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
Phase: PHASE2
Conditions: Plasmodium Falciparum Infection, Malaria
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Abbreviated Title: Anti-malaria MAb in Malian children  
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Abbreviated Title: Anti-malaria MAb in Malian children 
FMOS/FAPH Protocol #: 2022/34/CE/USTTB 
Version Date: 14 March 2024 
 
Title: 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 
 
FMOS/FAPH Principal 
Investigator: 
Kassoum Kayentao, MD, MPH, PhD  
Malaria Research and Training Center (MRTC) 
Faculté de Médecine Pharmacie d’Odontostomatologie 
(FMOS/FAPH) 
Université  of Sciences, Techniques, & Technologies of 
Bamako (USTTB) 
NIH Principal Investigator: 
Peter D. Crompton, MD, MPH 
Laboratory of Immunogenetics (LIG) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
 
Investigational Agent: 
Drug Name 
L9LS 
Investigational New 
Drug (IND) Number 
160213 
Sponsor 
Office of Clinical Research Policy and Regulatory Operations (OCRPRO), 
Division of Clinical Research (DCR), NIAID 
Manufacturer 
Vaccine Research Center (VRC), NIAID 
 
Data and Safety Monitoring Board (DSMB): NIAID Intramural DSMB 
 
 

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STUDY STAFF ROSTER 
FMOS/FAPH Investigators: 
The research activities of the following FMOS/FAPH investigators will be reviewed by:  
FMOS/FAPH Ethics Committee 
BP E302, Point G/FMOS/FAPH 
Bamako, Mali 
FWA #00001769 
FMOS/FAPH Principal 
Investigator: 
Kassoum Kayentao, MD, MPH, PhD  
MRTC, FMOS/FAPH, USTTB 
BP E302, Point G/FMOS/FAPH  
Bamako, Mali 
Phone: +223 7646 0173 
Email: kayentao@icermali.org 
Role(s): A, B, C, D, E, F 
 
FMOS/FAPH Associate 
Investigators: 
Boubacar Traore, PharmD, PhD (Senior Investigator) 
MRTC, FMOS/FAPH, USTTB 
Phone: +223 2022 8109 
Email: bouba.traore@mrtcbko.org  
Role(s): A, B, C, D, E, F 
 
Aissata Ongoiba, MD, MPH 
MRTC, FMOS/FAPH, USTTB 
Phone: +223 222 8109 
Email: ongoiba@icermali.org 
Role(s): A, B, C, D, E, F 
 
Safiatou Doumbo, MD, MS 
MRTC, FMOS/FAPH, USTTB 
Phone: +223 76 03 95 24 
Email: sdoumbo@icermali.org  
Role(s): A, B, C, E, F 
 
Didier Doumtabe, PharmD, MS 
MRTC, FMOS/FAPH, USTTB 
Phone: +223 74 44 44 44 
Email: ddidier@icermali.org  
Role(s): A, B, C, E, F 

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Abdrahamane Traore, MD 
MRTC, FMOS/FAPH, USTTB 
Phone: +223 76 49 76 58 
Email: boutraore@icermali.org 
Role(s): A, B, C, E, F 
 
Hamadi Traore, MD 
MRTC, FMOS/FAPH, USTTB 
Phone: +223 66 62 53 29 
Email: hamadit@icermali.org 
Role(s): A, B, C, E, F 
 
 
United States (US) Investigators: 
NIH 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 
Malian investigators in monitoring/oversight capacities, NIH investigators will not be engaged in 
human subjects research.  
NIH Principal Investigator and 
Referral Contact: 
Peter D. Crompton, MD, MPH 
LIG, NIAID, NIH 
5625 Fishers Lane Room 4N07D 
Rockville, MD 20852 
Phone: 240-383-7640 
Email: pcrompton@niaid.nih.gov  
Role(s): F 
 
NIH Employee Associate 
Investigators: 
Robert A. Seder, MD 
Chief, Cellular Immunology Section 
VRC, NIAID, NIH 
Phone: 301-594-8483 
Email: rseder@mail.nih.gov 
Role(s): F 
 
Anne C. Preston, RN, BS, CCRC  
LIG, NIAID, NIH 
Phone: 240-669-2876 
Email: anne.preston@nih.gov 
Role(s): F 
 

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Non-NIH Employee Associate 
Investigators: 
Sara Healy, MD, MPH (Pediatrician) (Contractor) 
Medical Science & Computing, LLC 
In support of LIG, NIAID, NIH 
Phone: 206-550-6493 
Email: sara.healy@nih.gov 
Role(s): F 
 
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 
 
Tuan M. Tran, MD, PhD 
Assistant Professor of Medicine and Pediatrics 
Indiana University School of Medicine, Indiana University 
1044 W Walnut Street, R4-427 
Indianapolis, IN 46202 
Phone: 317-278-6968 
Email: tuantran@iu.edu 
Role(s): F 
 
Statisticians:  Zonghui Hu, PhD 
Biostatistics Research Branch, NIAID, NIH 
Phone: 240-669-5240 

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Email: huzo@niaid.nih.gov 
Role(s): F 
 
Jing Wang, MS 
Leidos Biomedical Research, Inc.  
In support of Biostatistics Research Branch, NIAID, NIH 
Phone: 240-669-5259 
Email: jing.wang5@nih.gov 
Role(s): F 
 
For each person listed above, 
identify their roles with the 
appropriate letter:  
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 Sites: 
Kalifabougou MRTC Clinic 
Kalifabougou, Mali 
Région de Koulikoro 
Préfecture de Kati, Commune de Kalifabougou, Centre de 
Santé Communautaire de Kalifabougou 
 
Torodo MRTC Clinic 
Torodo, Mali 
Région de Koulikoro 
Préfecture de Kati, Commune de Torodo, Centre de Santé 
Communautaire de Torodo 
 
Sponsor Medical Monitor (SMM):  Saran Wells, MD  
Clinical Monitoring Research Program Directorate 
Leidos Biomedical Research, Inc. 
In support of NIAID/NIH 

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Phone 240-529-4337 
Email: Saran.Wells@nih.gov 
 
Independent Safety Monitor (ISM): Dr. Bourama Kane, MD 
 
Hospital of Mali, Pediatric Service 
 
Telephone: +223 20 72 7569 
 
E-mail: bkanebassidiki.bk@gmail.com 
 
 

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TABLE OF CONTENTS  
STUDY STAFF ROSTER .............................................................................................................. 2 
TABLE OF CONTENTS ................................................................................................................ 7 
List of Figures ............................................................................................................................... 10 
List of Tables ................................................................................................................................ 10 
STATEMENT OF COMPLIANCE .............................................................................................. 11 
1 
PROTOCOL SUMMARY .................................................................................................... 12 
 
Synopsis ......................................................................................................................... 12 
 
Schema ........................................................................................................................... 20 
 
Schedule of Activities (SOA) ......................................................................................... 25 
 
Adult cohort dose escalation ................................................................................. 25 
 
6-10 year old cohort dose escalation ..................................................................... 27 
 
6-10 year old cohort efficacy ................................................................................ 30 
 
Year 2 Extension ................................................................................................... 33 
2 
INTRODUCTION ................................................................................................................ 36 
 
Study Rationale .............................................................................................................. 36 
 
Year 2 Extension ................................................................................................... 36 
 
Background .................................................................................................................... 37 
 
Study Agent: L9LS ............................................................................................... 37 
 
Laboratory Assessments of L9LS ......................................................................... 40 
 
Repeat Dosing: ADA, PK ..................................................................................... 42 
 
Rebound/Delayed Malaria .................................................................................... 43 
 
Risk/Benefit Assessment ................................................................................................ 44 
 
Known Potential Risks .......................................................................................... 44 
 
Known Potential Benefits ..................................................................................... 48 
 
Assessment of Potential Risks and Benefits ......................................................... 48 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................... 48 
4 
STUDY DESIGN .................................................................................................................. 52 
 
Overall Design................................................................................................................ 52 
 
Year 2 Extension ................................................................................................... 54 
 
Scientific Rationale for Study Design ............................................................................ 57 
 
Year 2 Extension ................................................................................................... 57 
 
Justification for Dose ..................................................................................................... 57 
5 
STUDY POPULATION ....................................................................................................... 58 
 
Inclusion Criteria ............................................................................................................ 58 
 
Year 2 Extension Inclusion Criteria ...................................................................... 59 
 
Exclusion Criteria ........................................................................................................... 59 
 
Year 2 Extension Exclusion Criteria ..................................................................... 60 
 
Inclusion of Vulnerable Participants .............................................................................. 62 
 
Inclusion of Pregnant Women, Fetuses or Neonates ...................................................... 64 
 
Lifestyle Considerations ................................................................................................. 64 
 
Screen Failures ............................................................................................................... 64 
 
Strategies for Recruitment and Retention ...................................................................... 64 
 
Costs ...................................................................................................................... 65 
 
Compensation ....................................................................................................... 65 
6 
STUDY INTERVENTION ................................................................................................... 65 

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Study Interventions(s) Administration ........................................................................... 65 
 
Study Intervention Description ............................................................................. 65 
 
Dosing and Administration ................................................................................... 65 
 
Preparation/Handling/Storage/Accountability ............................................................... 68 
 
Acquisition and Accountability ............................................................................ 68 
 
Formulation, Appearance, Packaging, and Labeling ............................................ 68 
 
Product Storage and Stability................................................................................ 69 
 
Preparation ............................................................................................................ 69 
 
Measures to Minimize Bias: Randomization and Blinding ........................................... 71 
 
Randomization ...................................................................................................... 71 
 
Blinding................................................................................................................. 71 
 
Study Intervention Compliance ...................................................................................... 72 
 
Concomitant Therapy ..................................................................................................... 72 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 73 
 
Discontinuation of Study Intervention ........................................................................... 73 
 
Participant Discontinuation/Withdrawal from the Study ............................................... 73 
 
Missed Visits and Lost to Follow-up ............................................................................. 73 
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STUDY ASSESSMENTS AND PROCEDURES ................................................................ 74 
 
Screening Procedures ..................................................................................................... 74 
 
Efficacy Assessments ..................................................................................................... 75 
 
Clinical Evaluations .............................................................................................. 75 
 
Biospecimen Evaluations ...................................................................................... 76 
 
Correlative Studies for Research/Pharmacokinetic Studies .................................. 77 
 
Samples for Genetic/Genomic Analysis ............................................................... 77 
 
Safety and Other Assessments ....................................................................................... 78 
 
Safety Definitions, Management, and Sponsor Reporting ............................................. 78 
 
Definitions............................................................................................................. 78 
 
Documenting, Assessing, Recording, and Reporting Events ............................... 82 
 
Withdrawal Criteria for an Individual Subject...................................................... 88 
 
Additional Safety Oversight ................................................................................. 89 
 
Pausing Rules ........................................................................................................ 91 
 
Halting Rules for the Protocol .............................................................................. 92 
 
Unanticipated Problems ................................................................................................. 93 
 
Definition of Unanticipated Problems .................................................................. 93 
 
Unanticipated Problem Reporting......................................................................... 93 
 
ADDITIONAL REPORTING REQUIREMENTS ........................................................ 93 
 
Reporting to the FMOS/FAPH EC ....................................................................... 93 
 
Reporting to the NIAID Clinical Director ............................................................ 94 
 
Reporting Protocol Deviations that Result from the COVID-19 Pandemic ......... 94 
9 
STATISTICAL CONSIDERATIONS .................................................................................. 94 
 
Statistical Hypothesis ..................................................................................................... 94 
 
Sample Size Determination ............................................................................................ 95 
 
Sample Size Considerations for the Dose-Escalation Study ................................. 95 
 
Sample Size Considerations for the Efficacy Study ............................................. 96 
 
Sample Size Considerations for the Year 2 Extension Study ........................................ 97 

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Populations for Analyses ................................................................................................ 98 
 
Evaluable for toxicity ............................................................................................ 99 
 
Evaluable for objective response .......................................................................... 99 
 
Evaluable Non-Target Disease Response ............................................................. 99 
 
Statistical Analyses ........................................................................................................ 99 
 
General Approach ................................................................................................. 99 
 
Analysis of the Primary Endpoints ..................................................................... 100 
 
Analysis of the Secondary Endpoint(s)............................................................... 100 
 
Efficacy Analyses ............................................................................................... 100 
 
Safety Analyses ................................................................................................... 101 
 
Pharmacokinetics Analysis ................................................................................. 102 
 
Baseline Descriptive Statistics ............................................................................ 103 
 
Planned Interim Analyses ................................................................................... 103 
 
Sub-Group Analyses ........................................................................................... 103 
 
Tabulation of individual Participant Data ........................................................... 103 
 
Exploratory Analyses .......................................................................................... 103 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS ....................................... 104 
 
Informed Consent Process ........................................................................................ 104 
 
Consent Procedures and Documentation ............................................................ 104 
 
Consent for Minors When They Reach the Age of Majority .............................. 105 
 
Study Discontinuation and Closure .......................................................................... 106 
 
Confidentiality and Privacy ...................................................................................... 106 
 
Future use of Stored Specimens and Data ................................................................ 107 
 
Safety Oversight ....................................................................................................... 107 
 
Clinical Monitoring .................................................................................................. 107 
 
Quality Assurance and Quality Control .................................................................... 108 
 
Data Handling and Record Keeping ......................................................................... 108 
 
Data Collection and Management Responsibilities ............................................ 108 
 
Study Records Retention..................................................................................... 108 
 
Protocol Deviations and Non-Compliance ............................................................... 109 
 
NIH Definition of Protocol Deviation ................................................................ 109 
 
Publication and Data Sharing Policy ........................................................................ 109 
 
Human Data Sharing Plan ................................................................................... 109 
 
Genomic Data Sharing Compliance.................................................................... 110 
 
Collaborative Agreements ........................................................................................ 110 
 
Agreement Type.................................................................................................. 110 
 
Conflict of Interest Policy......................................................................................... 110 
11 ABBREVIATIONS ............................................................................................................ 110 
12 REFERENCES ................................................................................................................... 113 
APPENDIX A: MRTC URINE LABORATORY NORMAL VALUES ................................... 116 
APPENDIX B: MALI LABORATORY ADVERSE EVENT GRADING SCALE, ADULTS 117 
APPENDIX C: MALI LABORATORY ADVERSE EVENT GRADING SCALE, CHILDREN
..................................................................................................................................................... 118 
APPENDIX D: MALI vital signs ADVERSE EVENT GRADING SCALE, CHILDREN ...... 119 
APPENDIX E: DOSE ESCALATION PEDIATRIC STUDY EXTENSION ........................... 120 
 

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LIST OF FIGURES 
Figure 1. Dose-escalation study flow diagrams. ........................................................................... 21 
Figure 2. Efficacy study flow diagram. ........................................................................................ 22 
Figure 3. Year 2 extension study design. ...................................................................................... 24 
Figure 4. Age-stratified point prevalence of asymptomatic P. falciparum infection detected by 
polymerase chain reaction (PCR) or blood smear at the end of the dry season in Kalifabougou, 
Mali (ClinicalTrials.gov Identifier: NCT01322581). ................................................................... 47 
Figure 5. Kaplan-Meier plots, stratified by age for time to first Pf infection by PCR during the 
malaria season in Kalifabougou, Mali (ClinicalTrials.gov Identifier: NCT01322581). ............... 53 
Figure 6. Kaplan-Meier plot stratified by age for time to first clinical malaria episode during the 
malaria season in Kalifabougou, Mali. Enrollment occurred just prior to the malaria season. 
Clinical malaria is defined by an axillary temperature of ≥37.5°C and ≥2,500 asexual Pf 
parasites/µL of blood (ClinicalTrials.gov Identifier: NCT01322581). ......................................... 63 
 
LIST OF TABLES 
Table 1. Study agent assignment and dosing by arm. ................................................................... 66 
Table 2. Standard event recording, assessment, and reporting timeframes. ................................. 83 
Table 3. Probability of events for different safety scenarios within an arm (n=6 or n=9). .......... 95 
Table 4. Power for efficacy evaluation from a 2-sided log-rank test with type I error rate of 0.025 
assuming 10% dropout. ................................................................................................................. 96 
Table 5. Minimum detectable difference in the event rate in arms receiving L9LS or placebo 
under a 2-sided type I error rate of 0.025...................................................................................... 97 
Table 6. Exact 95% CI of AE rate estimate within each arm of size 42. ...................................... 97 
Table 7. Power for between-arm comparison on time to infection based on two-sided log rank 
test at significance level 0.05. ....................................................................................................... 98 
 
 

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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 forms will be submitted to the FMOS/FAPH Ethics 
Committee (EC) for review and approval. Approval of both the protocol and the consent forms 
must be obtained before any subject is enrolled. Any amendment to the protocol will require 
review and approval by the EC before the changes are implemented to the study. In addition, all 
changes to the consent forms will be EC-approved; a determination will be made regarding 
whether a new consent needs to be obtained from subjects who provided consent using a 
previously approved form. 
 
 

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1 
PROTOCOL SUMMARY 
 
Synopsis 
Title: 
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 
Study Description: 
A two-part, phase 2 trial evaluating the safety and tolerability of one-
time subcutaneous (SC) or intravenous (IV) administration of 
monoclonal antibody (MAb) L9LS in healthy Malian adults and 
one-time SC administration of L9LS in healthy Malian children, as 
well as its protective efficacy against naturally occurring 
Plasmodium falciparum (Pf) infection over a 7-month malaria season 
in healthy Malian children 6-10 years of age. The primary study 
hypotheses are that L9LS will be safe and will produce protection 
against malaria infection when administered prior to the malaria 
season. Before study agent administration, all subjects will be given 
artemether-lumefantrine to clear any preexisting Pf blood-stage 
infection. 
 
