven issue (i.e., out of an “abundance of caution”), is considered a 
UPnonAE. 
 
Protocol Deviation: Any change, divergence, or departure from the IRB-approved research 
protocol. 
1. 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. 
2. 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. 
 
Noncompliance: 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 IRBs, whether intentional or not. 
1. Serious noncompliance: Noncompliance, whether intentional or not, that results in harm 
or otherwise materially compromises the rights, welfare and/or safety of the subject. 
Noncompliance that materially affects 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. 
2. Continuing noncompliance: A pattern of recurring noncompliance 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. Such 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). 
 
Documenting, Assessing, Recording, and Reporting Events 
ALL AEs, including those that may appear to have a non-study cause (see “Causality” below), 
will be documented (e.g., on the clinical chart/progress notes/clinical laboratory record), 

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recorded (e.g., in the study-specified CRF/research database), and reported (e.g., cumulatively 
from the research database, or according to protocol-specified expedited reporting mechanism) to 
the sponsor from the time informed consent is obtained through the timeframe specified below. 
At each contact with the subject, information regarding AEs will be elicited by open-ended 
questioning and examinations. 
 
AEs and SAEs will generally be recorded, assessed, and reported according to the timeframes 
outlined in Table 4.  
 
Table 4. Standard event recording, assessment, and reporting timeframes. 
Event type 
Record, assess, and report through 
Related SAEs 
End of subject participation in study, or if study 
personnel become aware thereafter 
Unrelated SAEs 
End of subject participation in study  
Non-serious AEs of grade 3 or 
higher, irrespective of relatedness 
End of subject participation in study 
All malaria episodes, whether 
related or not, including 
asymptomatic parasitemias, 
irrespective of seriousness or 
severity  
End of subject participation in study 
Related non-serious AEs of grade 1 
and 2 
End of subject participation in study 
Unrelated non-serious AEs of 
grade 1 and 2 
End of subject participation in study in part 1 and 
part 1b; 28 days following IP dosing in part 2 and 
part 2 extension 
8.4.2.1 
Investigator Assessment of Adverse Events 
The investigator will assess all AEs with respect to seriousness (according to SAE definition 
above), severity (intensity or grade, see below), and causality (relationship to study agent and 
relationship to participation in the research, see below). 
8.4.2.1.1 Severity Grading 
The investigator will grade the severity of fever (by non-oral temperature reading) and each 
blood laboratory testing AE according to the “Adverse Event Grading Scale” (see Appendix B).  
 

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Events that are not gradable using the “Adverse Event Grading Scale” (e.g. seizures) will be 
graded according to the Common Toxicity Criteria for Cancer Research table version 2.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf) 
 
Events that are NOT gradable using either of the above specified tables will be graded as 
follows: 
• Mild = grade 1 
• Moderate = grade 2 
• Severe = grade 3 
• Potentially life threatening = grade 4 
• Death = grade 5 
 
NOTE: A subject death should always be reported as grade 5. 
8.4.2.1.1.1 Laboratory Value Assessment and Clinical Significance Criteria 
ALL abnormal lab values of grade 3 or above are REPORTABLE as AE or SAE (if applicable, 
i.e. if the child needs admission or other SAE criteria are fulfilled). 
Grade 1 and 2 abnormal laboratory values will be considered CLINICALLY SIGNIFICANT, and 
will be recorded in the research database, and reported, ONLY if they meet ONE or more of the 
following criteria:  
• result in a study agent dosage adjustment, interruption, or discontinuation 
• are accompanied by clinically abnormal signs or symptoms that are likely related to the 
laboratory abnormality (e.g., clinical jaundice) 
• indicate a possible organ toxicity (e.g., elevated serum creatinine [Cr]) 
• result in additional/repeat testing or medical intervention (procedures/treatments) (e.g., 
electrolytes have to be repeated after potassium supplementation for hypokalemia) 
• are considered clinically significant by the investigator or SMM 
8.4.2.1.2 Causality 
Causality (likelihood that the event is caused by the study agents) will be assessed by the 
principal investigator or designee considering the factors listed under the following categories: 
 
Definitely Related 
• reasonable temporal relationship 
• follows a known response pattern 
• clear evidence to suggest a causal relationship 
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Probably Related 
• reasonable temporal relationship 
• follows a suspected response pattern (based on similar agents) 
• no evidence of a more likely alternative etiology 
 
Possibly Related 
• reasonable temporal relationship 
• little evidence for a more likely alternative etiology 
 
Unlikely Related 
• does not have a reasonable temporal relationship 
AND/OR 
• there is good evidence for a more likely alternative etiology 
 
Not Related 
• does not have a temporal relationship 
AND/OR 
• definitely due to an alternative etiology 
 
Note: Other factors (e.g., dechallenge, rechallenge, if applicable) should also be considered for 
each causality category when appropriate. Causality assessment is based on available 
information at the time of the assessment of the AE. The investigator may revise the causality 
assessment as additional information becomes available. 
 
Causality assessment will be reviewed by the sponsor. The sponsor may make a separate and 
final determination on the “reasonable possibility” that the event was “related” (comprising 
definitely, probably, and possibly related) or “unrelated” (comprising unlikely and not related) to 
the study agent, in keeping with applicable (US FDA) guidance on sponsor IND safety reporting. 
8.4.2.2 
Recording of Events 
AEs will be promptly recorded in the research database, regardless of possible relationship to 
study interventions. If a diagnosis is clinically evident (or subsequently determined), the 
diagnosis rather than the individual signs and symptoms or laboratory abnormalities will be 
recorded as the AE. The investigator will review events regularly to ensure they have been 
captured correctly and to perform assessment of events individually and cumulatively to assess 
possible safety trends. 

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8.4.2.3 
Investigator Reporting Responsibilities 
The principal investigators and/or equally qualified designees will check daily for events that 
may require expedited reporting.  
 
The principal investigators and/or equally qualified designees will also monitor all accumulating 
data no less than weekly, or according to superseding NIH or NIAID policy, whichever is more 
frequent. 
 
Data will be reviewed by the principal investigators/designees on a regular basis for accuracy 
and completeness.  
 
Data will be submitted to the sponsor in keeping with all applicable agreements and when 
requested, such as for periodic safety assessments, review of IND annual reports, review of IND 
safety reports, and preparation of final study reports. 
 
The principal investigators and/or other study designee will ensure prompt reporting to safety 
oversight bodies (e.g., Clinical Safety Office [CSO], ISM, DSMB), regulatory entities, and 
stakeholders as specified below, and according to any additional requirements or agreements. 
8.4.2.3.1 Adverse Events 
Unless otherwise specified above, AE data will be entered into the research database no less than 
every other week and will include all data through 1 week prior to database entry. AEs will be 
reported in the form of a line list and sent periodically to the different IRBs/ regulatory 
authorities. 
8.4.2.3.2 Serious Adverse Events (Expedited Reporting) 
Unless otherwise specified above, all SAEs (regardless of relationship and whether or not they 
are also UPs) must be reported to the CSO as specified by the CSO (e.g., Research Electronic 
Data Capture [REDCap] system; use the Safety Expedited Report Form [SERF]/email if 
REDCap is not available). If the preferred/indicated mechanism for reporting is not available, the 
CSO/SMM should be contacted by telephone, fax, or other reasonable mechanism to avoid 
delays in reporting. 
 
CSO CONTACT INFORMATION: 
Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
Phone: 301-846-5301 
Fax: 301-846-6224 
Email: rchspsafety@mail.nih.gov  

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https://crimsonredcap.cc.nih.gov/redcap/index.php 
 
Unless otherwise specified above, deaths, related SAEs, and immediately life-threatening SAEs 
must be reported to the CSO promptly, and no later than the first business day following the day 
of study personnel awareness. All other unrelated SAEs must be reported to the CSO no later 
than the third business day following the day of study personnel awareness and to SERU within 
48 hours of the PI becoming aware of the SAE. 
 
KEMRI SERU Reporting 
Unless specified, all SAEs regardless of whether related or unrelated must be reported to the 
SERU via email (seru@kemri.org/kemriseru18@gmail.com) within twenty-four (24) hours 
after the PI becomes aware of the event. Follow-up reports should be submitted as soon as more 
information becomes available.  
 
Kenya Pharmacy and Poisons Board (KPPB) Reporting 
KPPB reporting follows the Guidelines for the Conduct of Clinical Trials in Kenya 
https://pharmacyboardkenya.org/files/?file=Guidelines%20for%20Conduct%20of%20Clinical%
20Trials%20in%20Kenya%202nd%20Revision.pdf (Section 16): All SAEs (including life-
threatening and fatal SUSARs) are to be reported to KPPB within 7 days via an online portal at 
http://www.ctr.pharmacyboardkenya.org/ 
 
All SAEs are also submitted to KEMRI SERU and KPPB in a line list during continuation 
approval requests. 
 
If an individual subject experiences multiple SAEs in a closely timed/overlapping “cause-and-
effect” (cascade) sequence, the principal investigators, after careful evaluation, will report 
ONLY primary/precipitating event(s) individually. SAEs that are determined to be definitely 
secondary to other SAEs will be detailed in the narrative portion of the report of the relevant 
primary/precipitating SAE. A clinical rationale and findings to support such reporting should be 
part of the narrative.  
 
For each SAE report, the research database entry MUST match the corresponding entries on the 
SAE report (e.g., start and stop dates, event type, relationship, and grade), and must be updated 
if necessary (e.g., if the SAE report was generated after the corresponding AE was entered in the 
research database). 
 
Unless otherwise specified above, SAEs that have not resolved by the end of the per-protocol 
follow-up period for the subject are to be followed until final outcome is known (to the degree 
permitted by the IRB-approved informed consent form). If it is not possible to obtain a final 
outcome for an SAE (e.g., the subject is lost to follow-up), and to update the CSO, the last 

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known status and the reason a final outcome could not be obtained will be recorded by the 
investigator on an SAE report update and the CRF. 
8.4.2.3.3 Unanticipated Problems 
Unless otherwise specified above, UPs (as defined in this protocol, or as defined by the IRB[s] of 
record, whichever definition is more conservative) that are also AEs or SAEs, must be reported 
to the CSO (by REDCap, or by email and SERF if REDCap is not available) no later than when 
they are due to be reported to the IRB(s). 
 
UPnonAEs are NOT reported to the CSO but must be reported to the Clinical Trials 
Management (CTM) group according to their requirements and preferred methods. If the 
UPnonAE raises a significant potential subject safety concern, the SMM should be consulted by 
email or phone no later than when reports are made to the CTM. 
8.4.2.4 
Sponsor’s Reporting Responsibilities 
Events reported to the sponsor will be promptly evaluated and will be reported as required 
according to FDA IND safety reporting guidance and regulations. IND safety reports will be sent 
to other investigators conducting research under the same IND and will be shared with other 
stakeholders according to applicable agreements. 
 
The sponsor will also submit an IND annual report of the progress of the investigation to the 
FDA as defined in 21 CFR 312.33. 
 
All UPs will be evaluated by the sponsor, and a summary of the event, and any necessary 
(corrective/preventative) actions, will be distributed to investigators conducting research under 
the same IND as may be relevant and appropriate. 
 
Withdrawal Criteria for an Individual Subject 
An individual subject will be withdrawn from the study for any of the following: 
• An individual subject’s/parent’s/guardian’s decision. (The investigator should attempt to 
determine the reason for the decision if the participant guardian is willing to disclose the 
reason.) 
• Non-compliance with study procedures to the extent that it is potentially harmful to the 
subject or to the integrity of the study data. 
• A change in the subject’s condition as follows: 
o Loss of the ability of the subject/parent/guardian to provide informed consent. 
• The investigator determines that continued participation in the study would not be in the 
best interest of the subject. 

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8.4.3.1 
Re-enrollment and Unplanned Procedure Repetition 
Unless otherwise specified within this protocol (e.g., rescreening as described in section 5.6), 
each person who is a subject in this study may be enrolled and may pass through each step and 
process outlined in the protocol, only ONCE (i.e., subjects may not “go back” and repeat a 
protocol step already completed). On a case-by-case basis, a request for re-enrollment, or for 
repetition of a protocol step or procedure already completed, may be submitted to, reviewed by, 
and approved by the SMM in writing. The SMM may also recommend or require consultation of 
the IRBs, DSMB, and/or ISM. 
8.4.3.2 
Replacement of Withdrawn Subjects or Subjects Who Discontinue Study 
Agent 
In the dose-escalation study, subjects withdrawn prior to the day 7 safety evaluation will be 
replaced. In the efficacy study, subjects withdrawn prior to study agent administration will be 
replaced. Subjects who are withdrawn prior to or during the year 2 extension study will not be 
replaced. 
 
All subjects exposed to study agents MUST be included in the safety dataset. 
 
Additional Safety Oversight 
8.4.4.1 
Safety Review and Communications Plan 
A safety review and communication plan (SRCP) is required for this protocol. The SRCP is an 
internal communications document between the principal investigators and the CSO, as the 
sponsor representative, which delineates key safety oversight responsibilities of the principal 
investigators, the CSO, and other stakeholders. The SRCP includes a plan for conducting 
periodic safety surveillance assessments by the CSO. 
8.4.4.2 
Sponsor Medical Monitor 
An SMM, representing the sponsor, has been appointed for oversight of safety in this clinical 
study. The SMM will be responsible for performing safety assessments as outlined in the SRCP. 
8.4.4.3 
Oversight Committees 
8.4.4.3.1 Independent Safety Monitor in Kenya 
The ISM is an expert who does not have direct involvement in the conduct of the study and has 
no significant conflicts of interest as defined by NIAID policy. An ISM in Kenya will review the 
study prior to initiation and will be available to advise the investigators on study-related medical 
issues and act as a representative for the welfare of the subjects. The ISM will conduct 
independent safety monitoring. The ISM is an expert in the oversight of clinical trials conducted 
in Kenya and in pediatrics, specifically in the population under study in Kenya.  

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All deaths, SAEs, UPs, and FDA IND safety reports will be reported by the principal 
investigators to the ISM prior to or at the same time they are submitted to the IRBs or CSO 
unless otherwise specified herein. The ISM will be notified immediately if any pausing rule is 
met. The principal investigators will also notify the ISM if intentional or unintentional 
unblinding occurs. If the ISM is unblinded to the study agent given to an individual subject 
during medical management, the ISM will report that unblinding to the DSMB Executive 
Secretary. The ISM will not have access to unblinded data reported to the DSMB.  
8.4.4.3.2 Data and Safety Monitoring Board 
The NIAID intramural DSMB includes independent experts that do not have direct involvement 
in the conduct of the study and have no significant conflicts of interest as defined by NIAID 
policy. The DSMB will review the study protocol, consent documents, and investigator brochure 
prior to initiation and twice a year thereafter, or as may be determined by the DSMB. 
Additionally, the DSMB will conduct 1 interim analysis when safety data are available from the 
dose-escalation study subjects (section 9.5.8). 
 
The DSMB may convene additional reviews as necessary. The DSMB will review the unblinded 
study data as needed to evaluate the safety, efficacy, study progress, and conduct of the study.  
 
All deaths, SAEs, UPs, and IND safety reports will be reported to the DSMB at the same time 
they are submitted to the IRBs and CSO unless otherwise specified herein.  
 
All cases of intentional or unintentional unblinding will be reported to the DSMB not later than 1 
business day from the time of study personnel awareness.  
 
The principal investigators will notify the DSMB at the time pausing or halting criteria are met 
and obtain a recommendation concerning continuation, modification, or termination of the study.  
 
Pausing Rules 
“Pausing” is a temporary discontinuation of study intervention/treatment/dosing 
(agent/placebo/procedure, etc.) in a protocol-defined group or “arm” (in part 1 or part 1b) or an 
individual (in part 2 and the follow-on) until a decision is made to either resume or permanently 
discontinue such activity. Subjects continue to be followed for safety during a pause. 
 
The pausing criteria in this study include the following: 
• A subject experiences 2 AEs of grade 3 or higher that are unexpected (per the 
investigator’s brochure or product label) and possibly, probably, or definitely related to a 
study agent. 
 