Age de-escalation and dose-escalation study: The first part of the 
study is an age de-escalation and dose-escalation study for safety and 
tolerability. Adult subjects (N=18) in the dose-escalation study will 
be assigned in open-label fashion to 1 of 3 L9LS dose arms (n=6 for 
each dose level). Dosing will begin in the lowest dose arm (300 mg 
SC). Once all subjects in that arm reach day 7 post-administration, if 
no safety concerns have arisen, dosing will begin at the next dose 
level (600 mg SC). Once all subjects in that arm reach day 7 
post-administration, if no safety concerns have arisen, dosing will 
begin at the highest dose level (20 mg/kg IV). Once all adult subjects 
reach day 7 post-administration, if no safety concerns have arisen, 18 
subjects aged 6-10 years will be randomized 1:1 in double-blind 
fashion to 150 mg of L9LS SC (n=9) versus placebo SC (n=9). Once 
all 18 subjects reach day 7 post-administration, if no safety concerns 
have arisen, an additional 18 subjects aged 6-10 years will be 
randomized 1:1 to 300 mg of L9LS SC (n=9) versus placebo SC 
(n=9). Randomization of subjects aged 6-10 years in each L9LS dose 
arm will be weight-stratified (26-30 kg, n=6; 20-25 kg, n=6; 15-19 
kg, n=6) and enrollment will be weight de-escalated starting with 

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subjects weighing 26-30 kg. Adult subjects will be followed for 
safety to assess adverse events (AEs) at study visits 1, 3, 7, 14, 21, 
and 28 days after administration, and once every month thereafter 
through 28 weeks. Subjects aged 6-10 years will be followed at study 
visits 1, 3, 7, 14, 21, and 28 days after administration, and once every 
2 weeks thereafter through 28 weeks. Primary study assessments 
include physical examination and blood collection for identification 
of Pf infection and other research laboratory evaluations. After the 
last subject in the pediatric 300-mg L9LS dose arm reaches day 7 
safety follow-up, an interim safety evaluation will be performed 
before enrollment begins for the efficacy part of the study. Data from 
the 36 subjects aged 6-10 years enrolled in the dose-escalation study 
will be included in a secondary analysis to determine the relationship 
between L9LS concentration and the risk of Pf infection. For these 
36 subjects, blinding will be maintained for treatment assignment 
(L9LS versus placebo), but not for possible L9LS dose group. 
 
Efficacy study: The second part of the study is a weight-stratified, 
randomized, double-blind, placebo-controlled trial (N=225 total, 
n=75 for each of 2 treatment arms, n=75 for placebo arm) to assess 
safety and protective efficacy of L9LS and placebo administered SC 
in children 6-10 years of age. In this part of the study, 225 subjects 
will be randomized 1:1:1 to 150 mg of L9LS (n=75), 300 mg of 
L9LS (n=75), or placebo (n=75). Randomization of subjects in each 
arm will be weight-stratified (26-30 kg, n=75; 20-25 kg, n=75; 15-19 
kg, n=75). Subjects in the efficacy study will receive the study agent 
prior to the malaria season and be followed at study visits 1, 3, 7, 14, 
21, and 28 days later, and once every 2 weeks thereafter through 24 
weeks. Primary study assessments include physical examination and 
blood collection for identification of Pf infection and other research 
laboratory evaluations. 
 
Year 2 extension: Prior to the last study visit of the original protocol 
described above (January 2023 - February 2023), study participants 
who remain enrolled in the dose-escalation and efficacy studies will 
be invited to participate in a 12-month extension study. After the 
safety and efficacy results are unblinded (approximately March/April 
2023), participants who agree to continue with the extension will be 
grouped into one of 3 arms based on their original study arm 
assignment:  

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Arm 1: Up to 84 subjects who received 150 mg of L9LS in year 1 (9 
from the dose-escalation study, plus 75 from the efficacy study). 
 
Arm 2: Up to 84 subjects who received 300 mg of L9LS in year 1 (9 
from the dose-escalation study, plus 75 from the efficacy study). 
 
Arm 3: Up to 93 subjects who received placebo in year 1 (18 from 
the dose-escalation study, plus 75 from the efficacy study). 
 
The protocol extension employs a pre-specified, adaptive design 
based on the time-to-event efficacy of 150 mg and 300 mg of L9LS 
against P. falciparum infection as detected by blood smear observed 
after the first malaria season in the original protocol. Specifically, if 
150 mg and 300 mg of L9LS both show ≥60% efficacy during the 
first malaria season (based on the upper bound of the two-sided 95% 
confidence interval [CI]), participants will be re-randomized 1:1 in a 
double-blind fashion within each arm to receive a single dose of 
either L9LS (150 or 300 mg depending on study arm) or placebo 
administered SC before the 2023 malaria season.  
 
The same randomization scheme will be followed if in the first 
malaria season the 300-mg dose of L9LS shows ≥60% efficacy 
(based on the upper bound of the two-sided 95% CI) and the 150-mg 
dose of L9LS shows <60% efficacy (based on the upper bound of the 
two-sided 95% CI) but the difference between their respective point 
estimates of efficacy is ≤10%, with the exception that children who 
received placebo in year 1 will receive 300 mg of L9LS (or placebo) 
in year 2.  
 
If 300 mg of L9LS shows ≥60% efficacy (based on the upper bound 
of the two-sided 95% CI) and 150 mg of L9LS shows <60% efficacy 
(based on the upper bound of the two-sided 95% CI) but the 
difference between their respective point estimates of efficacy is 
>10% during the first malaria season, participants will be re-
randomized 1:1 in a double-blind fashion within each arm to receive 
a single dose of either 300 mg of L9LS or placebo administered SC 
before the 2023 malaria season.  
 

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If 150 mg and 300 mg of L9LS both show <60% efficacy (based on 
the upper bound of the two-sided 95% CI) after the first malaria 
season, the protocol extension will be abandoned.  
 
Before study agent administration, all subjects will be given 
artemether-lumefantrine to clear any preexisting Pf blood-stage 
infection.  
 
Subjects will be followed at study visits 1, 3, 7, 14, 21, and 28 days 
after administration, and once every 2 weeks thereafter through 28 
weeks, with a final visit occurring on study day 252 (36 weeks) to 
collect a final PK sample. 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. 
Objectives: 
 
Primary Objectives: 
1. Dose escalation: To evaluate the safety and tolerability of 
L9LS administered at 300 mg and 600 mg SC and 20 mg/kg 
IV in healthy Malian adults, and at 150 mg and 300 mg SC in 
healthy Malian children. 
2. Efficacy: To evaluate the safety and tolerability of L9LS 
administered at 150 mg and 300 mg SC in healthy Malian 
children. 
3. Efficacy: To determine if SC administration of L9LS at 150 
mg and 300 mg (compared to placebo) mediates protection 
against naturally occurring Pf infection in healthy Malian 
children during a single malaria season as detected from 
microscopic examination of thick blood smear. 
 
Secondary Objectives: 
Data from both parts of this study will be used to address the 
following objectives: 
1. To evaluate the PK of L9LS throughout the study at dose 
levels of 300 mg and 600 mg SC and 20 mg/kg IV in healthy 
Malian adults, and at 150 mg and 300 mg SC in healthy 
Malian children, and to correlate L9LS serum concentration 
with Pf infection risk. 

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2. To determine if SC administration of L9LS at 150 mg and 
300 mg (compared to placebo) mediates protection against 
naturally occurring Pf infection in healthy Malian children 
during a single malaria season as detected by reverse 
transcription polymerase chain reaction (RT-PCR). 
3. To determine if SC administration of L9LS at 150 mg and 
300 mg (compared to placebo) mediates protection against 
clinical malaria in healthy Malian children during a single 
malaria season as defined by an illness accompanied by 
measured axillary fever ≥37.5°C, or history of fever 
(subjective or objective) in the previous 24 hours, and Pf 
asexual parasitemia >5,000 parasites/µL as detected from 
microscopic examination of thick blood smear. 
4. To determine if SC administration of L9LS at 150 mg and 
300 mg (compared to placebo) mediates protection against 
clinical malaria in healthy Malian children during a single 
malaria season as defined by an illness accompanied by any 
level of Pf asexual parasitemia as detected from microscopic 
examination of thick blood smear that results in the 
administration of anti-malarial treatment. 
5. To evaluate the PK of L9LS throughout the study at the dose 
of 150 mg and 300 mg and to correlate L9LS serum 
concentration with Pf infection risk. 
6. To evaluate the PK of L9LS throughout the study at the dose 
of 150 mg and 300 mg and to correlate L9LS serum 
concentration with clinical malaria risk. 
 
Extension Phase Primary Objectives: 
1. To evaluate the safety and tolerability of a second SC dose of 
L9LS administered at 150 mg and 300 mg (compared to 
placebo) in healthy Malian children.  
2. To evaluate the PK of L9LS throughout the study at dose 
levels of 150 mg and 300 mg SC in healthy Malian 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. 
 

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Extension Phase Exploratory Objectives (see Figure 3 for study arm 
definitions): 
1. To assess the efficacy of a second SC dose of L9LS at 150 
mg and 300 mg (compared to placebo) in mediating 
protection against Pf infection and clinical malaria in healthy 
Malian children during a second malaria season (arms 1a vs. 
1b; arms 2a vs. 2b), and to assess if this efficacy is influenced 
by whether or not a prior dose of L9LS was administered in 
year 1 (arms 1a vs. 3b; arms 2a vs. 3b).  
2. To assess the efficacy of a first SC dose of L9LS at 150 mg or 
300 mg (compared to placebo) in mediating protection 
against Pf infection and clinical malaria in healthy Malian 
children during the second malaria season (arms 3a vs. 3b).  
3. To assess the risk of clinical malaria in children who received 
L9LS in year 1 but not year 2 (compared to children who 
received placebo both years; arms 1b vs. 3b; arms 2b vs. 3b).  
4. To evaluate the PK of L9LS throughout the study at the dose 
of 150 mg and 300 mg and to correlate L9LS serum 
concentration with Pf infection risk. 
5. To evaluate the PK of L9LS throughout the study at the dose 
of 150 mg and 300 mg and to correlate L9LS serum 
concentration with clinical malaria risk. 
Endpoints: 
Primary Endpoints: 
1. Dose escalation and efficacy: Incidence and severity of local 
and systemic AEs occurring within 7 days after the 
administration of L9LS. 
2. Efficacy: Pf blood-stage infection as detected by microscopic 
examination of thick blood smears obtained between 1 week 
and 24 weeks after administration of L9LS or placebo. 
 
Secondary Endpoints: 
Data from both parts of this study will be used to assess the 
following endpoints: 
1. Measurement of L9LS in sera of recipients. 
2. Pf blood-stage infection as detected by RT-PCR for 28 weeks 
after administration of L9LS or placebo for dose escalation 
subjects or 24 weeks after administration of L9LS or placebo 
for efficacy subjects. 

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3. Incidence of clinical malaria (definition 1, see section 2.2.2.3) 
for 28 weeks after administration of L9LS or placebo for dose 
escalation subjects or 24 weeks after administration of L9LS 
or placebo for efficacy subjects. 
4. Incidence of clinical malaria (definition 2, see section 2.2.2.3) 
for 28 weeks after administration of L9LS or placebo for dose 
escalation subjects or 24 weeks after administration of L9LS 
or placebo for efficacy subjects. 
5. PK analysis of L9LS and the association of L9LS 
concentration with Pf infection risk. 
6. PK analysis of L9LS and the association of L9LS 
concentration with clinical malaria risk. 
 
Extension Phase Primary Endpoints: 
1. Incidence and severity of local and systemic AEs occurring 
within 7 days after the administration of L9LS. 
2. Measurement of L9LS in sera of recipients. 
3. Measurement of ADA in sera of recipients. 
 
Extension Phase Exploratory Endpoints: 
1. Pf blood-stage infection as detected by microscopic 
examination of thick blood smears obtained between 1 week 
and 28 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 28 weeks after 
administration of L9LS or placebo. 
3. Incidence of clinical malaria (definition 1, see section 2.2.2.3) 
between 1 week and 28 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 
concentration with clinical malaria risk. 
Study Population: 
Healthy Malian adults (aged ≥18 to 55 years) and children (aged 6 to 
10 years) residing in Kalifabougou and Torodo who are not receiving 
seasonal malaria chemoprevention (SMC). 
 
The year 2 extension phase will include only participants who are 
currently enrolled in the study and agree to continue in the extension.  

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Phase: 
2 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
The MRTC clinics in Kalifabougou and Torodo. All screening, day 0 
(study agent administration), and day 14 visits will be performed at 
Kalifabougou only. Both sites will conduct recruitment, enrollment, 
follow-up visits (other than day 14 as noted above), and unscheduled 
study visits. 
 
For the year 2 extension phase, all day 0 (study agent administration) 
will be performed at Kalifabougou only. Both sites (Kalifabougou 
and Torodo) will conduct recruitment, enrollment, follow-up visits, 
and unscheduled study visits. 
Description of Study 
Intervention: 
The study agent will be administered as a one-time SC injection or 
IV infusion as follows: L9LS at a dose of 150 mg SC (children only), 
300 mg SC (children and adults), 600 mg SC (adults only), or 20 
mg/kg IV (adults only), or matching placebo (children only). 
 
In the year 2 extension phase, the study agent will be administered as 
a one-time SC injection as follows: L9LS at a dose of 150 mg or 300 
mg, or matching placebo. 
Study Duration: 
36 months. 
Participant 
Duration: 
7 months for dose escalation subjects (plus 2 months for those in the 
pediatric dose-escalation cohort who agree to additional follow-up 
visits, see Appendix E); 6 months for efficacy subjects. 
 
Year 2 extension phase: 12 months from the time of enrollment in the 
extension. 
 
 

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Schema 
Figure 1a. Adult cohort. 
 
 
Screening: Obtain informed consent. Assess eligibility; obtain and document history and 
perform screening evaluations; assign study identification number. 
Enrollment (Day -14 ±7): Total N=18. Confirmation of eligibility; first dose of artemether-
lumefantrine. 
Follow-up 1, 3, 7, 14, 
21, and 28 days later, 
then every month 
through week 28. 
Final assessments week 
28 (day 196). 
Safety review when last  
Arm 1 subject reaches day 7. 
Arm 1 
n=6 
Day 0:  
Baseline assessments. 
L9LS 300 mg SC 
administration and 
monitoring. 
Follow-up 1, 3, 7, 14, 
21, and 28 days later, 
then every month 
through week 28. 
Final assessments week 
28 (day 196). 
 
Arm 3 
n=6 
Day 0:  
• Baseline assessments. 
• L9LS 20 mg/kg IV 
administration and 
monitoring. 
Follow-up 1, 3, 7, 14, 
21, and 28 days later, 
then every month 
through week 28. 
Final assessments week 
28 (day 196). 
Safety review when last  
Arm 2 subject reaches day 
Arm 2 
n=6 
Day 0:  
• Baseline assessments. 
• L9LS 600 mg SC 
administration and 
monitoring. 

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Figure 1b. 6-10 year old cohort. 
 
Figure 1. Dose-escalation study flow diagrams. 
 
 
Screening: Obtain informed consent. Assess eligibility; obtain and 
document history and perform screening evaluations; assign study 
identification number. 
Enrollment (Day -14 ±7): Total N=36. Confirmation of eligibility; first dose 
of artemether-lumefantrine. 
Follow-up 1, 3, 7, 14, 21, and 
28 days later, then every 2 
weeks through week 28. 
Final assessments week 28 
(day 196).* 
Safety review when last  
Arm 1 subject reaches day 7. 
Arm 1 
n=18 
Day 0:  
Baseline assessments. 
Randomization. 
150 mg L9LS (n=9) or placebo 
(n=9) administration and 
monitoring. 
Follow-up 1, 3, 7, 14, 21, 
and 28 days later, then every 
2 weeks through week 28. 
Final assessments week 28 
(day 196).* 
Interim DSMB safety analysis after last Arm 2 subject reaches day 7, 
prior to first enrollment in efficacy study. 
 
*Participants offered enrollment in extended follow-up for 2 additional months; see 
Appendix E. 
Arm 2 
n=18 
Day 0:  
• Baseline assessments. 
• Randomization. 
• 300 mg L9LS (n=9) or placebo 
(n=9) administration and 
monitoring. 

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Figure 2. Efficacy study flow diagram. 
 
 
Day 0: 
Baseline assessments. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded study agent administration (assigned by arm) and post-administration monitoring. 
Screening: Obtain informed consent. Assess eligibility; obtain and 
document history and perform screening evaluations. 
Enrollment (Day -14 ±7): Total  N=225. Confirmation of eligibility; first 
dose of artemether-lumefantrine; assign study identification number. 
Arm 3 
n=75 
Placebo 
Follow-up: 
Follow-up 1, 3, 7, 14, 21, and 28 days later, then every 2 weeks through 
week 24. 
[Unscheduled visits as needed due to malaria or other symptoms.] 
Arm 2 
n=75 
300 mg L9LS 
 
Arm 1 
n=75 
150 mg L9LS 
Randomize 
 
225 subjects will be randomized 1:1:1 to 150 
mg L9LS (n=75), 300 mg L9LS (n=75), or 
placebo (n=75). 
 

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Figure 3a. Extension study design if 150 mg and 300 mg of L9LS both show ≥60% efficacy by 
time-to-event analysis after the first malaria season (based on the upper bound of the two-sided 
95% CI).  Arm 3a or 3b may include 1 additional participant depending on randomization 
schema and total number that consent to the extension study. 
 
 
 
 
 
Figure 3b. Extension study design if 300 mg of L9LS shows ≥60% efficacy (based on the upper 
bound of the two-sided 95% CI) and 150 mg of L9LS shows <60% efficacy (based on the upper 
bound of the two-sided 95% CI) but the difference between their respective point estimates of 
efficacy is ≤10%. Arm 3a or 3b may include 1 additional participant depending on 
randomization schema and total number that consent to the extension study. 
 
 
 
 
 
 
 
Dose Escalation
150 mg
n=9
Dose Escalation
300 mg
n=9
Dose Escalation
placebo
n=18
Efficacy
150 mg
n=75
Efficacy
300 mg
n=75
Efficacy
placebo
n=75
Arm 1
n=84
Arm 1a
Yr 1: 150 mg L9LS
Yr 2: 150 mg L9LS
n=42
Year 1 
assignment
Year 2 
•
Randomize 1:1 
within each arm 
•
Double-blinded
•
Placebo-controlled
Arm 1b
Yr 1: 150 mg L9LS
Yr 2: placebo
n=42
Arm 2
n=84
Arm 2a
Yr 1: 300 mg L9LS
Yr 2: 300 mg L9LS
n=42
Arm 2b
Yr 1: 300 mg L9LS
Yr 2: placebo
n=42
Arm 3
n=93
Arm 3a
Yr 1: placebo
Yr 2: 150 mg L9LS
n=46
Arm 3b
Yr 1: placebo
Yr 2: placebo
n=46
Dose Escalation
150 mg
n=9
Dose Escalation
300 mg
n=9
Dose Escalation
placebo
n=18
Efficacy
150 mg
n=75
Efficacy
300 mg
n=75
Efficacy
placebo
n=75
Arm 1
n=84
Arm 1a
Yr 1: 150 mg L9LS
Yr 2: 150 mg L9LS
n=42
Year 1 
assignment
Year 2 
•
Randomize 1:1 
within each arm 
•
Double-blinded
•
Placebo-controlled
Arm 1b
Yr 1: 150 mg L9LS
Yr 2: placebo
n=42
Arm 2
n=84
Arm 2a
Yr 1: 300 mg L9LS
Yr 2: 300 mg L9LS
n=42
Arm 2b
Yr 1: 300 mg L9LS
Yr 2: placebo
n=42
Arm 3
n=93
Arm 3a
Yr 1: placebo
Yr 2: 300 mg L9LS
n=46
Arm 3b
Yr 1: placebo
Yr 2: placebo
n=46

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Figure 3c. Extension study design if 300 mg of L9LS shows ≥60% efficacy (based on the upper 
bound of the two-sided 95% CI) and 150 mg of L9LS shows <60% efficacy (based on the upper 
bound of the two-sided 95% CI) but the difference between their respective point estimates of 
efficacy is >10%. Arm 3a or 3b may include 1 additional participant depending on 
randomization schema and total number that consent to the extension study. 
 
 
Note: If 150 mg and 300 mg of L9LS both show <60% efficacy (based on the upper bound of 
their two-sided 95% CIs) by time-to-event analysis after the first malaria season, the protocol 
extension will be abandoned.  
 
Figure 3. Year 2 extension study design. 
 
Dose Escalation
150 mg
n=9
Dose Escalation
300 mg
n=9
Dose Escalation
placebo
n=18
Efficacy
150 mg
n=75
Efficacy
300 mg
n=75
Efficacy
placebo
n=75
Arm 1
n=84
Arm 1a
Yr 1: 150 mg L9LS
Yr 2: 300 mg L9LS
n=42
Year 1 
assignment
Year 2 
•
Randomize 1:1 
within each arm 
•
Double-blinded
•
Placebo-controlled
Arm 1b
Yr 1: 150 mg L9LS
Yr 2: placebo
n=42
Arm 2
n=84
Arm 2a
Yr 1: 300 mg L9LS
Yr 2: 300 mg L9LS
n=42
Arm 2b
Yr 1: 300 mg L9LS
Yr 2: placebo
n=42
Arm 3
n=93
Arm 3a
Yr 1: placebo
Yr 2: 300 mg L9LS
n=46
Arm 3b
Yr 1: placebo
Yr 2: placebo
n=46

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Schedule of Activities (SOA) 
 Adult cohort dose escalation 
Study Day 
Screen 
Enroll 1 
0 
1 
3 
7 
14 
21 
28 
56 
84 
112 
140 
168 
196 
Illness 
Visit 
ET 
Visit 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±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 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (temperature, 
blood pressure, and pulse) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Artemether-lumefantrine 
administration 
 
X 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
X 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy prevention 
counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory Evaluations 
Test 
Tube 
(Blood volume in mL) 
Urinalysis 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Day 
Screen 
Enroll 1 
0 
1 
3 
7 
14 
21 
28 
56 
84 
112 
140 
168 
196 
Illness 
Visit 
ET 
Visit 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
Pregnancy test 
(urine/serum; for 
women) 
- 
X 
X 
X 5 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
HIV, HBV, HCV 
screen 6 
SST 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
EDTA 
3 
3 
3 5 
 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
Hemoglobin type 
EDTA 
(X) 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT, Cr 
SST 
3 
3 
3 5 
 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
Blood smear and 
dried blood spot 
for Pf RT-PCR 8 
- 
 
X 
X 
 
 
 
X 
0.5 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK studies 
SST 
 
 
8 9 
4 
 
4 
4 
 
4 
4 
4 
4 
4 
4 
4 
 
 
Serum storage 
SST 
 
 
8 
 
 
8 
 
 
8 
 
8 
 
 
8 
8 
 
 
ADA 
SST 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
(X) 
 
 
(X) 
(X) 
 
 
PBMC storage 
CPT 
 
 
8 
 
 
8 
 
 
8 
 
 
 
 
 
8 
 
 
RNA-seq 
PaxGene 
 
2.5 
2.5 5 
 
 
2.5 
 
 
2.5 
 
2.5 
 
 
 
 
 
 
Daily volume (mL) 
9 
8.5 
32.5 
4 
6 
28.5 
10 
0.5 
22.5 
4 
14.5 
4 
4 
12 
20 
 
 
Cumulative volume (mL) 
9 
17.5 
50 
54 
60 
88.5 
98.5 
99 
121.5 
125.5 
140 
144 
148 
160 
180 
- 
- 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; CPT, cell preparation tube; Cr, creatinine; ECG, electrocardiogram; 
EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; ET, early termination; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; PBMC, peripheral blood mononuclear cell; Pf, Plasmodium falciparum; PK, pharmacokinetics; RDT, rapid diagnostic test; RT-PCR, 
reverse transcription polymerase chain reaction; SST, serum-separating tube. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from the tube shown in the preceding row. 
 
Notes: 
• Screening, day 0, and day 7 visits will take place at Kalifabougou for all subjects, regardless of residence. All other visits can take place at either site. 
• 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. Unscheduled illness visits will take place at Kalifabougou or Torodo, depending on the subject’s residence. 
 

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Footnotes: 
1 If enrollment is within 2 days of screening, duplicate procedures will not be repeated. 
2 Complete/comprehensive at screening; targeted/interim at other visits. 
3 Enrollment is defined as the time of first artemether-lumefantrine administration. (For women, negative pregnancy test must be confirmed prior to 
administration/enrollment.) The first dose will be directly observed in the clinic. The subsequent 5 doses given over 3 days will be observed by guides in the subject’s 
home or at the clinic. The study investigators will provide a fat-containing drink (e.g. milk) to study participants immediately prior to administering artemether-
lumefantrine to enhance its absorption. All artemether-lumefantrine doses will be completed prior to day 0. 
4 All other study procedures must be completed prior to study agent administration. Subject will be monitored after each administration, and vital signs will be recorded 
directly after administration and hourly during post-administration monitoring. The first subject in a dose arm will be monitored for at least 4 hours after administration; 
all other subjects will be monitored for at least 2 hours after administration. Prior to discharge, subject will be assessed for local reactogenicity (including pain/tenderness, 
swelling, redness, bruising, and pruritus at the site of administration) 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. 
5 Collected prior to study agent administration. For women, negative pregnancy test must be confirmed prior to administration. Other indicated tests may be performed 
after administration. 
6 Viral screenings will be performed according to international guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus enzyme-linked immunosorbent assay 
(ELISA) if the RDTs are discordant; subject will be referred for medical care for 2 positive RDTs or a positive ELISA. Pre- and post-test HIV counseling will be 
provided. Hepatitis testing will be an HBV surface antigen test (ELISA) and HCV test (ELISA, PCR if indicated). A subject who is HBV and/or HCV positive will be 
referred for care regardless of the ALT result.  
7 EDTA tube will be stored at screening, and hemoglobin typing will be performed if the subject is enrolled; this test will not be used in eligibility assessments. 
8 If positive for malaria parasite infection, parasite genotyping may be performed. Sample will be obtained by venipuncture. 
9 For PK, 4 mL serum will be collected prior to study agent administration, and an additional 4 mL serum will be collected about 1 hour (±30 minutes) after 
administration. 
 6-10 year old cohort dose escalation 
Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 112 126 
140 154 168 
182 
196 
Illness 
Visit 
ET 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Clinical Procedures/Evaluations 
Study comprehension exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of identity, 
age, and residency 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 112 126 
140 154 168 
182 
196 
Illness 
Visit 
ET 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Physical exam 2 
X 
X 
X 
X 
X 
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, 
blood pressure, and pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 2 
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 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Artemether-lumefantrine 
administration 
 
X 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
X 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
Urinalysis 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, 
HCV screen 6 
SST 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
EDTA 
1 
1 
1 5 
 
1 
1 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin 
type 
EDTA 
(X) 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT, Cr 
SST 
3 
3 
3 5 
 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood smear and 
dried blood spot 
for Pf RT-PCR 8 
- 
 
X 
X 
 
X 
X 
X 
0.5 
X 
0.5 
X 
0.5 X 
0.5 X 
0.5 
X 
0.5 
X 
0.5 
X 
X 
 
PK studies 
SST 
 
4 
4 9 
 
 
4 
 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
Serum storage 
SST 
 
 
(X)  
 
(X)  
 
(X)  
 
 
(X) 
 
 
 
 
 
(X) 
 
(X) 
 
 

Abbreviated Title: Anti-malaria MAb in Malian children  
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Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 112 126 
140 154 168 
182 
196 
Illness 
Visit 
ET 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
ADA 
SST 
 
 
(X)  
 
(X)  
 
(X)  
 
 
(X) 
 
 
 
 
 
(X) 
 
(X) 
 
 
PBMC storage 
CPT 
 
 
4 
 
 
4 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
RNA-seq            PaxGene 
 
(X) 
(X)5  
 
(X)  
 
0.5 
 
 
 
0.5 
 
 
 
 
 
 
 
 
 
 
Daily volume (mL) 
4 
8 
12 
- 
4 
12 
4 
0.5 
8.5 
0.5 
4 
0.5 
4.5 
0.5 
4 
0.5 
4 
0.5 
4 
0.5 
8 
 
 
Cumulative volume (mL) 
4 
12 
24 
24 
28 
40 
44 
44.5 
53 
53.5 
57.5 
58 
62.5 
63 
67 
67.5 
71.5 
72 
76 
76.5 
84.5 
- 
- 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; CPT, cell preparation tube; Cr, creatinine; ECG, electrocardiogram; 
EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; ET, early termination; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; PBMC, peripheral blood mononuclear cell; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum-separating tube; RDT, rapid 
diagnostic test; RT-PCR, reverse transcription polymerase chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from a tube collected for another indicated evaluation.  
 
Notes: 
• Screening, day 0, and day 14 visits will take place at Kalifabougou for all subjects, regardless of residence. All other visits can take place at either site. 
• 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. Unscheduled illness visits will take place at Kalifabougou or Torodo, depending on the subject’s residence. 
• Participants will be offered extended follow-up visits for an additional 2 months after Day 196, see Appendix E. 
 
Footnotes: 
1 If enrollment is within 2 days of screening, duplicate procedures will not be repeated. 
2 Complete/comprehensive at screening; targeted/interim at other visits. 
3 Enrollment is defined as the time of first artemether-lumefantrine administration. The first dose will be directly observed in the clinic. The subsequent 5 doses given over 
3 days will be observed by guides in the subject’s home or at the clinic. The study investigators will provide a fat-containing drink (e.g. milk) to study participants 
immediately prior to administering artemether-lumefantrine to enhance its absorption. All artemether-lumefantrine doses will be completed prior to day 0. 
4 All other study procedures must be completed prior to study agent administration. For the dose-escalation study, the first subject in a dose arm will be monitored for at 
least 4 hours after study agent administration and vital signs will be recorded hourly; all other subjects will be monitored for at least 2 hours after study agent 
administration and vital signs will be recorded hourly. 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. 
5 Collected prior to study agent administration. Other indicated tests may be performed after study agent administration. 

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6 Viral screenings will be performed according to international guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus enzyme-linked immunosorbent assay 
(ELISA) if the RDTs are discordant; subject will be referred for medical care for 2 positive RDTs or a positive ELISA. Pre- and post-test HIV counseling will be 
provided. Hepatitis testing will be an HBV surface antigen test (ELISA) and HCV test (ELISA, PCR if indicated). A subject who is HBV and/or HCV positive will be 
referred for care regardless of the ALT result. 
7 EDTA tube will be stored at screening, and hemoglobin typing will be performed if the subject is enrolled; this test will not be used in eligibility assessments. 
8 The blood smear will be read in real time only if medical history and/or physical exam are suggestive of clinical malaria. If positive for malaria parasite infection, 
parasite genotyping may be performed. 
9 For PK, 4 mL serum will be collected about 1 hour (±30 minutes) after administration. 
 6-10 year old cohort efficacy 
Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 112 126 
140 154 168 
Illness 
Visit
ET 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±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 2 
X 
X 
X 
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 
 
 
 
 
Vital signs (temperature, 
blood pressure, and pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Artemether-lumefantrine 
administration 
 
X 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
X 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
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 Malian children  
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Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 112 126 
140 154 168 
Illness 
Visit
ET 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Laboratory Evaluations 
Test 
Tube 
(Blood volume in mL) 
Urinalysis 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, 
HCV screen 6 
SST 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
EDTA 
1 
1 
1 5 
 
1 
1 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin 
type 
EDTA 
(X) 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT, Cr 
SST 
3 
3 
3 5 
 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood smear and 
dried blood spot 
for Pf RT-PCR 8 
- 
 
X 
X 
 
X 
X 
X 
0.5 
X 
0.5 
X 
0.5 X 
0.5 X 
0.5 
X 
0.5 X 
X 
 
PK studies 
SST 
 
4 
4 9 
 
 
4 
 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
Serum storage 
SST 
 
 
(X)  
 
(X)  
 
(X)  
 
 
(X) 
 
 
 
 
 
(X) 
 
 
ADA 
SST 
 
 
(X)  
 
(X)  
 
(X)  
 
 
(X) 
 
 
 
 
 
(X) 
 
 
PBMC storage 
CPT 
 
 
4 
 
 
4 
 
 
4 
 
 
 
 
 
 
 
 
 
4 
 
 
RNA-seq            PaxGene 
 
(X) 
(X)5  
 
(X)  
 
0.5 
 
 
 
0.5 
 
 
 
 
 
 
 
 
Daily volume (mL) 
4 
8 
12 
- 
4 
12 
4 
0.5 
8.5 
0.5 
4 
0.5 
4.5 
0.5 
4 
0.5 
4 
0.5 
4 
 
 
Cumulative volume (mL) 
4 
12 
24 
24 
28 
40 
44 
44.5 
53 
53.5 
57.5 
58 
62.5 
63 
67 
67.5 
71.5 
72 
76 
- 
- 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; CPT, cell preparation tube; Cr, creatinine; ECG, electrocardiogram; 
EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; ET, early termination; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; PBMC, peripheral blood mononuclear cell; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum-separating tube; RDT, rapid 
diagnostic test; RT-PCR, reverse transcription polymerase chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from a tube collected for another indicated evaluation.  
 
Notes: 
• Screening, day 0, and day 14 visits will take place at Kalifabougou for all subjects, regardless of residence. All other visits can take place at either site. 

Abbreviated Title: Anti-malaria MAb in Malian children  
32 
Version Date: 14 March 2024 
Template version date 05.06.2021 
 
• 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. Unscheduled illness visits will take place at Kalifabougou or Torodo, depending on the subject’s residence. 
 
Footnotes: 
1 If enrollment is within 2 days of screening, duplicate procedures will not be repeated. 
2 Complete/comprehensive at screening; targeted/interim at other visits. 
3 Enrollment is defined as the time of first artemether-lumefantrine administration. The first dose will be directly observed in the clinic. The subsequent 5 doses given over 
3 days will be observed by guides in the subject’s home or at the clinic. The study investigators will provide a fat-containing drink (e.g. milk) to study participants 
immediately prior to administering artemether-lumefantrine to enhance its absorption. All artemether-lumefantrine doses will be completed prior to day 0. 
4 All other study procedures must be completed prior to study agent administration. For the efficacy study, each subject will be monitored for at least 60 minutes after 
study agent administration and vital signs will be recorded 1 hour (± 15 min) 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. 
5 Collected prior to study agent administration. Other indicated tests may be performed after study agent administration. 
6 Viral screenings will be performed according to international guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus enzyme-linked immunosorbent assay 
(ELISA) if the RDTs are discordant; subject will be referred for medical care for 2 positive RDTs or a positive ELISA. Pre- and post-test HIV counseling will be 
provided. Hepatitis testing will be an HBV surface antigen test (ELISA) and HCV test (ELISA, PCR if indicated). A subject who is HBV and/or HCV positive will be 
referred for care regardless of the ALT result. 
7 EDTA tube will be stored at screening, and hemoglobin typing will be performed if the subject is enrolled; this test will not be used in eligibility assessments. 
8 The blood smear will be read in real time only if medical history and/or physical exam are suggestive of clinical malaria. If positive for malaria parasite infection, 
parasite genotyping may be performed. 
9 For PK, 4 mL serum will be collected about 1 hour (±30 minutes) after administration. 
 
 

Abbreviated Title: Anti-malaria MAb in Malian children  
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 Year 2 Extension 
Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 126 
140 154 168 
182 196 224 252 
Illness Visit 
ET 
Window (days) 
-56  
to -7 
-14±7 
- 
+1 ±1 ±2 ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 Clinical Procedures/Evaluations 
Study comprehension exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify informed consent for 
extension 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of identity, 
age, and residency 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 2 
X 
X 
X 
X 
X 
X 
X 
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 
 
 
 
X 
X 
X 
 
 
Vital signs (temperature, 
blood pressure, and pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 2 
X 
X 
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 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Artemether-lumefantrine 
administration 
 
X 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
X 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
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) 
Urinalysis 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, 
HCV screen 6 
SST 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Abbreviated Title: Anti-malaria MAb in Malian children  
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Version Date: 14 March 2024 
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Study Day 
Screen Enroll 1 
0 
1 
3 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 126 
140 154 168 
182 196 224 252 
Illness Visit 
ET 
Window (days) 
-56  
to -7 
-14±7 
- 
+1 ±1 ±2 ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
CBC with 
differential 
EDTA 
1 
1 
1 5 
 
1 
1 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT, Cr 
SST 
3 
3 
3 5 
 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood smear and 
dried blood spot 
for Pf RT-PCR 7 
- 
 
X 
X 
 
X 
X 
X 
0.5 
X 
0.5 
0.5 0.5 
X 
0.5 
0.5 0.5 
X 
0.5 0.5 
0.5 X 
0.5 
X 
0.5  
PK studies 
SST 
 
4 
4 8 
 
 
4 
 
 
4 
 
 
 
4 
 
 
 
4 
 
 
 
4 
 
4 
 
 
Serum storage 
SST 
 
 
(X)  
 
(X)  
 
(X)  
 
 
(X)  
 
 
(X) 
 
 
 
(X)  
(X)  
 
ADA 
SST 
 
 
(X)  
 
(X)  
 
(X)  
 
 
(X)  
 
 
(X) 
 
 
 
(X)  
(X)  
 
PBMC storage 
CPT 
 
 
4 
 
 
4 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
4 
 
4 
 
 
RNA-seq             PaxGene 
 
(X) 
(X)5  
 
(X)  
 
0.5 
 
 
 
0.5 
 
 
 
 
 
 
 
 
 
 
 
 
Daily volume (mL) 
4 
8 
12 
- 
4 
12 
4 
0.5 
8.5 
0.5 
0.5 
0.5 
4.5 
0.5 
0.5 
0.5 
4 
0.5 
0.5 
0.5 8 
0.5 
8 
0.5  
Cumulative volume (mL) 
4 
12 
24 
24 28 40 
44 44.5 
53 
53.5 
54 
54.5 
59 
59.5 
60 
60.5 
64.5 
65 
65.5 66 
74 
74.5 82.5 - 
- 
Abbreviations: ADA, anti-drug antibodies; ALT, alanine transaminase; CBC, complete blood count; CPT, cell preparation tube; Cr, creatinine; ECG, electrocardiogram; 
EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; ET, early termination; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; PBMC, peripheral blood mononuclear cell; Pf, Plasmodium falciparum; PK, pharmacokinetics; SST, serum-separating tube; RDT, rapid 
diagnostic test; RT-PCR, reverse transcription polymerase chain reaction. 
 