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The principal investigators or the CSO may also pause dosing/study interventions for one or 
more subjects for any safety issue. The study safety oversight bodies (e.g., DSMB, ISM) may 
recommend a pause to the CSO. 
8.4.5.1 
Reporting a Pause 
If a pausing criterion is met, a description of the AE(s) or safety issue must be reported by the 
principal investigators within 1 business day to the CSO and the IRBs according to their 
requirements. The principal investigators will also notify the DSMB and ISM. In addition, the 
CSO or designee will notify all other site investigators by email or through the specified 
pathway. 
8.4.5.2 
Resumption Following a Pause 
The CSO, in collaboration with the principal investigators, the DSMB, and the ISM, will 
determine if study activities, including agent administration and/or other study interventions may 
be resumed, and any additional modifications or requirements that may apply, for the impacted 
subject(s), or whether the events that triggered the pause require expansion to a study halt (see 
below). 
 
The CSO or sponsor designee will notify the principal investigators of the decision. The 
principal investigators will notify the IRBs of the decision according to the IRBs’ processes. 
8.4.5.3 
Discontinuation of Study Agent 
If a decision is made to permanently discontinue study agent administration, any subject who has 
received the study agent or undergone any other study intervention/treatment will continue to be 
followed for protocol-specified safety assessments or as clinically indicated, whichever is more 
conservative. 
 
Halting Rules for the Protocol 
“Halting” is discontinuation of study intervention/treatment/dosing (agent/placebo/procedure, 
etc.) for all subjects in a study and suspension of enrollment until a decision is made to either 
resume or permanently discontinue such activity. Subjects continue to be followed for safety 
during a halt. 
 
The halting rules are: 
• 
PART 1 AND PART 1B: Two or more subjects experience the same or similar SAEs 
that are  unexpected and possibly, probably, or definitely related to a study agent; OR 
ONE subject experiences an SAE of Grade 4 severity or greater that is unexpected (per 
the investigator’s brochure or product label) and possibly, probably, or definitely related 
to a study agent; OR  

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• 
PART 2 AND THE EXTENSION PHASE: Three or more subjects experience the same 
or similar SAEs that are unexpected and possibly, probably, or definitely related to a 
study agent; OR ONE subject experiences an SAE of severity 4 or greater that is 
unexpected (per the investigator’s brochure or product label) and possibly, probably, or 
definitely related to a study agent; 
OR 
• Any safety issue that the principal investigators or the CSO determines should halt the 
study (in Parts 1, 1b and 2 and the follow-on). The study safety oversight bodies (e.g., 
DSMB) may recommend a halt to the CSO. 
 
In addition, the FDA, IRBs, or any regulatory body having oversight authority may halt the study 
at any time. The DSMB or ISM may recommend a study halt. 
8.4.6.1 
Reporting a Study Halt 
If a halting criterion is met, a description of the AE(s) or safety issue must be reported by the 
principal investigators, within 1 business day to the CSO and the IRBs according to their 
requirements. The principal investigators will also notify the DSMB and ISM. In addition, the 
CSO or designee will notify all other site investigators by email or through the specified 
pathway. 
8.4.6.2 
Resumption of a Halted Study 
The CSO, in collaboration with the principal investigators and DSMB and ISM will determine if 
study activities, including enrollment, study agent administration, and/or other study 
interventions, may be resumed and any additional modifications or requirements that may apply. 
 
The CSO or sponsor designee will notify the principal investigators of the decision. The 
principal investigators will notify the IRBs of the decision according to the IRBs’ processes. 
8.4.6.3 
Discontinuation of Study Agent 
If a decision is made to permanently discontinue study agent administration, any subjects who 
have received study agent or undergone any other study intervention will continue to be followed 
for protocol-specified safety assessments or as clinically indicated, whichever is more 
conservative. 
 
Unanticipated Problems 
 
Definition of Unanticipated Problems 
The definition of a UP is provided in section 8.4.1. 

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 Unanticipated Problem Reporting  
The investigator will report UPs to the IRBs as described in section 8.6.1. 
 
ADDITIONAL REPORTING REQUIREMENTS 
 
Protocol Deviation Reporting  
 
8.6.1.1 
Reporting to NIAID 
The following will be reported within 7 calendar days of any investigator or individual 
associated with the protocol first becoming aware: 
• Actual or suspected noncompliance. Determinations by the IRB(s) of serious and/or 
continuing non-compliance by an NIH investigator must also be reported to the NIH 
within 7 calendar days. 
• Actual or suspected major deviation.  
• 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 sponsor, NIH or NIAID leadership, or any regulatory 
agency. 
 
Any death of a research subject that is possibly, probably, or definitely related to the research 
must be reported within 24 hours of the investigator becoming aware of the death. 
 
Additionally, investigators must provide the following information to the IRBs in summary 
format at the time of continuing review, or when otherwise specifically requested by the IRBs or 
the NIH Office of Human Subjects Research Protections Office of Compliance and Training: 
• Major and minor protocol deviations.  
• Noncompliance reported to the IRB(s) that is not related to a protocol deviation.  
• AEs and SAEs that do not meet the definition of an UP.  
• UPs reported to the IRB(s). 
8.6.1.2 
Reporting to the NIAID Clinical Director 
The protocol chair will report UPs, major protocol deviations, and deaths to the NIAID clinical 
director according to institutional timelines. 

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Reporting Protocol Deviations that Result from the COVID-19 Pandemic  
The following addresses the reporting requirements to the IRBs with regard to protocol 
deviations that result from disruption of study visits from the COVID-19 pandemic. These 
requirements follow the direction of the IRBs as well as the NIH reporting requirements. 
 
Investigators may modify the protocol without prospective IRB approval when necessary to 
prevent an immediate apparent harm to a study subject. Typically, when this occurs the event 
must be reported to the IRB(s) via a Reportable Event Form (REF) within 7 days of the 
deviation. Given the potential need for this to occur on a much larger than usual scale, it is not 
required that all planned deviations be reported to the IRBs in an expedited timeframe. Only 
those deviations which meet the definition of a major deviation will require reporting, as defined 
in section 8.4.1. 
 
If a subject cannot complete a protocol-specified study visit or intervention, the principal 
investigator should assess the impact of the missed visit on the safety of the subject and the 
scientific validity of the trial. If in the principal investigator’s determination neither of these are 
meaningfully impacted by the deviation, these do not need to be reported to the IRBs in an 
expedited manner. The event should be included in the summary of events reported at the time of 
continuing review. 
 
If in the opinion of the principal investigator the missed visit or intervention poses a risk to the 
safety of the subject, the investigator should develop a plan to minimize the impact of the 
deviation. For example, if the subject is scheduled to return to the study site for safety lab work, 
the investigator may arrange for labs to be drawn at a location closer to the subject’s home. In 
cases such as this, if the change is necessary to assure the safety of the subject, the investigator 
may implement the change without prospective IRB approval. If the change meets the definition 
of a major deviation, it must be reported via a REF within 7 days. 
9 
STATISTICAL CONSIDERATIONS 
 
Statistical Hypothesis 
The primary study hypotheses are that L9LS will be safe and will confer protection against Pf 
infection. In the dose-escalation study, the primary objective is to evaluate the safety and 
tolerability. In the efficacy study, the primary objective is to evaluate the efficacy of L9LS 
compared to placebo. 
 
Primary Endpoints: 
• Part 1 and Part 2: Incidence and severity of local and systemic AEs occurring within 7 
days after the administration of L9LS, and incidence of SAEs throughout the study 
period.  

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• Part 2: Pf blood-stage infection as detected by microscopic examination of thick blood 
smear for 52 weeks after administration of L9LS or placebo. 
 
Secondary Endpoints: 
Data from both parts of the study will be used to assess the following endpoints: 
• Pf blood-stage infection as detected by microscopic examination of thick blood smear for 
12 and 24 weeks after administration of L9LS or placebo  
• Pf blood-stage infection as detected by RT-PCR for 24 and 52 weeks after administration 
of L9LS or placebo. 
• Incidence of clinical malaria (definition 1, see section 2.2.2.3) for 24 and 52 weeks after 
administration of L9LS or placebo. 
• Incidence of clinical malaria (definition 2, see section 2.2.2.3) for 24 and 52 weeks after 
administration of L9LS or placebo. 
• To assess the primary objective and first four secondary objectives among children 5-17 
months of age. 
• To assess the primary objective and first four secondary objectives among children 18-59 
months of age. 
• Measurement of L9LS in sera of recipients. 
• PK analysis of L9LS and the association of L9LS concentration with Pf infection risk. 
• PK analysis of L9LS and the association of L9LS concentration with clinical malaria risk. 
 
Sample Size Determination 
 
Sample Size Considerations for the Dose-Escalation Study 
The ability of the study to identify safety events can be expressed in terms of the probability of 
observing 1 or more event of interest (e.g., AEs) within each arm. With the sample size n=9 
(receiving MAb) in each arm, there is over a 90% chance to observe at least 1 AE if the true rate 
is at least 0.226 and over a 90% chance to observe no AE if the true rate is no more than 0.011. 
Probabilities of observing 0 or more than 1 AE within a group are presented in Table 5 for a 
range of possible true event rates.  
 
Table 5. Probability of events for different safety scenarios within an arm (n=9). 
True event 
rate 
n=9 
Pr(0) 
Pr(>1) 
0.005 
0.956 
0.001 
0.01 
0.914 
0.003 
0.02 
0.834 
0.013 
0.035 
0.726 
0.037 

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True event 
rate 
n=9 
Pr(0) 
Pr(>1) 
0.05 
0.63 
0.071 
0.1 
0.387 
0.225 
0.15 
0.232 
0.401 
0.2 
0.134 
0.564 
0.3 
0.04 
0.804 
Abbreviations: Pr, probability. 
 
Sample Size Considerations for the Efficacy Study 
Table 6 shows initial sample size estimations powered to detect a 70% vaccine efficacy (1 – 
[proportion infected in L9LS/proportion infection in control]) at 12 months comparing L9LS at 
10-20 mg/kg to placebo. Sample size calculations were done assuming the endpoint of any Pf 
infection will be calculated using a proportional analysis, 80% or 90% power, an alpha of 0.05, 
and that either 30%, 35%, or 40% of children in the placebo group are infected at 6 months and 
that 40% or 45% are infected at 12 months. (Time-to-event analyses typically require smaller 
sample sizes.) The primary endpoint will be at 12 months and will combine both MAb age 
groups who received two doses of L9LS and compare those subjects to the overall placebo 
group, i.e., we will assess MAb efficacy among children 5–59 months. However, the trial sample 
size is based on the secondary endpoint of 12-month MAb efficacy with two doses among the 
younger age group (5–17 months) versus the 5–17-month-old subjects in the placebo group, as 
these will require larger sample sizes than the primary endpoint. Factoring in 25% loss to follow-
up over 12 months, and a doubling of the sample size in each intervention arm to allow for 
comparison of L9LS with a second dose (at 6 months) to placebo and comparison of L9LS 
without a second dose to placebo would require 108 children in each L9LS group and 54 
children in the placebo arm, assuming 35% infected in the placebo group at 6 months.  
 

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Table 6. Sample size calculations based on secondary 12-month endpoint, to achieve 80% power to detect efficacy of 70% at 6 
months and 60% at 12 months, assuming 35% of the control group are infected by 6 months and 45% by 12 months. 
 
Arm 
Assumed 
proportion 
infected in 
control 
group by 6 
mos 
mAb 
Efficacy 
at 6 
months Power 
Number 
needed at 
6 months 
Number 
needed to 
enroll 
assuming 
20% 
LTFU and 
booster 
split 
Assumed 
% 
infected in 
control 
group by 
12 mos 
mAb 
Efficacy 
at 12 
months 
Number 
needed at 
12 
months 
Number 
needed to 
enroll 
Number 
with 
20% 
LTFU* 
mAb 5-17 mos + Dose 2  
0.30 
70% 
80% 
52 
130 
0.40 
60% 
52 
104 
130 
mAb 5-17 mos No dose 2 
0.30 
0.40 
60% 
52 
mAb 18 mos-5 years + Dose 2 
0.30 
70% 
80% 
52 
130 
0.40 
60% 
52 
104 
130 
mAb 18 mos-5 years No dose 2 
0.30 
0.40 
60% 
52 
Placebo 5 -17 mos 
0.30 
70% 
80% 
52 
65 
0.40 
60% 
52 
52 
65 
Placebo 18 mos-5 years 
0.30 
70% 
80% 
52 
65 
0.40 
60% 
52 
52 
65 
mAb 5-17 mos + Dose 2 
0.30 
70% 
90% 
70 
175 
0.40 
60% 
69 
138 
173 
mAb 5-17 mos No dose 2  
0.30 
0.40 
60% 
69 
mAb 18 mos-5 years + Dose 2 
0.30 
70% 
90% 
70 
175 
0.40 
60% 
69 
138 
173 
mAb 18 mos-5 years No dose 2 
0.30 
0.40 
60% 
69 
Placebo 5-17 mos 
0.30 
70% 
90% 
70 
175 
0.40 
60% 
69 
69 
87 
Placebo 18 mos-5 years 
0.30 
70% 
90% 
70 
175 
0.40 
60% 
69 
69 
87 
mAb 5-17 mos + Dose 2 
0.35 
70% 
80% 
43 
108 
0.45 
60% 
43 
86 
108 
mAb 5-17 mos No dose 2  
0.35 
0.45 
60% 
43 
mAb 18 mos-5 years + Dose 2  
0.35 
70% 
80% 
43 
108 
0.45 
60% 
43 
86 
108 
mAb 18 mos-5 years No dose 2 
0.35 
0.45 
60% 
43 
Placebo 5-17 mos 
0.35 
70% 
80% 
43 
54 
0.45 
60% 
43 
43 
54 
Placebo 18 mos-5 years 
0.35 
70% 
80% 
43 
54 
0.45 
60% 
43 
43 
54 
mAb 5-17 mos + Dose 2 
0.35 
70% 
90% 
57 
143 
0.45 
60% 
57 
114 
143 

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mAb 5-17 mos No dose 2 
0.35 
0.45 
60% 
57 
mAb 18 mos-5 years + Dose 2 
0.35 
70% 
90% 
57 
143 
0.45 
60% 
57 
114 
143 
mAb 18 mos-5 years No dose 2 
0.35 
0.45 
60% 
57 
Placebo 5-17 mos 
0.35 
70% 
90% 
57 
72 
0.45 
60% 
57 
57 
72 
Placebo 18 mos-5 years 
0.35 
70% 
90% 
57 
72 
0.45 
60% 
57 
57 
72 
mAb 5-17 mos + Dose 2 
0.40 
70% 
80% 
35 
88 
0.45 
60% 
43 
86 
108 
mAb 5-17 mos No dose 2 
0.40 
0.45 
60% 
43 
mAb 18 mos-5 years + Dose 2 
0.40 
70% 
80% 
35 
88 
0.45 
60% 
43 
86 
108 
mAb 18 mos-5 years No dose 2 
0.40 
0.45 
60% 
43 
Placebo 5-17 mos 
0.40 
70% 
80% 
35 
44 
0.45 
60% 
43 
43 
54 
Placebo 18 mos-5 years 
0.40 
70% 
80% 
35 
44 
0.45 
60% 
43 
43 
54 
mAb 5-17 mos + Dose 2 
0.40 
70% 
90% 
47 
118 
0.45 
60% 
43 
86 
115 
mAb 5-17 mos No dose 2 
0.40 
0.45 
60% 
43 
mAb 18 mos-5 years + Dose 2  
0.40 
70% 
90% 
47 
118 
0.45 
60% 
43 
86 
115 
mAb 18 mos-5 years No dose 2 
0.40 
0.45 
60% 
43 
Placebo 5-17 mos 
0.40 
70% 
90% 
47 
59 
0.45 
60% 
43 
43 
58 
Placebo 18 mos-5 years 
0.40 
70% 
90% 
47 
59 
0.45 
60% 
43 
43 
58 
Note: If infections in the control group are higher at 6 or 12 months than assumed but VE remains the same, then the statistical power increases. 
*LTFU = loss to follow up 
  
  
  
  
  
  
  
  
  
  

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Sample Size Considerations for the Year 2 Extension Study 
In part 1b of the study for evaluating the safety of L9LS at 30mg/kg and 40mg/kg, 12 new 
participants will be enrolled into each age-dose group where 9 participants will receive L9LS of 
30mg/kg (or 40mg/kg) and 3 will receive placebo. The probabilities of observing 0 or more than 
1 AE among the L9LS recipients within a group are presented in Table 5 over a range of possible 
true event rates.  
 