(X) indicates that no additional blood will be drawn; the test will be performed from a tube collected for another indicated evaluation.  
 
Notes: 
• All day 0 visits will take place at Kalifabougou for all subjects, regardless of residence. All other visits can take place at either site. 
• 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. Unscheduled illness visits will take place at Kalifabougou or Torodo, depending on the subject’s residence. 
 
Footnotes: 
1 If enrollment is within 2 days of screening, duplicate procedures will not be repeated. 
2 Complete/comprehensive at screening; targeted/interim at other visits. 

Abbreviated Title: Anti-malaria MAb in Malian children  
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Version Date: 14 March 2024 
Template version date 05.06.2021 
 
3 Enrollment is defined as the time of first artemether-lumefantrine administration. The first dose will be directly observed in the clinic. The subsequent 5 doses given over 
3 days will be observed by guides in the subject’s home or at the clinic. The study investigators will provide a fat-containing drink (e.g. milk) to study participants 
immediately prior to administering artemether-lumefantrine to enhance its absorption. All artemether-lumefantrine doses will be completed prior to day 0. 
4 All other study procedures must be completed prior to study agent administration. The first 30 subjects will be monitored for at least 2 hours (+/- 15 minutes) after study 
agent administration and vital signs will be recorded for 1 hour (+/- 15 minutes) after study agent administration (based on randomization this will be approximately 5 
subjects in each sub-arm). Thereafter, all subjects will be monitored for at least 60 minutes (+/- 15 minutes) after study agent administration and vital signs will be 
recorded 1 hour (+/- 15 minutes) 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. 
5 Collected prior to study agent administration. Other indicated tests may be performed after study agent administration. 
6 Viral screenings will be performed according to international guidelines. HIV testing will be 2 rapid diagnostic tests (RDTs), plus enzyme-linked immunosorbent assay 
(ELISA) if the RDTs are discordant; subject will be referred for medical care for 2 positive RDTs or a positive ELISA. Pre- and post-test HIV counseling will be 
provided. Hepatitis testing will be an HBV surface antigen test (ELISA) and HCV test (ELISA, PCR if indicated). A subject who is HBV and/or HCV positive will be 
referred for care regardless of the ALT result. 
7 The blood smear will be read in real time only if medical history and/or physical exam are suggestive of clinical malaria. If positive for malaria parasite infection, 
parasite genotyping may be performed. 
8 For PK, 4 mL serum will be collected about 1 hour (±30 minutes) after administration. 
 
 

Abbreviated Title: Anti-malaria MAb in Malian children  
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Version Date: 14 March 2024 
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2 
INTRODUCTION 
 
Study Rationale 
Malaria is a mosquito-borne protozoan disease belonging to the genus Plasmodium that affects 
approximately 219 million people and kills approximately 435,000 individuals annually, with an 
enormous economic impact in the developing world, especially sub-Saharan Africa.1 The 5 
recognized species of Plasmodium that cause human malaria infection are Pf, P. vivax, P. ovale, 
P. malariae, and P. knowlesi. Among these, Pf causes more deaths in children worldwide than 
any other single infectious agent. An estimated 30,000 travelers from North America, Europe, 
and Japan contract malaria per year. Although malaria is preventable with chemoprophylaxis and 
completely curable with early intervention, drug treatment is not readily accessible in many parts 
of the world. Additionally, the use of antimalarial drugs over time has been associated with the 
emergence of drug-resistant strains. Lack of compliance with preventive drug treatment by 
individuals travelling to endemic areas may also result in fatal malaria infection. The world’s 
first malaria vaccine, RTS,S/AS01 (Mosquirix™), a recombinant protein-based vaccine targeting 
Pf, was approved for use by European regulatory authorities in 2015. RTS,S/AS01 is currently 
being evaluated in an ongoing pilot immunization program in sub-Saharan Africa despite having 
been found to provide only 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, the development of safe and effective malaria vaccines or protective 
antibodies for complete prevention and ultimate elimination of malaria remains an urgent unmet 
medical need with the potential to have a major impact on improving public health worldwide. 
 Year 2 Extension 
The primary objectives of the protocol extension are to assess the safety and PK of a second dose 
of L9LS in children exposed to seasonal malaria transmission in Mali. There are several potential 
clinical use cases for anti-malarial MAbs that may involve repeated administrations of the same 
MAb to the same individual. For example, the WHO currently recommends repeated, 
intermittent (e.g., monthly) courses of chemoprevention for high-risk groups such as children 
under 5 years of age exposed to seasonal malaria, and pregnant women.5 Although 
chemoprevention is a critically important tool, its effectiveness may be limited by the challenge 
of delivering frequent treatment courses,6,7 and the emergence of drug resistance.8,9 A single dose 
of a monoclonal antibody that prevents infection for up to 6 months could be administered before 
each malaria season for at-risk children and in early pregnancy, complementing 
chemoprevention and other malaria control measures. Therefore, it is important to assess the 
safety and PK of repeated dosing of L9LS in target populations such as children exposed to 
seasonal malaria who could receive annual dosing of an anti-malaria MAb before each malaria 
season. In addition, the study extension offers the opportunity to explore the efficacy of a second 

Abbreviated Title: Anti-malaria MAb in Malian children  
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dose of L9LS (first exploratory objective), to explore the risk of ‘rebound’ malaria in children 
who received L9LS in the first year of the study but not in the second year (third exploratory 
objective), and to explore the relationship between the PK of L9LS and the risk of Pf infection 
and clinical malaria (fourth and fifth exploratory objectives, respectively). 
 
Background  
 Study Agent: L9LS 
2.2.1.1 Development 
The VRC, 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 the 
anti-malaria MAb CIS43LS, which was also developed by the VRC. CIS43LS was shown to be 
safe and conferred complete protection against controlled Pf infection in a phase 1 study in 
healthy volunteers at the VRC.10 In a recent phase 2 trial involving healthy adults in Mali, the 
safety and efficacy of a single IV infusion of CIS43LS at doses of 10 mg/kg or 40 mg/kg were 
assessed. There were no evident safety concerns. Over the 6-month malaria season, 86 (78.2%) 
participants in the placebo group, 39 (35.5%) in the CIS43LS 10 mg/kg group, and 20 (18.2%) in 
the CIS43LS 40 mg/kg group had P. falciparum infections detected by blood smear. 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 (Kayentao et al. N Engl J Med, In press; 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 Pf circumsporozoite protein (CSP)-
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 NPNV motifs associated with NVDP minor repeats of PfCSP. When 
compared to a published panel of protective human PfCSP MAbs, L9 protected mice against IV 
and mosquito bite sporozoite challenge, and demonstrated the lowest ED80 and EC80 values 
(325.7 µg and 145.1 µg/mL, respectively) of any MAb evaluated, including CIS43LS (685.92 µg 
and 363.93 µg/mL, respectively).11 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.11  
 
Half-life extension of L9 was accomplished by modifying the L9 Fc heavy chain to include a LS 
mutation (L9LS). Restriction enzymes were used to digest plasmids carrying the L9 heavy chain 
and the CIS43LS heavy chain; subsequently, the variable region of the L9 heavy chain was 

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ligated to the Fc heavy chain bearing the LS mutation. 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 malaria prophylaxis. 
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, n=30) 
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 
The first generation anti-malaria MAb CIS43LS was shown to be safe and conferred complete 
protection against experimental controlled human malaria infections (CHMI) in a phase 1 study 
in healthy adult volunteers at the VRC.10 In the phase 1 study, subjects were protected against 
malaria infection when challenged in CHMI at about 4 weeks to 36 weeks post-product 
administration. As noted above, a phase 2 trial involving healthy adults in Mali demonstrated the 
safety and protective efficacy of a single IV infusion of CIS43LS at doses of 10 mg/kg or 40 
mg/kg. 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 (Kayentao et al. N Engl J Med, In press; ClinicalTrials.gov 

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Identifier: NCT04329104; FMOS/FAPH Protocol Number: 2020/32/CE/FMOS/FAPH). 
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.  
 
L9LS was recently evaluated in a phase 1, dose-escalation, open-label clinical trial with CHMI to 
evaluate safety and protective efficacy in healthy, malaria-naive adults at the VRC 
(ClinicalTrials.gov Identifier: NCT05019729). The trial 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 
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.12  
 
Unlike CIS43LS, which was administered IV in the Mali phase 2 trial, L9LS can be administered 
SC in children given its higher potency. As a follow-up to the VRC phase 1 trial of L9LS, this 
protocol is designed to evaluate the safety and efficacy of L9LS administered SC in healthy 
children aged 6-10 years in Mali, where Pf malaria infection is endemic. Unlike children aged 1-
5 years in Mali, who receive SMC as standard of care, SMC is not currently recommended in 
children aged 6-10 years in Mali. 
 Laboratory Assessments of L9LS 
Some laboratory assessments in this study are designed to characterize the investigational 
product. This includes PK analysis and evaluation for ADA development after product exposure. 
Other assays may also be completed from stored samples at a later date.  
The LIG International Center of Excellence in Research Lab at the USTTB in Bamako 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. The key to the code will remain at the USTTB. See section 1.3 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 1.3 to estimate blood volumes. Different tubes for clinical evaluations may be used to 
meet site requirements. Research sample tube types and blood volumes must be used as shown or 

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as otherwise instructed by the manufacturer. 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.13  
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.13  
2.2.2.3 Measures of MAb-Mediated Protection Against Pf infection and Clinical Malaria 
L9LS-mediated protection against naturally occurring Pf infection during a single 7-month 
malaria season 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 28 (day 196) after study agent 
administration just prior to the malaria season for the dose escalation subjects. The efficacy 
subjects will have samples collected through week 24 (day 168). The criteria 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 venipuncture 
blood sample. The smears will be examined microscopically.  
 
As secondary endpoints, L9LS-mediated protection against clinical malaria during a single 7-
month malaria season will be assessed and compared to control subjects from day 7 through 
week 28 (day 196) after study agent administration for the dose escalation subjects. The efficacy 
subjects will be assessed through week 24 (day 168). The two definitions of clinical malaria in 
this protocol are 1) an illness accompanied by measured fever ≥37.5°C, or history of fever 
(subjective or objective) 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 any level of Pf asexual parasitemia as detected from microscopic examination 
of thick blood smear that results in the administration of anti-malarial treatment. These 
definitions of clinical malaria are consistent with definitions used in recent trials of SMC and the 
RTS,S vaccine conducted in the Sahel region of sub-Saharan Africa.14,15  
 
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 real time only if the medical history and/or physical exam are 
suggestive of clinical malaria. Thick blood smears will be prepared from the blood remaining in 

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the collection device, or from a venipuncture sample at timepoints when no other blood 
collection is planned. Giemsa-stained thick blood films will be prepared and examined 
microscopically by trained personnel following the SOP based on the standard WHO protocol. 
Thick blood smears will be used for diagnosis throughout the study. 
 
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.16 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.16,17 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.18 
Formation of ADA to anti-TNF MAbs has also been linked to subtherapeutic serum MAb levels 
that may occur during intermittent dosing.19 Moreover, some studies suggest that intramuscular 
and subcutaneous administration of MAbs is more immunogenic than intravenous 
administration.19   
 
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.13,20-22 
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 trials10,12 or the ongoing phase 2 trials in Mali. 
 

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Regulatory authorities in the US and Europe request premarketing evaluations for 
immunogenicity (ADA testing) for all novel biologics.17,23 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 
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 252) represents approximately 5 half-lives after 
the last exposure since the estimated half-life of L9LS was 56 days in the phase 1 US trial. 
 Rebound/Delayed Malaria 
Repeated exposures to P. falciparum leads to the acquisition of clinical immunity that decreases 
the incidence and severity of malaria symptoms as children age (see Figure 6 below), although 
the acquisition of immunity that prevents P. falciparum infection altogether appears rare (see 
Figure 5 below).24,25 Therefore, when a highly effective malaria prevention measure is 
introduced into a population for a limited period of time and then withdrawn, there is a risk that 
in the subsequent period the population which received the intervention may be at greater risk 
from clinical malaria than if they had not received the intervention. This phenomenon has been 
commonly termed “rebound” malaria, and more recently has been termed “delayed” malaria 
when in reference to young children.26 The risk of rebound malaria will be explored in year 2 of 
the study by comparing the risk of clinical malaria in children who receive L9LS in year 1 and 
placebo in year 2 to those who receive placebo in both years. 

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Risk/Benefit Assessment 
 Known Potential Risks 
Risks of L9LS: As noted above, a similar malaria antibody, CIS43LS, was evaluated as safe and 
well tolerated, both in the VRC phase 1 study involving US adults,10 and in the phase 2 trial 
involving adults in Mali (Kayentao et al. N Engl J Med, In press). Similarly, no significant safety 
concerns were evident following administration of L9LS in a dose range of 1 mg/kg to 20 mg/kg 
IV and 5 mg/kg SC in the VRC phase 1 study involving US adults.12  
 
In this ongoing phase 2 trial of L9LS in Mali, all participants have been enrolled and there have 
been no significant safety concerns or serious adverse events (SAEs) to date. Specifically, in the 
open-label adult dose-escalation arm, 18 participants were enrolled and received L9LS at 300 mg 
SC (n=6), 600 mg SC (n=6), and 20 mg/kg IV (n=6). In the pediatric dose-escalation arm which 
remains blinded, 36 participants were enrolled and randomized 1:1 in a double-blind fashion and 
received L9LS 150 mg SC (n=9) vs. placebo SC (n=9), or L9LS 300 mg SC (n=9) vs. placebo 
SC (n=9). In the pediatric efficacy study which remains blinded, 225 participants were enrolled 
and randomized 1:1:1 in a double-blind fashion and received L9LS 150 mg SC (n=75), L9LS 
300 mg SC (n=75), or placebo SC (n=75). All IV and SC administrations of study agent were 
well tolerated. Among adults in the dose-escalation study (N=18), there have been a total of 42 
AEs reported in 14 participants (77.8% of participants), all of which were mild to moderate in 
severity and resolved without sequelae. The most common AEs were upper respiratory illness 
and headache, accounting for 38% of all AEs. There have been no clear trends or groupings 
among AEs by dose group in the adult dose-escalation study. Among children in the dose-
escalation study (N=36), there have been a total of 73 AEs reported in 30 participants (83.3% of 
participants). Except for 1 AE (describe in detail below), all AEs were mild to moderate in 
severity and resolved without sequelae. One AE involved a participant who had a grade 4 white 
blood cell count (WBC) increase that resolved after several weeks with no intervention. That 
participant never experienced any symptoms or manifested physical examination findings related 
to the WBC increase and the etiology remains unknown after detailed clinical, laboratory, and 
radiographic evaluations. The study investigators remain blinded to this participant’s 
randomization assignment. In the pediatric efficacy study (n=225), which remains blinded, there 
have been a total of 383 AEs reported for 174 participants (77.3%), all of which have been mild 
to moderate in severity and resolved without sequelae. 
 
As noted above, 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 

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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. Of note, the phase 1 
trial of L9LS in healthy adult volunteers at the VRC included prospective monitoring for signs 
and symptoms that may be indicative of salivary gland hypofunction, and none were noted.12 
In addition, this ongoing phase 2 trial of L9LS in Malian adults and children has included 
prospective monitoring for signs and symptoms that may be indicative of salivary gland 
hypofunction, and none have been noted to date. 
  
Risks of MAb Administration: Administration of MAbs may cause immune reactions such as 
acute anaphylaxis, serum sickness, and the generation of anti-drug antibodies. However, these 
reactions are rare and more often associated with MAbs targeted to human proteins or with the 
use of mouse MAbs that would have a risk of human anti-mouse antibodies.27 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;27 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.27 Most administration-related events occur within the first 
24 hours after initiation of MAb administration. 
 
Published experience with human MAbs directed against cell surface targets on lymphocytes 
shows that administration of a MAb may be associated with cytokine release, causing a reaction 
known as cytokine release syndrome (CRS).28 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 

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managed by administering histamine blockers.29 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.27 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.30  
 
Participation in this study may limit a subject’s eligibility for future MAb studies. 
 
Risks of Placebo Administration: There are no risks of the placebo (normal saline) other than 
injection-related events such as transient headache, dizziness, hypertension, and vasovagal-
mediated hypotension.  
 
Risks of Blood Drawing and IV insertion: Drawing blood by venipuncture or inserting an IV 
line may cause pain, bruising, and a feeling of lightheadedness or fainting. Rarely, an infection 
may develop at the site where blood is taken or the IV line is placed.  
 
Risks of ECG: The ECG is not painful, but the electrodes may cause discomfort or a self-
limiting rash. Participants may be asked to remove clothing for electrode placement, which may 
be uncomfortable or embarrassing. This will be done in a private setting. 
 
Risks of Artemether-Lumefantrine Administration: Before study agent administration, all 
subjects will be given artemether-lumefantrine to clear any preexisting Pf blood-stage infection. 
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. The historical 
prevalence of asymptomatic Pf blood-stage infection among 6-10 year olds at the end of the dry 
season (time of anticipated enrollment into the efficacy study) at the Kalifabougou study site 
ranges from 20 – 60%, as detected by PCR analysis of dried blood spots (Figure 4).31 In areas of 
high Pf transmission such as Mali, the true prevalence of asymptomatic Pf blood-stage infection 
is generally considered to be higher than that detected by PCR of dried blood spots, which has a 
limit of detection of approximately 1 parasite/µL of blood.32 Therefore, for this protocol it is 
assumed that all subjects are infected with Pf blood-stage parasites at the time of enrollment.  
 
An observational study in Kalifabougou found that treating asymptomatic Pf infection in 
children with artemether-lumefantrine at the end of the dry season does not increase the risk of 

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clinical malaria upon reinfection, suggesting that asymptomatic Pf infection does not provide 
benefit by maintaining immunity to clinical malaria.31 A recent observational study conducted in 
Kenya found that asymptomatic Pf infections were associated with an increased 1-month 
likelihood of symptomatic malaria in both children and adults, suggesting that treatment of 
asymptomatic infection may be beneficial,33 although this could vary by Pf transmission setting.  
 
 
 
Figure 4. Age-stratified point prevalence of asymptomatic P. falciparum infection detected 
by polymerase chain reaction (PCR) or blood smear at the end of the dry season in 
Kalifabougou, Mali (ClinicalTrials.gov Identifier: NCT01322581).  
 
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 kills sporozoites independently of the host immune system.11    
 
Adverse reactions (ARs) to artemether-lumefantrine occurring in more than 12% of children are 
pyrexia, cough, vomiting, anorexia, and headache. Reactions typically do not require stopping 
treatment. Individuals who may have any contraindication for the use of this drug (e.g., 
prolonged corrected QT interval [QTc]) will be excluded at screening. In postmarketing 
experience, serious hypersensitivity reactions including anaphylaxis and serious skin reactions 
(bullous eruption) have been reported. Individuals with known sensitivity or contraindications to 
the antimalarials administered in this study are excluded from participation.  
 
Of note, artemether-lumefantrine is the first-line antimalarial drug for uncomplicated malaria in 
an ongoing observational cohort study that has been conducted in Kalifabougou, Mali since 2011 
(ClinicalTrials.gov Identifier: NCT01322581; same study site as current protocol). To date, no 
serious reactions to artemether-lumefantrine have been noted in the Kalifabougou cohort study.  
 

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A complete list of side effects and contraindications is provided in the package insert. 34  
 Known Potential Benefits 
In the dose-escalation study and efficacy study, 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 during part or all of the malaria transmission season.  
 
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 an area where malaria is endemic 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 during the malaria season. 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. Dose escalation: To evaluate the 
safety and tolerability of L9LS 
administered at 300 mg and 600 
mg SC and 20 mg/kg IV in 
healthy Malian adults, and at 150 
mg and 300 mg SC in healthy 
Malian children. 
2. Efficacy: To evaluate the safety 
and tolerability of L9LS 
administered at 150 mg and 300 
mg SC in healthy Malian 
children. 
3. Efficacy: To determine if SC 
administration of L9LS at 150 
mg and 300 mg (compared to 
placebo) mediates protection 
against naturally occurring Pf 
infection in healthy Malian 
1. Dose escalation and efficacy: 
Incidence and severity of 
local and systemic AEs 
occurring within 7 days after 
the administration of L9LS. 
2. Efficacy: Pf blood-stage 
infection as detected by 
microscopic examination of 
thick blood smears obtained 
between 1 week and 24 
weeks after administration of 
L9LS or placebo. 
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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children during a single malaria 
season as detected from 
microscopic examination of thick 
blood smear. 
Secondary (to be addressed using data from both parts of the study) 
1. To evaluate the PK of L9LS 
throughout the study at dose 
levels of 300 mg and 600 mg SC 
and 20 mg/kg IV in healthy 
Malian adults, and at 150 mg and 
300 mg SC in healthy Malian 
children, and to correlate L9LS 
serum concentration with Pf 
infection risk. 
2. To determine if SC 
administration of L9LS at 150 
mg and 300 mg (compared to 
placebo) mediates protection 
against naturally occurring Pf 
infection in healthy Malian 
children during a single malaria 
season as detected by RT-PCR. 
3. To determine if SC 
administration of L9LS at 150 
mg and 300 mg (compared to 
placebo) mediates protection 
against clinical malaria in 
healthy Malian children during a 
single malaria season as defined 
by an illness accompanied by 
measured axillary fever ≥37.5°C, 
or history of fever (subjective or 
objective) in the previous 24 
hours, and Pf asexual parasitemia 
>5,000 parasites/µL as detected 
from microscopic examination of 
thick blood smear. 
4. To determine if SC 
administration of L9LS at 150 
mg and 300 mg (compared to 
placebo) mediates protection 
against clinical malaria in 
healthy Malian children during a 
single malaria season as defined 
1. Measurement of L9LS in 
sera of recipients. 
2. Pf blood-stage infection as 
detected by RT-PCR for 28 
weeks after administration of 
L9LS or placebo in the dose 
escalation study and for 24 
weeks after administration of 
L9LS or placebo in the 
efficacy study. 
3. Incidence of clinical malaria 
(definition 1, see section 
2.2.2.3) for 28 weeks after 
administration of L9LS or 
placebo in the dose 
escalation study and for 24 
weeks after administration of 
L9LS or placebo in the 
efficacy study. 
4. Incidence of clinical malaria 
(definition 2, see section 
2.2.2.3) for 28 weeks after 
administration of L9LS or 
placebo in the dose 
escalation study and for 24 
weeks after administration of 
L9LS or placebo in the 
efficacy study. 
5. PK analysis of L9LS and the 
association of L9LS 
concentration with Pf 
infection risk. 
6. PK analysis of L9LS and the 
association of L9LS 
concentration with clinical 
malaria risk. 
1. Concentrations of L9LS 
in blood will help 
assess durability of 
L9LS at each dose 
level. 
2. RT-PCR is more 
sensitive than blood 
smear for detecting Pf 
blood-stage infection. 
3. 6–10-year-old children 
in Mali are at high risk 
for clinical malaria. 
4. 6–10-year-old children 
in Mali are at high risk 
for clinical malaria. 
5. Concentrations of L9LS 
in blood will help 
assess durability of 
L9LS and will allow for 
correlation with Pf 
infection risk. 
6. Concentrations of L9LS 
in blood will help 
assess durability of 
L9LS and will allow for 
correlation with clinical 
malaria risk. 

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by an illness accompanied by 
any level of Pf asexual 
parasitemia as detected from 
microscopic examination of thick 
blood smear that results in the 
administration of anti-malarial 
treatment. 
5. To evaluate the PK of L9LS 
throughout the study at the dose 
of 150 mg and 300 mg and to 
correlate L9LS serum 
concentration with Pf infection 
risk. 
6. To evaluate the PK of L9LS 
throughout the study at the dose 
of 150 mg and 300 mg and to 
correlate L9LS serum 
concentration with clinical 
malaria risk. 
Tertiary/Exploratory 
1. To determine whether ADA to 
L9LS can be detected in sera of 
recipients at specific timepoints 
throughout the study. 
2. To assess for IgG1 allotypes 
and allotype-specific effects on 
L9LS PK.  
3. To explore and characterize the 
cellular immune response to 
L9LS. 
4. To determine if the efficacy of 
L9LS is specific to certain 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. 
1. Measurement of ADA to 
L9LS in sera of recipients. 
2. Assessment of IgG1 
allotypes and allotype-
specific effects on L9LS PK.  
3. Characterization of the 
cellular immune response to 
L9LS. 
4. CSP genotyping of parasites 
isolated from study subjects. 
5. Pre-existing parasitemia 
detected by microscopic 
examination of thick blood 
smears or RT-PCR before 
L9LS administration. 
6. Pre-existing CSP-specific 
antibodies measured in sera 
collected before L9LS 
administration. 
1. ADA to L9LS may 
impact the PK and 
activity of L9LS. 
2. Subject IgG1 allotype 
may impact the PK and 
activity of L9LS.  
3. L9LS-induced cellular 
immune responses may 
be associated with Pf 
infection risk. 
4. L9LS efficacy may be 
specific to certain 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. 
Extension Phase Primary 

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1. To evaluate the safety and 
tolerability of a second SC dose 
of L9LS administered at 150 mg 
and 300 mg (compared to 
placebo) in healthy Malian 
children.  
2. To evaluate the PK of L9LS 
throughout the study at dose 
levels of 150 mg and 300 mg SC 
in healthy Malian 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. 
1. Incidence and severity of 
local and systemic AEs 
occurring within 7 days after 
the administration of L9LS. 
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. 
 
Extension Phase Exploratory (see Figure 3 for study arm definitions) 
1. To assess the efficacy of a 
second SC dose of L9LS at 150 
mg and 300 mg (compared to 
placebo) in mediating protection 
against Pf infection and clinical 
malaria in healthy Malian 
children during a second malaria 
season (arms 1a vs. 1b; arms 2a 
vs. 2b), and to assess if this 
efficacy is influenced by whether 
or not a prior dose of L9LS was 
administered in year 1 (arms 1a 
vs. 3b; arms 2a vs. 3b).  
2. To assess the efficacy of a first 
SC dose of L9LS at 150 mg or 
300 mg (compared to placebo) in 
mediating protection against Pf 
infection and clinical malaria in 
healthy Malian children during 
the second malaria season (arms 
3a vs. 3b).  
3. To assess the risk of clinical 
malaria in children who received 
L9LS in year 1 but not year 2 
(compared to children who 
received placebo both years; 
arms 1b vs. 3b; arms 2b vs. 3b).  
1. Pf blood-stage infection as 
detected by microscopic 
examination of thick blood 
smears obtained between 1 
week and 28 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 28 
weeks after administration of 
L9LS or placebo. 
3. Incidence of clinical malaria 
(definition 1, see section 
2.2.2.3) between 1 week and 
28 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 
concentration with clinical 
malaria risk. 
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. 6–10-year-old children 
in Mali 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. 

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4. To evaluate the PK of L9LS 
throughout the study at the dose 
of 150 mg and 300 mg and to 
correlate L9LS serum 
concentration with Pf infection 
risk. 
5. To evaluate the PK of L9LS 
throughout the study at the dose 
of 150 mg and 300 mg and to 
correlate L9LS serum 
concentration with clinical 
malaria risk. 
 
4 
STUDY DESIGN 
 
Overall Design 
This is a two-part, phase 2 trial evaluating the safety and tolerability of one-time SC or IV 
administration of L9LS in healthy Malian adults and one-time SC administration of L9LS in 
healthy Malian children, as well as its protective efficacy against naturally occurring Pf infection 
over a 7-month malaria season in healthy Malian children 6-10 years of age. The primary study 
hypotheses are that L9LS administered prior to the malaria season will be safe and will produce 
protection against malaria infection. Before study agent administration, all subjects will be given 
artemether-lumefantrine to clear any preexisting Pf blood-stage infection. Interim safety data 
from the ongoing VRC phase 1 trial of L9LS will be regularly reviewed, and if needed, the 
protocol and relevant study documents will be amended to reflect any new information. 
 
The study will recruit from 2 MRTC clinics, 1 in Torodo and 1 in Kalifabougou. All of the 
screening, day 0, and day 14 visits will take place at Kalifabougou for all subjects, regardless of 
residence. The rural village of Kalifabougou is situated 46 km from the MRTC laboratory in 
Bamako where biological samples collected for this protocol will be processed and stored. 
Torodo is located 12 km north of Kalifabougou. The economy is based on subsistence farming. 
Kalifabougou and Torodo are similar in terms of geographic, demographic, and epidemiological 
characteristics, and both typically experience intense seasonal Pf transmission from June through 
December each year. 25 Based on data collected in Kalifabougou, approximately 85% of children 
aged 6-10 years who are uninfected (PCR negative) before the malaria season become infected 
with Pf during the ensuing malaria season (Figure 5). 25  
 
 

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Figure 5. Kaplan-Meier plots, stratified by age for time to first Pf infection by PCR during 
the malaria season in Kalifabougou, Mali (ClinicalTrials.gov Identifier: NCT01322581).  
 
The first part of the study is an age de-escalation and dose-escalation study for safety and 
tolerability. Adult subjects (N=18) in the dose-escalation study will be assigned in open-label 
fashion to 1 of 3 L9LS dose arms (n=6 for each dose level). Dosing will begin in the lowest dose 
arm (300 mg SC). Once all subjects in that arm reach day 7 post-administration, if no safety 
concerns have arisen, dosing will begin at the next dose level (600 mg SC). Once all subjects in 
that arm reach day 7 post-administration, if no safety concerns have arisen, dosing will begin at 
the highest dose level (20 mg/kg IV). Once all adult subjects reach day 7 post-administration, if 

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no safety concerns have arisen, 18 subjects aged 6-10 years will be randomized 1:1 in double-
blind fashion to 150 mg of L9LS versus placebo administered SC. Once all 18 subjects reach day 
7 post-administration, if no safety concerns have arisen, an additional 18 subjects aged 6-10 
years will be randomized 1:1 to 300 mg of L9LS versus placebo administered SC. 
Randomization of subjects aged 6-10 years in each L9LS dose arm will be weight-stratified (26-
30 kg, n=6; 20-25 kg, n=6; 15-19 kg, n=6) and enrollment will be weight de-escalated starting 
with subjects weighing 26-30 kg. All subjects will be followed for safety to assess AEs at study 
visits over 28 weeks. Primary study assessments include medical history, physical examination 
and blood collection for identification of Pf infection and other research laboratory evaluations. 
After the last 6-year-old subject in the 300-mg L9LS arm reaches day 7 safety follow-up, an 
interim safety evaluation will be performed before enrollment begins for the efficacy part of the 
study. Data from the 36 subjects aged 6-10 years enrolled in the dose-escalation study will be 
included in a secondary analysis to determine the relationship between L9LS concentrations and 
the risk of Pf infection. For these 36 subjects, blinding will be maintained for treatment 
assignment (L9LS versus placebo), but not for possible L9LS dose group. 
 
The second part of the study is a weight-stratified, randomized, double-blind, placebo-controlled 
trial to assess safety and protective efficacy of L9LS and placebo in children 6-10 years of age. 
In this part of the study, 225 subjects will be randomized 1:1:1 to SC administration of 150 mg 
of L9LS (n=75), 300 mg of L9LS (n=75), or placebo (n=75). Randomization of subjects in each 
arm will be weight-stratified (26-30 kg, n=75; 20-25 kg, n=75; 15-19 kg, n=75). Subjects in the 
efficacy study will receive the study agent and be followed at study visits over 24 weeks. 
Primary study assessments include medical history, physical examination, and blood collection 
for identification of Pf infection and other research laboratory evaluations. 
 Year 2 Extension 
In the extension phase, all participants who are currently enrolled in the dose escalation or 
efficacy study will be invited to extend their participation for approximately 1 year from the time 
of re-consenting. After the results of the first year of the study are unblinded (approximately 
March 2023), children will be re-randomized 1:1 in a double-blind fashion within their original 
study arm assignment to receive either L9LS or placebo administered SC before the 2023 
malaria season (Figure 3).  
 
The protocol extension employs a pre-specified, adaptive design based on the time-to-event 
efficacy of 150 mg and 300 mg of L9LS observed after the first malaria season in the original 
protocol. Specifically, if 150 mg and 300 mg of L9LS both show ≥60% time-to-event efficacy 
against P. falciparum infection as detected by blood smear during the first malaria season (based 
on the upper bound of the two-sided 95% CI), children who received 150 mg of L9LS in year 
one will be randomized 1:1 in year 2 to receive either a second 150-mg dose of L9LS (arm 1a) or 
placebo (arm 1b); children who received 300 mg of L9LS in year one will be randomized in year 
2 to receive either a second 300-mg dose of L9LS (arm 2a) or placebo (arm 2b); and children 

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who received placebo in year 1 will be randomized in year 2 to receive either a first 150-mg dose 
of L9LS (arm 3a) or placebo (arm 3b) (Figure 3a).  
 
If the 300-mg dose of L9LS shows ≥60% efficacy (based on the upper bound of the two-sided 
95% CI) and the 150-mg dose of L9LS shows <60% efficacy (based on the upper bound of the 
two-sided 95% CI) but the difference between their respective point estimates of efficacy is 
≤10%, children who received 150 mg of L9LS in year one will be randomized 1:1 in year 2 to 
receive either a second 150-mg dose of L9LS (arm 1a) or placebo (arm 1b); children who 
received 300 mg of L9LS in year one will be randomized in year 2 to receive either a second 
300-mg dose of L9LS (arm 2a) or placebo (arm 2b); and children who received placebo in year 1 
will be randomized in year 2 to receive either a first 300-mg dose of L9LS (arm 3a) or placebo 
(arm 3b) (Figure 3b). In the unlikely event that the 150-mg dose of L9LS shows ≥60% efficacy 
(based on the upper bound of the two-sided 95% CI) and the 300-mg dose of L9LS shows <60% 
efficacy (based on the upper bound of the two-sided 95% CI) but the difference between their 
respective point estimates of efficacy is ≤10%, the same design (Figure 3b) will be employed 
with the following exception: children who received placebo in year 1 will be randomized in 
year 2 to receive either a first 150-mg dose of L9LS (arm 3a) or placebo (arm 3b). 
 
If the 300-mg dose of L9LS shows ≥60% efficacy (based on the upper bound of the two-sided 
95% CI) and the 150-mg dose of L9LS shows <60% efficacy (based on the upper bound of the 
two-sided 95% CI) but the difference between their respective point estimates of efficacy is 
>10%, the 150 mg dose will be abandoned and children who received 150 mg of L9LS in year 
one will be randomized 1:1 in year 2 to receive either a 300-mg dose of L9LS (arm 1a) or 
placebo (arm 1b); children who received 300 mg of L9LS in year one will be randomized in year 
2 to receive either a second 300-mg dose of L9LS (arm 2a) or placebo (arm 2b); and children 
who received placebo in year 1 will be randomized in year 2 to receive either a first 300-mg dose 
of L9LS (arm 3a) or placebo (arm 3b) (Figure 3c).  
 
If 150 mg and 300 mg of L9LS both show <60% efficacy (based on the upper bound of the two-
sided 95% CI) by time-to-event analysis after the first malaria season, the protocol extension will 
be abandoned. 
 
Before study agent administration, all subjects will be given artemether-lumefantrine to clear any 
preexisting Pf blood-stage infection.  
 
Subjects will be followed at study visits 1, 3, 7, 14, 21, and 28 days after administration, and 
once every 2 weeks thereafter through 28 weeks, with a final visit occurring on study day 252 
(36 weeks) to collect a final PK sample. Primary study assessments include medical history, 
physical examination and blood collection for PK, ADA assessments, identification of Pf 
infection by microscopic examination of thick blood smears and RT-PCR, and other research 
laboratory evaluations. 

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If 150 mg and 300 mg of L9LS both show ≥60% efficacy during the first malaria season in the 
original protocol, the schema depicted in Figure 3a will be followed, and safety outcomes will be 
evaluated within arms to assess the safety of a second 150-mg dose of L9LS vs. placebo (1a vs. 
1b); the safety of a second 300-mg dose of L9LS vs. placebo (2a vs. 2b), and the safety of a first 
150-mg dose of L9LS vs. placebo (3a vs. 3b). In addition, safety outcomes will be evaluated 
between arms to assess the safety of a second 150-mg dose of L9LS vs. a first 150-mg dose of 
L9LS (1a vs. 3a). Finally, safety outcomes of L9LS vs. placebo will be evaluated in aggregate 
(1a + 2a + 3a vs. 1b + 2b + 3b).  
 
PK of L9LS will be evaluated throughout the study at dose levels of 150 mg and 300 mg SC. 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.  
 
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 the following arms: 
1. Children who receive a second 150 mg dose of L9LS versus children who receive 
placebo (arms 1a vs. 1b). 
2. Children who receive a second 300 mg dose of L9LS versus children who receive 
placebo (arm 2a vs. 2b).  
3. Children who receive a second 150 mg dose of L9LS versus children who received 
placebo in years 1 and 2 (arms 1a vs. 3b). 
4. Children who receive a second 300 mg dose of L9LS versus children who received 
placebo in years 1 and 2 (arms 2a vs. 3b).  
5. Children who receive a first 150 mg dose of L9LS versus children who received placebo 
in years 1 and 2 (arms 3a vs. 3b).  
 