In year 2 extension study, safety endpoints will be assessed within each arm, and each L9LS arm 
will additionally be compared with the placebo arm. Table 7 presents the minimum detectable 
difference in adverse event rate with 80% and 90% power over possible event rates under 
placebo, with each arm of 108 participants. 
 
Table 7. The minimum detectable difference in event rate between L9LS arm and placebo 
arm 
Event rate 
(under 
placebo) 
With 80% power 
With 90% power 
Detectable 
difference 
Event rate 
(under 
L9LS) 
Detectable 
difference 
Event rate 
(under 
L9LS) 
0.05 
0.119 
0.169 
0.143 
0.193 
0.1 
0.143 
0.243 
0.17 
0.27 
0.2 
0.172 
0.372 
0.201 
0.401 
0.3 
0.186 
0.486 
0.215 
0.515 
 
In year 2 extension study to assess the protective efficacy, each L9LS arm will be compared with 
the placebo arm. Assuming a lost to follow up rate of 20%, Table 8 shows the comparison power 
at various rates of the infection with 108 participants per arm. In addition, the two L9LS arms 
will also be compared with each other, and the comparison power is shown  in Table 9. 
 
 
 

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Table 8.The comparison power with 108 participants per arm and a lost to follow up rate 
of 20% 
Sample 
size per 
arm 
Lost to 
follow up 
rate 
(%) 
Infection rate 
(under placebo) 
Infection rate 
(under L9LS)  
 mAb 
efficacy 
Power 
(%) 
108 
20% 
0.45 
 
0.225 
0.5 
89 
0.18 
0.6 
97 
0.135 
0.7 
100 
0.4 
 
0.2 
0.5 
82 
0.16 
0.6 
95 
0.12 
0.7 
99 
0.35 
 
0.175 
0.5 
75 
0.14 
0.6 
90 
0.105 
0.7 
98 
 
Table 9. The comparison power between two  L9LS arms  with 108 participants per arm 
and a lost to follow up rate of 20% 
Sample 
size per 
arm 
Lost to 
follow up 
rate 
Infection rate 
in the high 
infection arm 
Infection rate in 
the low infection 
arm 
Power 
(%) 
108 
20% 
0.15 
0.05 
59 
0.15 
0.1 
17 
0.2 
0.05 
85 
0.2 
0.1 
45 
0.2 
0.15 
14 
0.25 
0.05 
96 
0.25 
0.1 
74 
0.25 
0.15 
37 
0.25 
0.2 
12 
0.3 
0.05 
99 
0.3 
0.1 
91 
0.3 
0.15 
66 
0.3 
0.2 
33 
 
 
 
 

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Populations for Analyses 
The following datasets will be considered in study analyses: 
• Intention-to-treat (ITT) analysis dataset will include all subjects that are randomized and 
will be analyzed according to the initial randomization assignment.  
• Modified intention-to-treat (MITT) analysis dataset will include all randomized subjects 
that receive the study intervention and will be analyzed according to the initial 
randomization assignment. 
• Per-protocol (PP) analysis dataset will include all randomized subjects that receive the 
study intervention consistent with the initial randomization assignment and complete the 
scheduled visits, and will be analyzed according to the initial randomization assignment. 
In cases where subjects receive an intervention other than the one randomly assigned, an 
as-treated analysis will be additionally performed according to the actual product 
received. 
 
Evaluable for toxicity  
All participants will be evaluable for toxicity from the time of their first treatment with L9LS or 
placebo. The toxicity analysis will be MITT.  
 
Evaluable for objective response  
Not applicable. 
 
Evaluable Non-Target Disease Response 
Not applicable. 
 
Statistical Analyses 
A detailed study statistical analytical plan for the final analysis, which will supersede the study 
protocol, will be drawn up during the study before the unblinding of data at database lock.  
 
General Approach 
In general, descriptive statistics will be tabulated by treatment arm for endpoints of interest. This 
will include point estimates (mean, geometric mean, median, or proportions) and their respective 
95% confidence intervals. Formal comparisons will use standard methods, contingency tables for 
categorical variables, t-tests for comparing means if data follow a normal distribution or 
geometric means if data after log transformation follow a normal distribution, or nonparametric 
analogs for comparing medians. Unless specified in the subsequent sections, comparisons will be 
two-sided with type I error rate of 0.05. 
 
Missing data will be considered as “missing completely at random” provided the amount of 
missing data is modest (e.g., <10%). We will examine the “missing completely at random” 

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assumption if the amount of missing data is more than 10%. If the assumption does not hold, 
missing data will be handled under the “missing at random” assumption (that is, missingness 
depends only on observed variables) via methods such as multiple imputation and inverse 
propensity weighting. To handle the possibility of “missing not at random,” a sensitivity analysis 
will be performed by imputing missing binary observations with the observed proportion in the 
opposite arm. A secondary sensitivity analysis will be considered by imputing missing binary 
observations as failures.  
 
Randomization: In the efficacy study, participants will be stratified by age (5-17 months versus 
18-59 months) and then each age group will be randomized 2:1 to the L9LS arm and the placebo 
arm. The total number of participants will be 108 in each arm. In the dose-escalation study, 
participants in each age group, starting with 5-10 years, followed by 5-59 months, will be 
recruited and randomized 3:1 to receive L9LS at the dose of 5 mg/kg or placebo; if no safety 
concerns arise, randomization into the L9LS at the dose of 10 mg/kg or placebo, and finally 20 
mg/kg or placebo, ensues in the same manner. To limit the number of dropouts before L9LS 
administration, randomization and L9LS administration will occur as close in time as possible. 
 
Analysis of the Primary Endpoints 
Analysis for the primary endpoint for safety and tolerability is described in section 9.5.5. 
 
Analysis for the primary efficacy endpoint, protective efficacy with Pf infection determined by 
blood smear, is described in section 9.5.4. 
 
Analysis of the Secondary Endpoint(s) 
Analysis of the secondary efficacy endpoints, for example, incidence of Pf infection determined 
by RT-PCR and incidence of Pf infection against clinical malaria, is described in section 9.5.4. 
 
Analyses of the secondary endpoints for the PK of L9LS and the association of L9LS 
concentration with Pf infection risk are described in section 9.5.6. 
 
Efficacy Analyses 
The primary efficacy endpoint (efficacy study primary endpoint) is the incidence of malaria 
infection defined as blood smear–positive Pf infection, starting on Day 7 after MAb/placebo 
administration, through 52 weeks after administration. The secondary efficacy endpoints are the 
incidence of malaria infection as determined by RT-PCR and the incidence of clinical malaria, 
up to 12, 24 weeks and up to 52 weeks, as well as the incidence of malaria infection by blood 
smear up to 12 and up to 24 weeks. The efficacy analyses will be MITT over participants in the 
efficacy study.  
 

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The primary efficacy analysis will be based on time to the first infection. The survival patterns 
will be described by Kaplan-Meier curves for each arm and compared by the logrank test across 
different arms. The protective efficacy of the study product will be estimated by the hazard ratio 
from the Cox proportional hazards model. These analyses will be carried out by R packages or 
commands in similar statistical software that account for interval censoring: package “interval” 
for deriving a nonparametric maximum likelihood estimation based on the Kaplan-Meier 
survival curve and logrank test, and package “icenReg” for Cox proportional hazards regression. 
To address the heterogeneity of the study population, a Cox regression with regressors other than 
the study arm will be additionally performed to account for potential differences among 
participants. The regressors will include time of enrollment and possibly those covariates that are 
significantly different between the study product arms and the placebo arm in spite of 
randomization. The primary analysis will compare all children (both age groups) receiving MAb 
to placebo. Secondary endpoint analyses will compare the younger children receiving MAb to 
the younger children in the placebo group and the older children receiving MAb to the older 
children in the placebo group. Since these are secondary endpoints, no adjustments for multiple 
comparisons will be made. 
 