The risk of ‘rebound’ malaria will be assessed in year two of the study by comparing the risk of 
clinical malaria in the following arms: 
1. Children who received a 150 mg dose of L9LS in year 1 and placebo in year 2 versus 
children who received placebo in years 1 and 2 (arms 1b vs. 3b). 
2. Children who received a 300 mg dose of L9LS in year 1 and placebo in year 2 versus 
children who received placebo in years 1 and 2 (arms 2b vs. 3b) 
 
If 300 mg of L9LS shows ≥60% efficacy (based on the upper bound of the two-sided 95% CI) 
and 150 mg of L9LS shows <60% efficacy (based on the upper bound of the two-sided 95% CI) 
but the difference between their respective point estimates of efficacy is ≤10% during the first 
malaria season, the schema depicted in Figure 3b will be followed, and safety, PK, and efficacy 

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outcomes will be conducted as described above, with the exception of Arm 3a that will evaluate 
children who received placebo in year 1 followed by 300 mg of L9LS in year 2.  
 
If 300 mg of L9LS shows ≥60% efficacy (based on the upper bound of the two-sided 95% CI) 
and 150 mg of L9LS shows <60% efficacy (based on the upper bound of the two-sided 95% CI) 
but the difference between their respective point estimates of efficacy is >10% during the first 
malaria season, the schema depicted in Figure 3c will be followed, and safety, PK, and efficacy 
outcomes will be conducted as described above, with the exception of Arm 1a that will evaluate 
children who received 150 mg of L9LS in year 1 followed by 300 mg of L9LS in year 2.  
 
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 adults prior to proceeding with the enrollment of children. 
 
Both parts of the study will use randomization and 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. 
 Year 2 Extension 
The protocol extension was designed to evaluate the safety and PK of a second dose of L9LS in 
the setting of naturally occurring Pf infection and in a population that could potentially benefit 
from a novel therapeutic for malaria prevention.  
 
As with the original protocol, the protocol extension will use randomization and 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 
ongoing phase 1 VRC study, which tested the dose range included in this protocol. This study 
will test fixed doses of L9LS in children in a defined range of subject weights 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.  
 

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In the safety study, subjects aged ≥18 years weighing 60 kg or less will receive a SC dose of 300 
mg (2 mL) or 600 mg (4 mL), approximating the weight-based dosing of 5 mg/kg and 10 mg/kg, 
respectively, in a 60-kg adult. An additional group of subjects aged ≥18 years weighing 60 kg or 
less in the safety study will receive an IV dose of 20 mg/kg. This dose will be administered IV 
rather than SC because 4 mL is the maximum volume of L9LS that will be administered SC in 
this study. In Kalifabougou, the average weight of adult females and males is 55.6 kg and 61.7 
kg, respectively. In the safety and efficacy studies, subjects aged 6-10 years weighing ≥15 kg and 
≤30 kg will receive a dose of 150 mg or 300 mg SC, approximating the weight-based dosing of 5 
mg/kg and 10 mg/kg, respectively, in a 30-kg child, and 10 mg/kg and 20 mg/kg, respectively, in 
a 15-kg child. Based on recent data from the study site, approximately 85% of children aged 6-10 
years in Kalifabougou weigh between 15 kg and 30 kg. The doses used in the efficacy study will 
complement the data generated in the ongoing 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;11 and 2) PK data from nonhuman primate 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.  
5 
STUDY POPULATION  
 
Inclusion Criteria 
Individuals must meet all of the following criteria to be eligible for study participation: 
1. Is within the appropriate age range for the respective cohort: 
a. Children: Aged ≥6 years and <11 years. 
b. Adults: Aged ≥18 years. 
2. Able to provide proof of identity to the satisfaction of the study clinician completing the 
enrollment process. 
3. In good general health and without clinically significant medical history. 
4. Adult participants or parent and/or guardian of minor participants able to provide 
informed consent. 
5. Willing to have blood samples and data stored for future research. 
6. Resides in or near Kalifabougou or Torodo, Mali, and available for the duration of the 
study. 
7. For the adult cohort, females of childbearing potential must be willing to use reliable 
contraception from 21 days prior to study day 0 through the final study visit as described 
below.   
• Reliable methods of birth control include 1 of the following: confirmed 
pharmacologic contraceptives via parenteral delivery or intrauterine or 
implantable device.  

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• Nonchildbearing women will be required to report date of last menstrual period, 
history of surgical sterility (i.e., tubal ligation, hysterectomy) or premature 
ovarian insufficiency, and will have urine or serum pregnancy test performed per 
protocol. 
 Year 2 Extension Inclusion Criteria 
Individuals must meet all of the following criteria to be eligible for participation: 
1. Participated in the first year of the protocol.  
2. Able to provide proof of identity to the satisfaction of the study clinician completing the 
enrollment process. 
3. In good general health and without clinically significant medical history. 
4. Parent and/or guardian able to provide informed consent. 
5. Willing to have blood samples and data stored for future research. 
6. Resides in or near Kalifabougou or Torodo, Mali, and available for the duration of the 
study. 
 
Exclusion Criteria 
Individuals meeting any of the following criteria will be excluded from study participation: 
1. Body weight <15 kg or >30 kg for children, or >60 kg for adults.  
2. Currently receiving or planning to receive SMC. 
3. Any history of menses (for 6-10 year old cohort) or positive pregnancy test at screening 
(for adult cohort).  
4. 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. 
5. Subject (for adult subjects) or parental (for minor subjects) study comprehension 
examination score of <80% correct or per investigator discretion. 
6. Hemoglobin, 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 “not clinically significant” values.) 
7. 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 “not 
clinically significant” values.) 
8. Infected with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV). 
9. Known or documented sickle cell disease by history. (Note: Known sickle cell trait is 
NOT exclusionary.) 
10. Clinically significant abnormal electrocardiogram (ECG; QTc >460 or other significant 
abnormal findings, including unexplained tachycardia or bradycardia). 

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11. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, 
rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, 
physical examination, and/or laboratory studies including urinalysis. 
12. Receipt of any investigational product within the past 30 days. 
13. Participation or planned participation in an interventional trial with an investigational 
product until the last required protocol visit. (Note: Past, current, or planned participation 
in observational studies is NOT exclusionary.) 
14. Medical, occupational, or family problems as a result of alcohol or illicit drug use during 
the past 12 months. 
15. History of a severe allergic reaction or anaphylaxis. 
16. Severe asthma (defined as asthma that is unstable or required emergent 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). 
17. Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, 
salivary gland tumors).  
18. 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. 
19. Known immunodeficiency syndrome. 
20. Known asplenia or functional asplenia. 
21. 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. 
22. Receipt of a live vaccine within the past 4 weeks or a killed vaccine or COVID-19 
vaccine within the past 2 weeks prior to study agent administration. 
23. Receipt of immunoglobulins and/or blood products within the past 6 months. 
24. Previous receipt of an investigational malaria vaccine or monoclonal antibody in the last 
5 years. 
25. Known allergies or contraindication against artemether-lumefantrine. 
26. Clinical signs of malnutrition.  
27. 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. 
 Year 2 Extension Exclusion Criteria 
Individuals meeting any of the following criteria will be excluded from participation: 
1. Currently receiving or planning to receive SMC. 

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2. Any history of menses.  
3. 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. 
4. Parental study comprehension examination score of <80% correct or per investigator 
discretion. 
5. Hemoglobin, 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 “not clinically significant” values.) 
6. 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 “not 
clinically significant” values.) 
7. Infected with HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV). 
8. Known or documented sickle cell disease by history. (Note: Known sickle cell trait is 
NOT exclusionary.) 
9. Clinically significant abnormal electrocardiogram (ECG; QTc >460 or other significant 
abnormal findings, including unexplained tachycardia or bradycardia). 
10. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, 
rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, 
physical examination, and/or laboratory studies including urinalysis. 
11. Receipt of any investigational product within the past 30 days. 
12. Participation or planned participation in another interventional trial with an 
investigational product other than L9LS until the last required protocol visit. (Note: Past, 
current, or planned participation in observational studies is NOT exclusionary.) 
13. Medical, occupational, or family problems as a result of alcohol or illicit drug use during 
the past 12 months. 
14. History of a severe allergic reaction or anaphylaxis. 
15. Severe asthma (defined as asthma that is unstable or required emergent 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). 
16. Currently active salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, 
sialolithiasis, salivary gland tumors).  
17. 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. 
18. Known immunodeficiency syndrome. 
19. Known asplenia or functional asplenia. 

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20. 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. 
21. Receipt of a live vaccine within the past 4 weeks or a killed vaccine or COVID-19 
vaccine within the past 2 weeks prior to study agent administration. 
22. Receipt of immunoglobulins and/or blood products within the past 6 months. 
23. Previous receipt of an investigational malaria vaccine or any other monoclonal antibody 
other than L9LS in the last 5 years. 
24. Known allergies or contraindication against artemether-lumefantrine. 
25. Clinical signs of malnutrition.  
26. 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. 
 
Inclusion of Vulnerable Participants 
• Children: L9LS is currently being evaluated in an ongoing phase 1 clinical trial to 
evaluate safety and protective efficacy of L9LS in healthy, malaria-naive adults. Interim 
safety results available from that trial as of December 26, 2021 (see section 2.3.1) 
indicate that L9LS is safe and well tolerated upon IV and SC administration. Therefore, 
this protocol will proceed with administration of L9LS in healthy adults followed by 
children aged 6-10 years in Mali, an age group that is particularly vulnerable to 
symptomatic malaria infection (Figure 6). Unlike children aged 1-5 years in Mali, who 
receive SMC as standard of care, SMC is not currently recommended in children aged 6-
10 years in Mali. Children and adolescents aged 11-17 years have acquired some degree 
of clinical immunity to malaria and are less likely to experience symptomatic malaria 
(Figure 6). Irrespective of the decreased risk of clinical malaria risk with increased age, 
children, adolescents, and adults in Mali appear to be equally susceptible to Pf infection 
as detected by PCR (Figure 5). 

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Figure 6. Kaplan-Meier plot stratified by age for time to first clinical malaria episode 
during the malaria season in Kalifabougou, Mali. Enrollment occurred just prior to the 
malaria season. Clinical malaria is defined by an axillary temperature of ≥37.5°C and ≥2,500 
asexual Pf parasites/µL of blood (ClinicalTrials.gov Identifier: NCT01322581).  
 
Children aged 6-10 years who weigh <15 kg are excluded because they are below the 
15th percentile in weight-for-age according to WHO growth standards. Children who 
weigh >30 kg are excluded because the 150 mg or 300 mg doses administered to children 
in this study would fall below the minimum weight-based dosing target of 5 mg/kg and 
10 mg/kg, respectively. The maximum volume of study agent that will be administered to 
children in this study is 2 mL (300 mg of L9LS). Based on recent data from the study 
site, approximately 85% of children aged 6-10 years in Kalifabougou weigh between 15 
kg and 30 kg. 

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• Illiterate Individuals: We anticipate that many individuals eligible for this study and 
their parents/guardians will be illiterate in French, so the study team will translate the 
consent orally into local languages when appropriate, as described in section 10.1. 
 
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 
subsequently enrolled in the study. 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 SAE. 
 
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 ECG, ALT, or other transient lab evaluations) may be rescreened or may repeat 
individual screening procedures at the investigator’s discretion. All data (screening and re-
screening) will be collected under the same subject number. 
 
Strategies for Recruitment and Retention 
Study subjects will be selected based on the eligibility criteria described in sections 5.1 and 
5.1.1. The total target sample size across both study sites is 54 subjects in the dose-escalation 
study (accrual ceiling 90). The total target sample size across both study sites is 225 subjects in 
the efficacy study (accrual ceiling 380). We expect to enroll all subjects for both parts of the 
study within the first 6 months of the study from March through August. Subject selection will 
not be limited based on sex, race, or ethnicity. 
 
The study team will hold community meetings in Kalifabougou and Torodo to explain and 
discuss the study and obtain community permission from the village elders, heads of families, 
and other community members in each village where the study will take place (section 10.1.1.1). 
Afterward, an announcement via local radio or another traditional channel of communication 
may be made to invite households to come to participating clinics to learn about the study. 
 

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For the year 2 extension, study participants who remain enrolled in the dose-escalation and 
efficacy studies will be invited to participate in the extension study before completing their last 
visit on the original study.    
 Costs 
There are no costs associated with participation in this trial. 
 Compensation 
Adult subjects and parents or guardians of minor subjects will be compensated for the time and 
inconvenience of participating in the study as follows:  
• 5,000 Communauté Financière Africaine (CFA) Franc for each of the following: 
screening visit, enrollment visit, and day 0 visit (injection). 
• 3,000 CFA Franc for all other visits. 
 
The total compensation amount for adults subjects will be 51,000 CFA Franc (valued at 
approximately USD $88) and for the 6-10 year old subjects will be 69,000 CFA Franc (valued at 
approximately USD $119) in the dose escalation study. Total compensation amount for the 6-10 
year old subjects will be 63,000 CFA Franc (valued at approximately USD $109) in the efficacy 
study. Total compensation for the year 2 extension study will be 75,000 CFA Franc (valued at 
approximately USD $112). Payment will be provided in cash after the completion of each visit.  
 
Subjects will be provided with transportation to and from study visits but will not receive 
additional reimbursement for travel. 
6 
STUDY INTERVENTION 
 
Study Interventions(s) Administration 
 Study Intervention Description 
The study intervention involves a single administration of L9LS SC or IV or placebo SC to each 
subject. An additional single SC administration of L9LS or placebo will be delivered to 
participants who enroll in the year 2 extension study. All study agent administration will take 
place at the Kalifabougou study site. 
 Dosing and Administration 
Study agent and dosing will be dependent on the progress of the study and study arm assignment 
(Table 1). The dose-escalation study dosing plan is described in section 0. Procedures for 
administration are described in section 6.1.2.4.  
 

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Table 1. Study agent assignment and dosing by arm. 
Arm 
Total Subjects 
Study Agent and Dose 
Dose-escalation study – adult cohort 
1 
6 
300 mg L9LS SC 
2 
6 
600 mg L9LS SC 
3 
6 
20 mg/kg L9LS IV 
Dose-escalation study – 6-10 year old cohort 
1 
18 
150 mg L9LS (n=9) or placebo SC (normal saline; n=9) 
2 
18 
300 mg L9LS (n=9) or placebo SC (normal saline; n=9) 
Efficacy study – 6-10 year old cohort 
1 
75 
150 mg L9LS SC 
2 
75 
300 mg L9LS SC 
3 
75 
Placebo (normal saline) SC 
Year 2 extension study 
1a 
42 
150 mg L9LS SC 
1b 
42 
Placebo (normal saline) SC 
2a 
42 
300 mg L9LS SC 
2b 
42 
Placebo (normal saline) SC 
3a 
46 
150 mg L9LS SC a 
3b 
46 
Placebo (normal saline) SC 
a This dose will be 300 mg if schema b or c are implemented as shown in Figure 3. 
6.1.2.1 Dose Escalation 
In the dose-escalation study, dose escalation will proceed in 3 study arms for the adult cohort and 
2 study arms for the 6-10 year old cohort. The study will begin with enrollment into the adult 
cohort. When the last subject in arm 3 reaches day 7, if there are no safety concerns, enrollment 
into the 6-10 year old cohort will begin. For each cohort, enrollment will begin with arm 1. 
Subjects enrolled in this arm will be scheduled for study intervention, with at least 1 hour of 
observation between study agent administration in each subject, and follow-up procedures. Once 
all subjects in arm 1 complete day 7 post-injection, if no safety concerns have arisen, then 
enrollment will begin for arm 2. In the adult cohort, once all subjects in arm 2 complete day 7 
post-injection, if no safety concerns have arisen, then enrollment will begin for arm 3. 
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 
This study involves administering a single dose to each subject, so there will be no dose 
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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). For subjects receiving study agent SC, the total volume of assigned study agent will be 
divided into 2 syringes, except for the 300 mg adult cohort which will receive 1 syringe only.  
The study agent will be administered in each upper outer triceps area as a SC injection (1 
injection per arm, except for the 300 mg adult cohort which will receive 1 injection), 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 may be used as an 
alternate injection site if the outer triceps area 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. For 
subjects receiving study agent IV, each subject will have IV access placed in an arm vein in an 
aseptic manner. A different site may be used for collection of PK blood samples; however, the 
same site may be used after flushing the line if another site is not available. The study agent will 
be administered with approximately 100 mL of normal saline IV over about 30-60 minutes, with 
a target of 30 minutes. Infusions lasting longer than 30 minutes are allowed. If the subject 
experiences side effects during the infusion, the rate of infusion may be slowed or stopped to 
alleviate the symptoms. At the end of product administration, the IV administration set must be 
flushed with about 30 mL (or appropriate volume) of normal saline. The IV will remain in for 
safety through the end of post-administration observation. Only adult subjects in Arm 3 of the 
dose-escalation study will receive study agent IV, and this will be done in open-label fashion. 
 
The first subject in each arm of the dose-escalation study 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. All subjects in the efficacy study 
will be observed for at least 60 minutes following completion of product administration. In the 
year 2 extension study, the first 30 subjects will be monitored for at least 2 hours (+/-15 minutes) 
after study agent administration and vital signs will be recorded for 1 hour (+/-15 minutes) after 
study agent administration (based on randomization this will be approximately 5 subjects in each 
sub-arm). Thereafter, all subjects will be monitored for at least 60 minutes (+/-15 minutes) after 
study agent administration and vital signs will be recorded 1 hour (+/-15 minutes) after study 
agent 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 
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in the clinic until evaluation and discharge by a study clinician. If necessary, the subject would 
be referred to the district hospital to evaluate for safety and possible treatment. Clinicians will 
follow any solicited symptoms 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 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 for 
in vitro experimental studies. These vials will be disposed of in accordance with 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.  
 

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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. 
 
Prior to preparation for SC and IV 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. 35  
 
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. 35  
 
Placebo: Normal saline will be stored at room temperature in a controlled room per product 
standards. 
 Preparation 
For children: Study product will be prepared by an unblinded pharmacist. For the dose-
escalation study, one syringe will be prepared for each subject in the 150-mg L9LS/placebo arm.  
For the 300-mg L9LS/placebo arm of the dose-escalation study, all arms of the efficacy study, 
and all arms of the year 2 extension study, two syringes will be prepared for each subject for a 
total of two 1-mL SC injections for each subject. 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. 
 