The secondary efficacy analysis will be based on the proportion of infection. The proportion of 
infection will be estimated for each arm and compared across arms based on Kaplan-Meier 
estimates: the proportion of infection by one minus the Kaplan-Meier estimate in the arm, and 
the vaccine efficacy by one minus the relative risk of infection with melding method for 
constructing the melded 95% confidence interval of the vaccine efficacy.34 
 
Finally, all clinical malaria episodes will be included in exploratory analyses. All person-time 
during the trial, including the time after the initial positive evaluation for Pf infection or clinical 
malaria, will be included in these analyses. This approach will use a counting process which is an 
extension of the Cox proportional hazards model to incorporate multiple events.35 The 14 days 
following treatment with artemether-lumefantrine will be removed from these analysis. In these 
models the number of prior events will be included as a covariate in order to ensure that the 
conditional independence assumption of the counting process is still met since a previous 
infection may confer some future protection.36 
 
Although the trial will not be weight-stratified, given that we have age stratification, we 
anticipate that participants will cover the dose range from 10 mg/kg to 20 mg/kg in the efficacy 
analyses. In addition to the above efficacy analyses that compare each dose arm with the placebo 
arm, an exploratory analysis will be additionally conducted to assess how dosage, in terms of mg 
of L9LS per kg of subject body weight, affects the protective efficacy. 
 
 
 

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Making these data available in a timely manner will add to the evidence base needed to plan a 
potential phase 3 trial of L9LS in settings with seasonal malaria transmission.  
 
Safety Analyses 
Safety analysis will be primarily MITT where individuals who receive assignment but do not 
receive any product are excluded. Because of blinding and the brief length of time between 
assignment and administration, such cases will be very few. In the rare case of subjects receiving 
a regimen different from assignment, an as-treated analysis will be additionally performed where 
subjects will be analyzed according to the product they actually receive. 
 
Safety data will be presented by line listings and tables at the individual level to provide details 
on safety events such as severity, duration, and relationship to study product. The number and 
percentage of subjects with 1 or more AE(s) will be summarized by dose arm along with the 
exact 95% confidence intervals of the AE rate. For subjects experiencing more than 1 AE, the 
subjects will be counted once under the event of highest severity. 
 
In the efficacy study, comparisons between the dose arms and the control arm will be 
additionally performed in terms of the proportions of solicited AEs, related AEs, and SAEs. 
 
In the rare case of subjects receiving a regimen different from assignment, a per-protocol 
analysis will be performed as a secondary analysis, which will include subjects according to the 
product they actually receive in the study. 
 
Pharmacokinetics Analysis 
PK analysis will be carried out for subjects in the dose-escalation study and in the efficacy study 
with blood samples collected at defined timepoints as listed in section 0. The PK analysis will be 
PP. The following PK analysis will be performed as needed. 
 
Individual Subject Pharmacokinetic Analysis: A non-compartmental (NC) PK analysis will be 
performed on the L9LS concentration data generated from each subject. Individual subject and 
dosing arm concentration-versus-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 subject’s L9LS concentration falls below the quantitative limit (QL) 
of the assay, the sample with concentration below the QL will be assigned a L9LS concentration 
value of “0” for AUC calculations. In addition to the total AUC, partial AUCs will also be 
determined over certain time intervals. 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, z, will be determined by regression of the 

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terminal, log-linear portion of the concentration-versus-time profile. If the final PK sample has 
measurable L9LS concentrations greater than the assay QL, the AUC post-final PK collection 
(AUClast-infinity) will be estimated as Clast / z and AUC0-infinity will be calculated as the sum of 
AUC0-last + AUClast-infinity. 
 
Population Pharmacokinetic Analyses: Based on preclinical PK results for L9LS and known 
PK behavior studies of MAbs, the two-compartment model will be used for population PK 
analysis. The population analysis will estimate compartmental PK parameters such as the 
clearance (CL), central and peripheral volumes of distribution (Vd1 and Vd2), and 
intercompartmental clearance (Q). 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. 37 
 
To assess the association of L9LS concentration with protection, we will perform a Cox 
proportional hazards regression for the time to the first infection with L9LS concentration as a 
time-varying covariate. A logistic regression analysis will be additionally performed to model 
the infection rate as a function of L9LS concentration using generalized estimating equation to 
account for repeated measures. This analysis will be performed over all participants that receive 
L9LS including those aged 5-10 years in the dose-escalation study and those in the efficacy 
study. 
 
Baseline Descriptive Statistics 
Treatment arms will be compared for baseline subject characteristics using descriptive statistics. 
For continuous variables, the mean or median will be calculated for each treatment arm. For 
categorial variables, the proportion under each category will be calculated for each arm.  
 
Planned Interim Analyses 
Interim safety analysis will be performed when safety data are available from the age de-
escalation and dose escalation study subjects, starting at least 7 days after the last participant in 
part 1 receives their antibody (or placebo) dose. The purpose of the interim analysis on safety 
data is to clear safety concerns for proceeding to the efficacy study.  
 
An interim efficacy analysis will be conducted when clean data are available for all participants 
through the 6-month endpoint (at 24 weeks). This will assess Pf infection up to 24 weeks by 
blood smear and clinical malaria using time-to-event analysis and proportional analyses. Having 
these data available in a timely manner will add to the evidence base needed to plan a potential 
phase 3 trial of L9LS in settings with seasonal malaria transmission where the time for protection 
is 6 months. The interim analysis will not impact the conduct of this trial or induce significance 
level adjustment in the efficacy analyses of this trial.  
 

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Sub-Group Analyses 
Not applicable. 
 
Tabulation of individual Participant Data 
Safety data will be presented by line listing and tables at the individual level, as described in 
section 9.5.5. 
 
Exploratory Analyses 
To explore the impact of L9LS on the genotype of infection -inducing parasites at the CSP locus, 
a genotypic sieve analysis will be performed to analyze CSP sequences of breakthrough parasites 
in the blood samples of infected subjects. The sieve analysis will differentiate protective efficacy 
against different genotypes of infection-inducing parasites with genotype defined by, for 
example, number of mismatches to the L9LS footprint. To explore whether receipt of MAb 
affects development of measles-specific antibodies among those who receive the measles 
vaccine after their first MAb dose, mean and median antibody titers will be compared among 
subjects <9 months of age at enrollment, prior to and after receipt of MAb. The exploratory 
analysis comparing one versus two doses of L9LS against Pf infection and clinical malaria will 
be done as outlined in section 9.5.4 above.  
10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
 
Informed Consent Process 
 
Consent/Assent Procedures and Documentation 
As this study will include only children 10 years of age and younger, informed 
consent/permission will be obtained from parents or guardians prior to any study procedure. All 
consent forms will be translated into Dholuo and Kiswahili and back translated into English to 
ensure accuracy.  
The consent form will detail the design of the study, the intervention (vaccination with L9LS or 
placebo), collection of blood samples, and study requirements for follow-up. A designated and 
trained study staff will describe the protocol to potential participants’ parent(s)/guardian(s) face 
to face, the informed consent form will be read together with the participants’ 
parent(s)/guardian(s), and the participants’ parent(s)/guardian(s) shall be given ample 
opportunity to inquire about details of the study and ask any questions, including from clinical 
staff, before dating and signing (or thumbprinting, in the case of illiterate persons) the informed 
consent form. Consenting of an illiterate parent/guardian will be performed in the presence of an 
impartial witness who will sign the consent/permission form on behalf of the parent/guardian. 
The illiterate parent/guardian will be asked to sign or place their thumbprint on the consent form 
to document their consent/permission. 

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Details about the trial and its benefits and potential risk will be explained to the parent/guardian 
in the language in which they are most fluent. All information regarding the participants will 
remain confidential to the extent allowed by law. Unique numerical identifiers will be used for 
data entry.   
 
The storage of blood samples will then be explained to the parents or guardians. If they agree to 
have their child’s blood samples stored at KEMRI, each individual will be asked to sign consent 
to store samples. Permission will also be sought for shipping of some samples to the NIH and 
other collaborating laboratories in the US for immunologic testing and parasite genotyping. All 
parents/ guardians will be provided with a signed consent form after they have agreed to 
participate in the study. Should a parent/guardian prefer not to keep a copy of the consent form, 
this will be documented. Should the consenter be non-medical personnel, a clinical/medical 
officer or nurse will be available to answer further questions.  
 
Each parent’s/guardian’s signed informed consent form will be kept on file by the investigator 
for possible inspection by regulatory authorities. Any amendments to the written information 
will be provided to participants’ parents/guardians.  
10.1.1.1 
Justification for Alteration of Informed Consent 
Due to the high illiteracy rate in the area, we are seeking an alteration of informed consent to 
accept a witnessed thumbprint in lieu of a signature for parent(s)/guardian(s) who cannot sign 
their names. 
 
Study Discontinuation and Closure 
The study may be temporarily suspended or permanently terminated as described in the halting 
rules (section 8.4.6). In addition to the reporting described in that section, the principal 
investigator(s) will promptly contact the study subjects, provide the reason(s) for the termination 
or suspension, and, if applicable, inform them of changes to study visit schedule. 
 
The principal investigators will consult with the IRBs prior to resuming the study following a 
halt. 
 
Confidentiality and Privacy 
All records will be kept confidential to the extent provided by federal, state, and Kenyan law. 
The study monitors and other authorized representatives of the sponsor may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records. Records will be kept in the study clinics and/or KEMRI-CGHR under key 
and lock and data will be coded. Any personally identifiable information maintained for this 
study will be kept on restricted-access computers and networks. Personally identifiable 

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information will only be shared with individuals authorized to receive it under this protocol. 
Individuals not authorized to receive personally identifiable information will be provided with 
coded information only, as needed. Clinical information will not be released without written 
permission of the subject, except as necessary for monitoring by the IRBs, FDA, NIAID, Office 
for Human Research Protections (OHRP), the VRC, or the sponsor’s designee. 
 
To further protect the privacy of study subjects, a Certificate of Confidentiality has been issued 
by the 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 subjects, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to subjects. 
 
Samples and data will be collected and stored under this protocol. All of the stored study 
research samples are labeled by a code that only the investigators can link to the subject. 
Samples are stored in secure research laboratories in locked freezers with limited access at the 
KEMRI, and the NIH. Data will be kept in password-protected computers. Only investigators or 
their designees will have access to the samples and data. 
 
Samples and data acquired under this protocol will be tracked using BSI Systems software. 
 
Any loss or unanticipated destruction of samples (for example, due to freezer malfunction) or 
data (for example, misplacing a printout of data with identifiers) that meets the definition of a 
reportable event will be reported to the IRBs. 
 
Additionally, subjects may decide at any point before the end of the trial not to have their 
samples stored. In this case, the principal investigator will destroy all known remaining samples 
and report what was done to both the subject and to the IRBs. This decision will not affect the 
individual’s participation in this protocol or any other protocols at NIH. 
 
Future use of Stored Specimens and Data 
Subjects are consented at enrollment for permission for storage and future use of specimens and 
data. Samples, specimens, and data collected under this protocol may be used to study malaria 
and the immune system. Genetic testing will only be performed on the malaria parasite, but no 
human genetic testing will be conducted. 
 
Storage and Tracking: Access to and tracking of stored samples and data will be secured and 
limited as described above (section 10.3).  

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Disposition: In the future, other investigators (both at NIH and outside) may wish to use these 
samples and/or data for research purposes. If the planned research falls within the category of 
“human subjects research” on the part of the NIH researchers, IRB review and approval will be 
obtained. This includes the NIH researchers sending out coded and linked samples or data and 
getting results that they can link back to their subjects. 
 
Safety Oversight 
Safety oversight is described in section 8.4.4. 
 
Clinical Monitoring 
According to the ICH E6(R2) GCP guidelines, section 5.18, and FDA 21 CFR 312.50, clinical 
protocols are required to be adequately monitored by the study sponsor. This study monitoring 
will be conducted according to the “NIAID Intramural Clinical Monitoring Guidelines.” 
Monitors under contract to the NIAID/OCRPRO will visit the clinical research site to monitor 
aspects of the study in accordance with the appropriate regulations and the approved protocol. 
The objectives of a monitoring visit will be: 1) to verify the existence of signed informed consent 
documents and documentation of the consent process for each monitored subject; 2) to verify the 
prompt and accurate recording of all monitored data points in DFdiscover and prompt reporting 
of all SAEs; 3) to compare abstracted information entered into DFdiscover with individual 
subjects’ records and source documents (subjects’ charts, laboratory analyses and test results, 
physicians’ progress notes, nurses’ notes, and any other relevant original subject information); 
and 4) to help ensure investigators are in compliance with the protocol. The monitors also will 
inspect the clinical site regulatory files to ensure that regulatory requirements (OHRP, FDA) and 
applicable guidelines (ICH GCP) are being followed. During the monitoring visits, the 
investigator (and/or designee) and other study personnel will be available to discuss the study 
progress and monitoring visit. 
 
The investigator (and/or designee) will make study documents (e.g., consent forms, DFdiscover 
abstracts) and pertinent hospital or clinical records readily available for inspection by the local 
IRB, FDA, the site monitors, and the NIAID staff for confirmation of the study data. 
 
A specific protocol monitoring plan will be discussed with the principal investigator and study 
staff prior to enrollment. The plan will outline the frequency of monitoring visits based on such 
factors as study enrollment, data collection status, and regulatory obligations. 
 
Quality Assurance and Quality Control 
During the study, the principal investigator and study team will be responsible for ensuring study 
activities are conducted in compliance with the protocol, ICH GCP, and applicable regulatory 

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requirements. Each clinical site will perform internal quality management of study conduct, data 
and biological specimen collection, and documentation according to study SOPs. 
 
Data Handling and Record Keeping 
 
Data Collection and Management Responsibilities 
Study data will be maintained in CRFs and collected directly from subjects during study visits 
and telephone calls or will be abstracted from subjects’ medical records. Source documents 
include all recordings of observations or notations of clinical activities, including CRFs, and all 
reports and records necessary to confirm the data abstracted for this study. Data entry into CRFs 
will be performed by authorized individuals. The investigator is responsible for assuring that the 
data collected are complete, accurate, and recorded in a timely manner. Study data, including 
cumulative subject accrual numbers, should be generated via the chosen data capture method and 
submitted to the IRBs as needed. 
 
Study Records Retention 
Study documents will be retained in accordance with regulatory and institutional requirements, 
ICH GCP guidelines, and the NIH Intramural Records Retention Schedule. No records will be 
destroyed without the written consent of the principal investigators/protocol chair and sponsor, 
as applicable.  
 
Should the investigator wish to assign the study records to another party and/or move them to 
another location, the investigator will provide written notification of such intent to 
OCRPRO/NIAID and SERU with the name of the person who will accept responsibility for the 
transferred records and/or their new location. NIAID will be notified in writing and written 
OCRPRO/NIAID permission shall be obtained by the site prior to destruction or relocation of 
research records. 
 
Protocol Deviations and Non-Compliance 
It is the responsibility of the investigators to use continuous vigilance to identify and report 
deviations and non-compliance to the IRBs and the NIH (as applicable) according to NIH 
Human Research Protection Program Policy 801 (as described in section 8.6.1). All deviations 
must be addressed in study source documents and reported to the NIAID Program Official and 
sponsor. The investigators are responsible for knowing and adhering to the reviewing IRB 
requirements. 
 
NIH Definition of Protocol Deviation 
The definition of a protocol deviation is provided in section 8.4.1. 