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For each SC injection order, the dose level and study arm code will be included in the pharmacy 
order. To prepare a SC injection, the pharmacist will do the following:  
• For subjects assigned to L9LS:  
1) Retrieve the minimum number of thawed vials required to prepare the full dose. 
After vials are thawed, vials should be gently swirled for 30 seconds while 
avoiding foaming. DO NOT SHAKE THE VIAL. 
2) Withdraw the total amount of L9LS from the vial into the syringe(s) using a 5-
micron filter needle. A new filter needle must be used for each syringe in the case 
of multiple syringes. The filter needle must be discarded prior to dispensing and 
replaced with a needle suitable for SC injection at the time of administration. 
3) For subjects assigned to the 150-mg L9LS arm in the efficacy study and the year 
two extension study ONLY: Withdraw half of the total amount of L9LS from the 
vial into each of 2 syringes using a 5-micron filter needle, and then fill each 
syringe with normal saline as needed for a total volume of 1 mL in each syringe. 
A new filter needle must be used for each syringe. The filter needle must be 
discarded prior to dispensing and replaced with a needle suitable for SC injection 
at the time of administration. 
• For subjects assigned to placebo: 
1) Withdraw 1 mL of normal saline placebo into the syringe(s) using a 5-micron 
filter needle. A new filter needle must be used for each syringe. The filter needle 
must be discarded prior to dispensing and replaced with a needle suitable for SC 
injection at the time of administration. 
 
For adult SC administration: Study product will be prepared by an unblinded pharmacist. For 
subjects receiving the 300-mg dose, one syringe will be prepared which will contain 2 mL of 
L9LS, as described below. For subjects receiving the 600-mg dose, two syringes will be prepared 
and each syringe will contain 2 mL of L9LS (for a total of two 2-mL SC injections for each 
subject), as described below. The adult safety study is open-label without a placebo arm. 
 
For each SC injection order, the dose level and study arm code will be included in the pharmacy 
order. To prepare a SC L9LS injection, the pharmacist will do the following:  
1) Retrieve the minimum number of thawed vials required to prepare the full dose. 
After vials are thawed, vials should be gently swirled for 30 seconds while 
avoiding foaming. DO NOT SHAKE THE VIAL. 
2) Withdraw the total amount of L9LS from the vial into the syringe(s) using a 5-
micron filter needle. A new filter needle must be used for each syringe in the case 
of multiple syringes. The filter needle must be discarded prior to dispensing and 
replaced with a needle suitable for SC injection at the time of administration. 
 

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For adult IV administration: Study product will be prepared by an unblinded pharmacist. For 
each IV infusion order, the subject’s weight, dose level, and study arm code will be included in 
the pharmacy order. The adult safety study is open-label without a placebo arm. To prepare an 
IV infusion, the pharmacist will do the following: 
1) Calculate the total milligrams of L9LS needed. 
2) Retrieve the minimum number of thawed vials required to prepare the full dose. 
After vials are thawed, prior to preparation for administration in the IV bag, vials 
should be gently swirled for 30 seconds while avoiding foaming. DO NOT 
SHAKE THE VIAL. 
3) Withdraw all air from the 100-mL bag of normal saline. 
4) Withdraw the necessary amount of L9LS. 
5) Add this volume to a 150-mL capacity, partial fill, 100-mL bag of normal saline 
using sterile compounding techniques to maintain sterility. 
 
An in-line filter infusion set must be used for IV product administrations and MUST comply 
with the following specifications: 1.2-micron polyethersulfone filter membrane, 
diethylhexylphthalate-free, latex-free (equivalent to Braun #473994 filter extension set). When 
the in-line filter is added to the tubing, the administration set must then be primed. 
 
Measures to Minimize Bias: Randomization and Blinding 
 Randomization 
Randomization lists for each randomized phase of the trial will be generated by the blinded 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 
This trial will be conducted with a double blind for subjects aged 6-10 years and for the year 2 
extension study; dose assignments of adult subjects will be open label. 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. The subjects, the clinical staff, and 
the study team will be blinded to study treatment allocation for subjects aged 6-10 years and 
those in the year 2 extension study, 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 pharmacy team at the study site where administration is taking place will be unblinded, and 
they are responsible for maintaining security of study treatment assignments. For the 36 subjects 

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aged 6-10 years enrolled in the dose-escalation study, blinding will be maintained for treatment 
assignment (L9LS versus placebo), but not for possible L9LS dose group. 
 
Data will remain blinded for the original protocol until the last subject completes the final study 
visit of the original protocol. Data will remain blinded for the protocol extension until the last 
subject completes the final study visit of the protocol extension. 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 EC. 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 vaccines within 4 weeks of study agent administration. 
• Killed vaccine or any COVID-19 vaccine within 2 weeks of study agent administration. 
(In Mali there are no standard vaccines for 6-10 year old children or adults) 
• Immunoglobulins and/or blood products 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) or 
immunosuppressive drugs for the duration of the study.  

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
 
Discontinuation of Study Intervention 
Study intervention may be discontinued for a protocol-defined group or arm (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 1.3) as possible. 
 
Missed Visits and Lost to Follow-up 
If a participant misses 1 visit after D28 or 2 visits after D28 that are not sequential, these will not 
be considered protocol deviations. However, 2 missed visits in a row or a total of 3 or more 
missed visits (regardless of whether or not they are sequential) over the duration of the study will 
be considered protocol deviations. 
 
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.  
 
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. If a missed 
visit cannot be rescheduled, the participant may continue with the next scheduled visit. 
• 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). 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. 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
Screening Procedures 
Screening will be performed at the Kalifabougou and Torodo study sites. The study staff will 
explain the study to the prospective subject/parent/guardian, complete the study comprehension 
examination (completed by adult subject or parent/guardian of minor subject), obtain consent 
(section 10.1), and assess eligibility. Consent will be obtained before any study-related 
procedures are performed. At this time, the subject will be assigned a unique study identification 
number in the clinical database. The identification number will link subject samples and data 
collected throughout the study. 
 
The following screening procedures and evaluations must be performed within -56 to -7 days of 
study intervention. Screening may take place over multiple visits if necessary. 
• Confirmation of identity, age, and residency. 
• Complete review of medical history, including solicited information related to recurrent 
or persistent dry mouth or swelling of salivary glands.   
• Complete review of medication use. 
• Complete physical examination, including height and weight. 
• Vital signs (temperature, blood pressure, and pulse). 
• 12-lead ECG. 
• Urine collection for urinalysis (urine dipstick or formal urinalysis; acceptable laboratory 
parameters defined in Appendix A). 
• Blood collection via venipuncture for screening evaluations: 
o HIV tests: 2 rapid diagnostic tests (RDTs), plus enzyme-linked immunosorbent 
assay (ELISA) if the RDTs are discordant. A subject will be referred for medical 
care for 2 positive RDTs or a positive ELISA. If the ELISA is negative, no further 
work-up will be done. Pre- and post-test HIV counseling will be provided. 
o HBV and HCV tests. If either test is positive, the subject will be referred for care 
regardless of the ALT result. 
o Hemoglobin typing (will not be repeated for the protocol extension).  
o Complete blood count (CBC) with differential. 
o ALT. 
o Cr. 
• Pre- and post-test HIV counseling. 
• Pregnancy test (urine or serum; females in adult cohort only). 
 

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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, 
confirmed positive test results for HIV, HBV, and HCV 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 the dose-escalation 
study but for any reason does not receive study agent, they may later consent to be screened and 
enrolled in the efficacy study. 
 
Enrollment: If the individual is eligible and agrees to participate, he or she will be scheduled to 
come for an enrollment visit, as described in section 1.3. Enrollment is defined as the time of 
artemether-lumefantrine administration. A clinician will discuss the target dates and timing of 
the study agent administration and sample collections before completing an enrollment to help 
ensure that the subject can comply with the projected schedule. 
 
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. 
 
Artemether-Lumefantrine: At enrollment, all subjects will be orally administered standard 
artemether-lumefantrine treatment to clear any possible Pf blood-stage infection prior to study 
agent administration. Dosing in adults will be 4 tablets twice daily for 3 days. Dosing in children 
will follow standard treatment dosing. Study investigators will provide a fat-containing drink 
(e.g. milk) to study participants immediately prior to administering artemether-lumefantrine to 
enhance its absorption, as per 2021 WHO Guidelines for Malaria.36 
 

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Randomization: At randomization, a randomization code will be assigned. Randomization 
procedures are described in sections 6.3.1 and 9.4.1. 
 
Study Agent Administration and Monitoring: Study agent administration and monitoring will 
be performed according to the assigned arm, 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 
referred for standard care 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 venipuncture 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 Mali National Malaria Control Program. According to the national guidelines, 
asymptomatic malarial infections in children are not treated. Malaria treatment is given only 
when symptoms are present along with positive blood smear results. 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. In adults assigned to IV drug 
administration, blood may be drawn from the IV line if an adequate venipuncture site is 
not available. Venous blood samples will be used as follows: 
o Safety evaluations described in section 8.3. 
o Shipment to the research laboratory in Bamako and NIAID for evaluation 
(including assays described in section 8.2.3) and storage. 
o Blood smear and dried blood spot for Pf RT-PCR. 
 
The amount of blood drawn for research purposes will be within the limits allowed for research 
subjects by the NIH Clinical Center:  
• Adult subjects: no more than 10.5 mL/kg or 550 mL, whichever is smaller, over any 8-
week period. 
• Pediatric subjects: 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 1.3. 

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 Correlative Studies for Research/Pharmacokinetic Studies 
The following evaluations will be performed according to the schedule presented in section 1.3. 
 
Blood smear: Thick 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 centrally in the laboratory in 
Bamako, 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.  
 
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 on coded 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 1.3) 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. 
 
Whole blood RNA-seq: Whole blood will be collected into PaxGene tubes to preserve RNA for 
human transcriptome analysis, to correlate transcriptomic signatures with Pf infection risk.  
 Samples for Genetic/Genomic Analysis 
8.2.4.1 Description of the Scope of Genetic/Genomic Analysis 
Genetic testing performed in this protocol will include performing human RNA-
seq/transcriptomic analysis of whole blood as well as analyzing the genetic material of infection-
inducing parasites in blood samples. 
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. 

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8.2.4.3 Management of Results 
As the human transcriptomic analyses performed in this protocol are research tests that do not 
have clinical implications for participants, no genetic results will be returned to subjects. 
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 1.3 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, blood pressure, 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 1.3: 
• CBC with differential. 
• ALT, Cr. 
 
Pregnancy Testing: Urine or serum pregnancy tests will be conducted for female subjects in the 
adult cohort only. Results must be confirmed negative prior to study agent administration. 
 
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. 
 

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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. 
 
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: An SAE: 
• is an AE that results in death. 
• is an AE that is 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 congenital anomaly/birth defect/miscarriage/stillbirth. 
NOTE: This definition is more inclusive than some commonly published definitions. It 
includes an affected conceptus/neonate whose: 
o biological mother was exposed to a study agent at any point from conception 
through the end of the pregnancy, AND/OR, if breastfeeding, the 30-day neonatal 
period; or 

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o biological father was exposed to a study agent at any point during the 90 days 
prior to conception. 
This is separate from, and in addition to, general reporting of pregnancy in a study 
participant or female partner of a male participant (see section 8.4.2.3.4 below). 
• 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 
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 EC-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. 

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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 prolonged shedding of a vaccine virus beyond the anticipated timeline 
o unexpectedly large number of pregnancies on a study 
o subject departure from an isolation unit prior to meeting all discharge criteria 
o accidental destruction of study records 
o unaccounted-for study agent 
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 EC-approved research 
protocol (except for some missed visits as specified in section 7.3). 
1. Major deviations: Deviations from the EC-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. 

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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 EC, 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 EC). 
 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), 
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 2.  
 

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Table 2. 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  
Related non-serious 
AEs of grade 1 to 3 
End of subject participation in study 
All other related non-
serious AEs 
End of subject participation in study 
Unrelated non-serious 
AEs 
End of subject participation in study 
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 “Mali Adverse Event Grading Scale” provided in 
Appendix B (separate tables provided for adults and children). Events that are not gradable 
using this table (e.g., urinalysis abnormalities) will be graded according to the “Guidance for 
Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials” which can be found at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-
adolescent-volunteers-enrolled-preventive-vaccine-clinical 
 
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. 

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8.4.2.1.1.1 Laboratory Value Assessment and Clinical Significance Criteria 
Except as specified below, ALL abnormal lab values of grade 1 or above are REPORTABLE. 
Grade 1 and 2 abnormal laboratory values are considered CLINICALLY SIGNIFICANT, and 
are to be recorded in the research database, and reported, 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 Cr) 
• result in additional/repeat testing or medical intervention (procedures/treatments) (e.g., 
ECG to evaluate arrhythmia potential with a high serum potassium; one or more ECGs to 
assess an elevated troponin level; potassium supplementation for hypokalemia) 
• indicates possible over-dosage  
• 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 
• there is no alternative etiology 
 
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 
 

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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. 
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.  
 

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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], 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. 
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  
https://crimsonredcap.cc.nih.gov/redcap/index.php  
 
Unless otherwise specified above, deaths 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 SAEs must be reported to the CSO no later than the third business day following the 
day of study personnel awareness. 
 
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 

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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 EC-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 
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 EC 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 EC. 
 
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. 
8.4.2.3.4 Pregnancy 
Unless otherwise specified above, all pregnancies will be reported (by REDCap, or by email and 
SERF if REDCap is not available) to the CSO no later than the first business day following the 
day of study personnel awareness. 
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous or elective termination of the 
pregnancy) will be reported to the CSO no later than the third business day following the day of 
study personnel awareness (by REDCap, or by email and SERF if REDCap is not available). 
Pregnancy itself is not an AE. Events that meet AE or SAE criteria in relation to pregnancy, 
delivery, or the conceptus/neonate (see section 8.4.1) are reportable (by REDCap, or by email 
and SERF if REDCap is not available). 
 
In the event of pregnancy in a study subject exposed to study agent, the following actions will be 
taken, with the goal of ensuring maternal and fetal well-being, in consultation with the SMM, 
ISM, and DSMB: 

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• Sample collection will continue per guidelines below: 
o Only proceed with PK blood draw if subject’s hemoglobin value is ≥8.0 
gm/dL (assessed via venipuncture collection of 0.5 mL of blood). 
o PK samples (4-8 mL) will be collected according to the regular study 
schedule (see sections 1.3.1 and 1.3.2). 
o The venipuncture used to measure hemoglobin at the visits specified 
above will also be used to collect blood smears for detection of Pf 
infection by microscopic examination, and dried blood spots for Pf RT-
PCR.  
o Serum storage samples will not be drawn if a subject becomes pregnant. 
• Continue to follow for safety on a monthly basis for the duration of the pregnancy and for 
a period of up to 6 months (per investigator discretion) following delivery for assessment 
of the neonate. 
• Request to unblind the subject, if applicable, AND if doing so would offer a benefit to the 
subject. 
• Report, no later than the first business day after study personnel awareness, to the ISM 
and DSMB. 
• Advise subject to notify the obstetrician of study participation and study agent exposure, 
providing contact information for the obstetrician to contact the study principal 
investigator, should this be required, and with the subject’s consent. 
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.) 

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• 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. 
o Withdraws permission to have blood samples or data stored for future research. 
o Positive pregnancy test prior to study agent administration. 
• The investigator determines that continued participation in the study would not be in the 
best interest of the subject. 
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 EC and/or DSMB and 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 in 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 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 
A 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. 

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8.4.4.3 Oversight Committees 
8.4.4.3.1 Independent Safety Monitor in Mali 
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 Mali 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 field of oversight of clinical trials 
conducted in Mali and internal medicine, specifically in the population under study in Mali.  
 
All deaths, SAEs, UPs, pregnancies, 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 EC 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 have access to unblinded data, by group, only as the entire DSMB does. 
The ISM may also serve as an ad hoc member of 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). They will also review available data from Year 1 
of the study prior to starting participant visits for Year 2. 
 
The DSMB may convene additional reviews as necessary. The DSMB will review the study data 
as needed to evaluate the safety, efficacy, study progress, and conduct of the study.  
 
All deaths, SAEs, UPs, pregnancies, and IND safety reports will be reported to the DSMB at the 
same time they are submitted to the EC 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.  

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 Pausing Rules 
“Pausing” is discontinuation of study intervention/treatment/dosing (agent/placebo/procedure, 
etc.) in a protocol-defined group or “arm,” 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 for a group or arm (e.g., a specific dosing group) in this study include any 
one or more of the following: 
• A subject experiences an SAE that is unexpected (per the investigator’s brochure or 
product label) and possibly, probably, or definitely related to a study agent; 
• A subject experiences 2 grade 3 or greater AEs that are unexpected (per the investigator’s 
brochure or product label) and possibly, probably, or definitely related to a study agent. 
 
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 EC 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 and DSMB and 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 EC of the decision according to the EC’s process. 
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. 

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 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: 
• Two or more subjects experience the same or similar grade 3 or greater AEs that are 
unexpected 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. The study safety oversight bodies (e.g., DSMB) may recommend a halt to the 
CSO. 
 
In addition, the FDA, Malian Ministry of Health, FMOS/FAPH EC, 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 EC 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 EC of the decision according to the EC’s process. 
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. 

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Unanticipated Problems 
 Definition of Unanticipated Problems 
The definition of a UP is provided in section 8.4.1. 
  Unanticipated Problem Reporting  
The investigator will report UPs to the FMOS/FAPH EC according to NIH Human Research 
Protection Program (HRPP) Policy 801, as described in section 8.6.1. 
 
ADDITIONAL REPORTING REQUIREMENTS 
 Reporting to the FMOS/FAPH EC 
Non-compliance and other reportable events will be reported to the FMOS/FAPH EC according 
to NIH HRPP Policy 801, which requires reporting as described below. 
 
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 FMOS/FAPH EC 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 EC in summary format 
at the time of continuing review, or when otherwise specifically requested by the EC or the NIH 
Office of Human Subjects Research Protections Office of Compliance and Training: 
• Major and minor protocol deviations.  
• Noncompliance reported to the EC that is not related to a protocol deviation.  
• AEs and SAEs that do not meet the definition of an UP.  
• UPs reported to the EC. 

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 Reporting to the NIAID Clinical Director 
The principal investigator will report UPs, major protocol deviations, and deaths to the NIAID 
clinical director according to institutional timelines. 
 Reporting Protocol Deviations that Result from the COVID-19 Pandemic  
The following addresses the reporting requirements to the FMOS/FAPH EC with regard to 
protocol deviations that result from disruption of study visits from the COVID-19 pandemic. 
These requirements follow the direction of the FMOS/FAPH EC as well as the NIH reporting 
requirements. 
 
Investigators may modify the protocol without prospective FMOS/FAPH EC approval when 
necessary to prevent an immediate apparent harm to a study subject. Typically, when this occurs 
the event must be reported to the EC 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 FMOS/FAPH EC 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 FMOS/FAPH 
EC 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 FMOS/FAPH EC 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. 
 