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 Publication and Data Sharing Policy 
 
Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
• NIH Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
• This study will comply with the NIH Data Sharing Policy and Policy on the 
Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials 
Registration and Results Information Submission rule. As such, this trial will be 
registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. Data from this study may be requested from other researchers 
indefinitely after the completion of the primary endpoint by contacting one of the 
principal investigators. 
 
Human data generated in this study for future research will be shared as follows: 
• De-identified or identified data with approved outside collaborators under appropriate 
agreements. 
• De-identified results or data in publication and/or public presentations. 
 
Data will be shared at the time of publication or shortly thereafter. 
 
Genomic Data Sharing Compliance 
Not applicable. 
 Collaborative Agreements  
Not applicable.  
 
Agreement Type 
Not applicable. 
 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 

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and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership will follow policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
11 BUDGET AND BUDGET JUSTIFICATION 
 
Budget 
  
Country : Kenya 
Study: Malaria mAb Vaccine 
ANNUAL BUDGETS 
KEMRI Research 
YEAR 1 
YEAR 2 
TOTAL (USD) 
Cooperative Agreement 
Budget 
Budget 
 
Jan-Dec 2024 
Jan-Dec 2025 
Personnel 
86,149.15 
90,233.26 
176,382.40 
 
 
 
 
Equipment 
65,000.00 
35,000.00 
100,000.00 
 
 
 
 
Supplies 
131,510.20 
140,762.90 
272,273.10 
 
 
 
 
Travel 
26,387.40 
15,368.30 
41,755.70 
 
 
 
 
Other 
311,801.81 
297,180.05 
608,981.87 
 
 
 
 
Contractual 
1,143,250.59 
1,170,397.39 
2,313,647.98 
 
 
 
 
TOTAL DIRECT COSTS 
1,764,099.15 
1,750,441.90 
3,514,541.05 
 
 
 
 
INDIRECT COSTS 
44,467.88 
43,603.56 
88,071.45 
 
 
 
 
TOTAL AWARD 
1,808,567.04 
1,794,045.46 
3,602,612.49 
 
 
 
 
 

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11.2 
Budget Justification 
 
Personnel: Funds will be used to pay salary and fringe benefits for study personnel. 
Laboratory supplies: These funds will be used to purchase supplies (rapid tests, reagents,  
transport medium and other disposable lab supplies) to be used in the laboratory for the conduct 
of the study. 
Clinical supplies: Funds will be used to purchase clinical supplies; drugs, PPE, syringes, gloves  
and other clinical supplies for use in hospital where study participants will be enrolled and  
managed. 
Subcontracts: These funds will be utilized to procure the Clinical Trials Insurance for the study 
Equipment:Funds will be utlised to purchase study equipment ie laptops and preventative 
maintenance of lab and pharmacy equipment.  
Travel: These are funds for both local and international travel to conferences and meetings 
related to study activities. 
Transportation: The funds will be utilized for fuel and maintenance of the study motorvehicles 
and motorcycles. 
Other project costs:These include funds for payment of regulatory institutions ie KPPB, SERU 
and other general study costs ie internet, airtime, customas clearance of study supplies and 
samples among others. 
Other supplies: These include transport reimbursement and refreshments for study participants. 
KEMRI OH Costs: These are indirect costs paid to KEMRI to cater for administrative support 
and utilities. 
 
 
 
 

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Bain BJ. Ethnic and sex differences in the total and differential white cell count and 
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Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute 
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APPENDIX A: KENYA NATIONAL IMMUNIZATION SCHEDULE 
 
 
 

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APPENDIX B: KENYA ADVERSE EVENT GRADING SCALE 
PART 1 AND 1B: 
Evaluation 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Hematology and Biochemistry Values 1, 2 
Hemoglobin1  – gm/dL 
7.9 – 6.0 
5.9 – 5.0 
< 5.0 
< 5.0 and clinical 
signs of heart failure 
WBC Increase2 – 103/µL 
14.5 – 16.0 
16.1 – 20.0 
20.1 – 30.0 
> 30.0 
WBC Decrease1 – 103/µL 
2.5 – 4.0 
1.5 – 2.4 
1.0 – 1.4 
< 1.0  
Neutrophil/Granulocyte 
Decrease2, 3 – 103/µL 
0.75 – 0.99 
0.50 – 0.74 
< 0.50 
< 0.50 with fever 
Platelet Decrease1 – 103/µL 
50 - 99 
25 - 49 
<25 
< 25 with clinical 
signs of bleeding 
Creatinine 1  
1.1–1.5 x ULN 
1.6-3.0 x ULN 
3.1-6.0 x ULN 
>6.0 x ULN or 
requires dialysis  
Liver Function Test/ALT1  
1.1-2.5 x ULN 
2.6-5.0 x ULN 
5.1 – 10 x ULN 
>10 x ULN 
Other Values 
Fever 4 – °C 
37.5 – 37.9 
38.0 – 38.4 
38.5 – 39.5 
> 39.5 
Abbreviations: ALT, alanine transaminase; WBC, white blood cell. ULN – Upper limit of normal 
1 The same grading was used in the most recent clinical trial of the RTS,S Malaria vaccine at the same site (Efficacy, 
safety and immunogenicity study of GSK Biologicals’ candidate malaria vaccine (SB257049) evaluating schedules 
with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age)  
2 The same grading is used  in the ‘Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against 
Plasmodium falciparum, in a Dose-Escalation Trial in Adults and Children and a Randomized, Double-Blind Trial 
of Children in Mali’ 
3 Note: Neutropenias are graded and followed, but based on previous experience in African populations, should be 
interpreted with caution since lower values are more frequently observed in people of African descent.38,39   
4 Values presented are for non-oral temperature reading (i.e., axillary or no-touch), which is the preferred method at 
the study site. 
 
 
 

Abbreviated Title: Anti-malaria MAb in Kenyan children  
Page 126 of 126 
Version 6.0  Date: 2 Apr 2024 
Anti-malaria Mab in Kenyan Children  
 
 
 
 
 
Version 6.0 Date XX Mar 2024 
PART 2 AND THE EXTENSION PHASE: 
Evaluation 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Hematology and Biochemistry Values 1, 2 
Hemoglobin1  – gm/dL 
7.9 – 6.0 
5.9 – 5.0 
< 5.0 
< 5.0 and clinical 
signs of heart failure 
WBC Increase2 – 103/µL 
15.5-20.0 
20.1-30.0 
> 30.0 
Not applicable 
WBC Decrease1 – 103/µL 
2.5 – 4.0 
1.5 – 2.4 
1.0 – 1.4 
< 1.0  
Neutrophil/Granulocyte 
Decrease2, 3 – 103/µL 
0.75 – 0.99 
0.50 – 0.74 
< 0.50 
< 0.50 with fever 
Platelet Decrease1 – 103/µL 
50 - 99 
25 - 49 
<25 
< 25 with clinical 
signs of bleeding 
Creatinine 1  
1.1–1.5 x ULN 
1.6-3.0 x ULN 
3.1-6.0 x ULN 
>6.0 x ULN or 
requires dialysis  
Liver Function Test/ALT1  
1.1-2.5 x ULN 
2.6-5.0 x ULN 
5.1 – 10 x ULN 
>10 x ULN 
Other Values 
Fever 4 – °C 
37.5 – 38.4 
38.5 – 39.4 
39.5 – 41.9 
≥ 42 
Abbreviations: ALT, alanine transaminase; WBC, white blood cell. ULN – Upper limit of normal 
1 The same grading was used in the most recent clinical trial of the RTS,S Malaria vaccine at the same site (Efficacy, 
safety and immunogenicity study of GSK Biologicals’ candidate malaria vaccine (SB257049) evaluating schedules 
with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age)  
2 WBC increase numbers in part 2 have been adjusted to reflect the fact that this is a younger population than in Mali 
or in Part 1, and the normal range is higher.  Additionally, elevated WBC in and of itself is not life threatening, thus 
we have noted this as not applicable. 
3 Note: Neutropenias are graded and followed, but based on previous experience in African populations, should be 
interpreted with caution since lower values are more frequently observed in people of African descent.38,39   
4 Values presented are for non-oral temperature reading (i.e., axillary or no-touch), which is the preferred method at 
the study site.