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Primary Endpoints: 
• Dose escalation and efficacy: Incidence and severity of local and systemic AEs occurring 
within 7 days after the administration of L9LS.  
• Efficacy: Pf blood-stage infection as detected by microscopic examination of thick blood 
smears obtained between 1 week and 24 weeks after administration of L9LS or placebo. 
 
Secondary Endpoints: 
Data from both parts of the study will be used to assess the following endpoints: 
• Measurement of L9LS in sera of recipients. 
• Pf blood-stage infection as detected by RT-PCR for 28 weeks after administration of 
L9LS or placebo for the dose escalation study and for 24 weeks after administration of 
L9LS or placebo for the efficacy study. 
• Incidence of clinical malaria (definition 1, see section 2.2.2.3) for 28 weeks after 
administration of L9LS or placebo for the dose escalation study and for 24 weeks after 
administration of L9LS or placebo for the efficacy study. 
• Incidence of clinical malaria (definition 2, see section 2.2.2.3) for 28 weeks after 
administration of L9LS or placebo for the dose escalation study and for 24 weeks after 
administration of L9LS or placebo for the efficacy study. 
• 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 sample size n=6 in each 
arm, there is over 90% chance to observe at least 1 AE if the true rate is at least 0.319 and over a 
90% chance to observe no AE if the true rate is no more than 0.017. With sample size n=9 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 3 for a range of possible 
true event rates.  
 
Table 3. Probability of events for different safety scenarios within an arm (n=6 or n=9). 
True event 
rate 
n=6 
n=9 
Pr(0) 
Pr(>1) 
Pr(0) 
Pr(>1) 
0.005 
0.97 
<0.001 
0.956 
0.001 
0.01 
0.941 
0.001 
0.914 
0.003 
0.02 
0.886 
0.006 
0.834 
0.013 

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True event 
rate 
n=6 
n=9 
Pr(0) 
Pr(>1) 
Pr(0) 
Pr(>1) 
0.035 
0.808 
0.017 
0.726 
0.037 
0.05 
0.735 
0.033 
0.63 
0.071 
0.1 
0.531 
0.114 
0.387 
0.225 
0.15 
0.377 
0.224 
0.232 
0.401 
0.2 
0.262 
0.345 
0.134 
0.564 
0.3 
0.118 
0.58 
0.04 
0.804 
Abbreviations: Pr, probability. 
 Sample Size Considerations for the Efficacy Study 
The efficacy study is designed to evaluate protective efficacy (PE) of L9LS at each dose by 
testing the null hypothesis,  
H0: PE = 0%, 
versus the alternative hypothesis,  
H1: PE ≠ 0%,  
where PE is 1 minus the relative risk of infection under L9LS versus under placebo. To account 
for the two comparisons, each L9LS dose arm with the placebo arm, two-sided tests each with 
significance level of 0.025 will be adopted to ensure the overall type I error rate is no more than 
0.05. The sample size considerations are based on the power of rejecting H0 over a range of 
possible protective efficacy and infection rates under placebo (Figure 5). Assuming a drop-out 
rate of 10%, Table 4 presents the power under a 2-sided log-rank test with significance level of 
0.025. If the infection rate under placebo is 0.4, there will be 90% power to detect the protective 
efficacy of 0.7 with 75 participants enrolled into each arm of the efficacy study. Based on 
historical data collected in Kalifabougou, approximately 85% of children aged 6-10 years who 
are uninfected (PCR negative) before the malaria season become infected with Pf during the 
ensuing malaria season (Figure 5). Therefore, the conservative estimate of infection rate under 
placebo of 0.4 will ensure that the study has adequate power if the malaria season is 
unexpectedly delayed or truncated. 
 
Table 4. Power for efficacy evaluation from a 2-sided log-rank test with type I error rate of 
0.025 assuming 10% dropout. 
Sample size  
(per arm) 
Infection rate 
under 
placebo 
Protective 
efficacy 
Power  
(%) 
60  
0.4 
0.6 
68 
0.4 
0.7 
83 
0.4 
0.8 
92 
0.5 
0.6 
82 

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0.5 
0.7 
92 
0.5 
0.8 
97 
0.6 
0.6 
92 
0.6 
0.7 
97 
0.6 
0.8 
99 
75  
0.4 
0.6 
78 
0.4 
0.7 
91 
0.4 
0.8 
97 
0.5 
0.6 
90 
0.5 
0.7 
97 
0.5 
0.8 
99 
0.6 
0.6 
97 
0.6 
0.7 
99 
0.6 
0.8 
100 
 
Table 5 presents the minimum detectable difference between an L9LS arm and placebo arm in 
terms of the event rate, for example the proportion of infection, based on a two-sided proportion 
test with type I error rate of 0.025.  
 
Table 5. Minimum detectable difference in the event rate in arms receiving L9LS or placebo 
under a 2-sided type I error rate of 0.025. 
Sample 
size within 
each arm 
(#) 
Event rate 
(under 
placebo) 
Detectable with 80% power 
Detectable with 90% power 
Difference 
Event rate 
(under 
L9LS) 
Difference 
Event rate 
(under 
L9LS) 
75 under 
L9LS and 
75 under 
placebo 
0.4 
0.226 
0.174 
0.253 
0.147 
0.5 
0.243 
0.257 
0.273 
0.227 
0.6 
0.25 
0.35 
0.283 
0.317 
0.7 
0.247 
0.453 
0.282 
0.418 
 
Sample Size Considerations for the Year 2 Extension Study 
For safety assessment, Table 6 shows the precision for estimating the AE rate within each arm of 
42 participants for a range of underlying event rates. 
 
Table 6. Exact 95% CI of AE rate estimate within each arm of size 42. 
Observed 
number of 
events  
Observed 
event rate 
95% confidence interval 
Lower 
bound 
Upper 
bound 
0 
0 
0 
0.084 

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1 
0.024 
0.001 
0.126 
2 
0.048 
0.006 
0.162 
3 
0.071 
0.015 
0.195 
4 
0.095 
0.027 
0.226 
5 
0.119 
0.04 
0.256 
6 
0.143 
0.054 
0.285 
7 
0.167 
0.07 
0.314 
8 
0.19 
0.086 
0.341 
9 
0.214 
0.103 
0.368 
10 
0.238 
0.121 
0.395 
11 
0.262 
0.139 
0.42 
12 
0.286 
0.157 
0.446 
13 
0.31 
0.176 
0.471 
14 
0.333 
0.196 
0.495 
 
With 42 participants per arm, there is 90% power to detect the difference between two arms if 
the event rate is 0.01, 0.05, or 0.1 in one arm and no less than 0.24, 0.33, or 0.42 in the other 
arm, respectively, based on two-sided proportion test at significance level 0.05. 
 
Table 7 shows the power for comparing two arms on the primary efficacy endpoint, namely, the 
time from receiving the second dose of L9LS (or placebo) to the first Pf blood-stage infection 
during extension study with each arm of 42 participants. 
 
Table 7. Power for between-arm comparison on time to infection based on two-sided log rank 
test at significance level 0.05. 
 
Infection rate 
in one arm 
Infection rate in 
the other arm 
Relative efficacy  Power (%) 
0.5 
0.2 
0.6 
79 
0.5 
0.15 
0.7 
90 
0.6 
0.24 
0.6 
89 
0.6 
0.18 
0.7 
96 
0.7 
0.28 
0.6 
96 
0.7 
0.21 
0.7 
99 
 
 
Populations for Analyses 
The following datasets will be considered in study analyses: 
• Intention-to-treat (ITT) analysis dataset will include all subjects that receive assignment 
and will be analyzed according to the initial randomization assignment.  

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• 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 ITT.  
 Evaluable for objective response  
Not applicable. 
 Evaluable Non-Target Disease Response 
Not applicable. 
 
Statistical Analyses 
 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% CIs. 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” 
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.  

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Randomization: Weight-stratified randomization will be implemented in the dose-escalation 
study and the efficacy study. In the efficacy study, 75 participants will be recruited into each 
weight group (15-19 kg, 20-25 kg, and 26-30 kg). Within each weight group, randomization will 
be 1:1:1 allocation to the 2 L9LS arms and the placebo arm. The total number of participants will 
be 75 in each arm (25 of weight 15-19 kg, 25 of weight 20-25 kg, and 25 of weight 26-30 kg). A 
similar stratified randomization will be applied to the dose-escalation study: six participants in 
each weight group, starting with 26-30 kg, followed by 20-25 kg, and then 15-19 kg, will be 
recruited and randomized 1:1 to receive L9LS at the dose of 150 mg or placebo; if no safety 
concerns arise, randomization into the L9LS at the dose of 300 mg 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. 
9.5.1.1 Year 2 Extension Study 
The same analysis methods for safety, PK, and efficacy endpoints described for the original 
study (year 1) below will be applied to the year 2 extension study. There will be no multiplicity 
adjustment in extension study analyses. All comparisons will be conducted at two-sided 
significance level 0.05. 
 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, incidence of Pf infection determined by RT-PCR, 
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 between 1 week and 24 weeks after 
administration. The secondary efficacy endpoints are the incidence of malaria infection as 
determined by RT-PCR and the incidence of clinical malaria. 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 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. An additional Cox regression 
will be performed with pre-existing parasitemia (Pf infection status determined by blood smear 
at baseline) as the stratification variable. The Holm method will be adopted to handle the issue of 
multiplicity in comparing the two dose arms against the placebo. 
 
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 assuming events occur at the time they are detected: 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% CI of the vaccine 
efficacy.37  
 
Since this trial adopts weight-stratified randomization, participants cover the dose range from 
5 mg/kg to 20 mg/kg. 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. 
 
The above analyses will apply to both the primary and the secondary efficacy endpoints.  
 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 listing 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% CIs of the AE rate. The number and percentage of subjects under each AE will be 

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additionally reported. 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 1.3. 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 
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. 38  
 

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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 via the method of generalized estimating 
equation (GEE) to account for repeated measures. The GEE estimation will only be performed 
over the scheduled visits with the binary outcome (infected or not) as the response and the L9LS 
concentration as the covariate. This analysis will be performed over all participants that receive 
L9LS including those aged 6-10 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. The purpose of the interim analysis on safety data 
is to clear safety concerns for proceeding to the efficacy study. This interim analysis will not 
affect the power or type I error in the primary analysis on efficacy in the efficacy study. 
 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.  
 
For assessment of ADA in the year 2 extension study, the count and percentage (as well as the 
exact 95% CI) of participants with detectable ADA in each arm will be reported. The percentage 
of participants with detectable ADA will be compared between two arms via Fisher’s exact test. 

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10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
 Informed Consent Process 
 Consent Procedures and Documentation 
The informed consent process for this study will involve obtaining initial community permission 
followed by individual informed consent. 
10.1.1.1 Community Permission for the Conduct of the Study 
Prior to the start of this study, community permission will be obtained as described in 
section 5.7. Following the process of Diallo and colleagues, 39 the community permission process 
will involve the following: 
1. Study investigators/personnel explain the study to village leaders, including the village 
chief, family heads, women association, and elders. 
2. The village leaders discuss the study with family heads and community members and 
relay any additional questions or concerns to the study personnel. 
3. The study and the informed consent process are explained in detail to heads of families 
by study investigators/personnel.   
10.1.1.2 Individual Informed Consent 
Consent process: The study informed consent form will be written in French. The study team 
will review the consent form word-for-word and will translate it orally into local languages, 
since most potential study subjects and minor subjects’ parents/guardians do not read or speak 
French. An independent witness who is not a member of the study team will verify that oral 
translations are accurate and that potential adult subjects and parents/guardians of minor subjects 
understand the contents of the consent form.  
 
Local households and families will be invited to come to the study clinic for review of the 
informed consent. At the consenting visit, the adult subject or minor subject’s parent/guardian 
will read the consent form or have it explained to them (in cases of illiteracy). Individuals in each 
family will be separately consented, and not all individuals from a household need to participate. 
Adult subjects will provide consent by signing or fingerprinting (if illiterate) the consent form. 
Parents/guardians will provide permission for their child/ward to participate by signing or 
fingerprinting (if illiterate) the consent form.  
 
Also, a study comprehension examination will be conducted to make sure that the study is 
understood by the potential adult subject or minor subject’s parent/guardian prior to signing 
consent. The exam will be written in French and translated orally into local languages. All 
incorrect responses will be reviewed, and individuals must orally confirm their understanding of 
all incorrect responses. A score of at least 80% correct responses by the potential adult subject or 

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by the parent/guardian is mandatory to enroll the adult or their child/ward, respectively. For 
individuals scoring below 80%, study staff may choose to review study details again and reassess 
comprehension by repeating the examination. At the discretion of the investigator, any potential 
adult subject whose comprehension is questionable, or the child/ward of any individual whose 
comprehension is questionable, regardless of score, may be excluded from enrollment. 
 
Minor participants will be included in all discussions about the study, and age-appropriate 
language will be used to describe the procedures and tests involved in this study, along with the 
risks, discomforts, and benefits of participation. However, children will not be required to 
provide assent as the age ranges included in this study typically do not have the ability to fully 
understand the nature of research.  
 
The consent process will be documented in the adult or child subject’s medical record. 
 Consent for Minors When They Reach the Age of Majority  
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained. 
 
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
prior to reaching the age of majority. 
 
Requirements for Waiver of Consent consistent with 45 CFR 46.116(f)(3): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again. A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research.  
(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format.  
a. Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies. Such information would be unavailable if access to medical record 
numbers was unavailable.  

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(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects.  
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority. 
 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 EC 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 local 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 locked and data will be coded. Any personally identifiable 
information maintained for this study will be kept on restricted-access computers and networks. 
Personally identifiable 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 
FMOS/FAPH EC, 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. 

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Samples are stored in secure research laboratories in locked freezers with limited access at the 
USTTB, Bamako, 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 FMOS/FAPH EC. 
 
Additionally, subjects may decide at any point 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 EC. 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 to indefinite 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 may be performed. 
 
Storage and Tracking: Access to and tracking of stored samples and data will be secured and 
limited as described above (section 10.3).  
 
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, EC 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 

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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 
EC, 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 
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 EC 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 investigator and sponsor, as applicable.  
 

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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 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 investigator to use continuous vigilance to identify and report 
deviations and non-compliance to the FMOS/FAPH EC and the NIH (as applicable) according to 
NIH HRPP 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 investigator is 
responsible for knowing and adhering to the reviewing EC requirements. 
 NIH Definition of Protocol Deviation 
The definition of a protocol deviation is provided in section 8.4.1. 
 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 Peter Crompton or 
LIG. 
 
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. 
 

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Data will be shared at the time of publication or shortly thereafter. 
Genomic Data Sharing Compliance 
This study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use 
of these data for subsequent research. Large-scale data may include genome-wide association 
studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, 
transcriptomic, epigenomic, and gene expression data. 
 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 
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 ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AR 
Adverse Reaction 
AUC 
Area Under the Concentrations vs. Time Curve 
Cave 
Average Concentrations 
CBC 
Complete Blood Count 
CFA 
Communauté Financière Africaine 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CHMI 
Controlled Human Malaria Infection 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum Concentration 

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CONSORT 
Consolidated Standards of Reporting Trials 
Cr 
Creatinine 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CSO 
Clinical Safety Office 
CSP 
Circumsporozoite Protein 
CTM 
Clinical Trials Management 
DCR 
Division of Clinical Research 
DS 
Drug Substance 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
EC80 
Effective Concentration in 80% of the population 
ED80 
Effective Dose in 80% of the population 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FDA 
Food and Drug Administration 
FMOS/FAPH 
Faculté de Médecine Pharmacie d’Odontostomatologie 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation 
GLP 
Good Laboratory Practices 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HRPP 
Human Research Protection Program 
ICH 
International Council on Harmonisation  
IND 
Investigational New Drug Application 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
IV 
Intravenous(ly) 
LIG 
Laboratory of Immunogenetics 
MAb 
Monoclonal Antibody 
MITT 
Modified Intention-To-Treat 
MRTC 
Malaria Research and Training Center 
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 

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PCR 
Polymerase Chain Reaction 
PE 
Protective Efficacy 
Pf 
Plasmodium falciparum 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
Q 
Intercompartmental Clearance 
QL 
Quantitative Limit 
QTc 
Corrected QT Interval 
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 
SERF 
Safety Expedited Report Form 
SMC 
Seasonal Malaria Chemoprevention 
SMM 
Sponsor Medical Monitor 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
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 
USD 
United States Dollar 
USTTB 
University of Sciences, Techniques, & Technologies of Bamako 
VCMP 
Vaccine Clinical Materials Program 
Vd 
Volume of Distribution 
Vdss 
Volume of Distribution at Steady-State 
VRC 
Vaccine Research Center 
WHO 
World Health Organization 
 

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12 REFERENCES  
1. 
World Health Organization. World Malaria Report 2018. 2018. 
https://www.who.int/publications/i/item/9789241565653 
2. 
RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine 
with or without a booster dose in infants and children in Africa: final results of a phase 3, 
individually randomised, controlled trial. Lancet. Jul 4 2015;386(9988):31-45. 
doi:10.1016/S0140-6736(15)60721-8 
3. 
Mahmoudi S, Keshavarz H. Efficacy of phase 3 trial of RTS, S/AS01 malaria vaccine: 
The need for an alternative development plan. Hum Vaccin Immunother. Sep 2 2017;13(9):2098-
2101. doi:10.1080/21645515.2017.1295906 
4. 
World Health Organization. WHO recommends groundbreaking malaria vaccine for 
children at risk: Historic RTS,S/AS01 recommendation can reinvigorate the fight against 
malaria. 6 October 2021. Accessed 13 October 2021. https://www.who.int/news/item/06-10-
2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-risk 
5. 
WHO. WHO Guidelines for malaria. 3 June 2022 2022; 
6. 
Access-Smc Partnership. Effectiveness of seasonal malaria chemoprevention at scale in 
west and central Africa: an observational study. Lancet. Dec 5 2020;396(10265):1829-1840. 
doi:10.1016/S0140-6736(20)32227-3 
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APPENDIX A: MRTC URINE LABORATORY NORMAL VALUES 
Urine Dip/Urinalysis - Adults 
Urine1 
Reference Ranges 
Protein 
None or Trace 
Blood (Microscopic) –  
 
RBC/HPF 
None or Trace 
 
< 5 
Abbreviations: HPF, high power field; RBC, red blood cell. 
1 The laboratory values provided in the table are based on Bancoumana, Malian adults (age 18-45 years). 
 
Urine Dip/Urinalysis - Pediatrics 
Urine 
Reference Ranges 
Protein 
< 10 mg/L 
Blood (Microscopic) –  
 
RBC/HPF 
< 25 WBC/µg 
 
None 
Abbreviations: HPF, high power field; RBC, red blood cell; WBC, white blood cell. 
 
 
 

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APPENDIX B: MALI LABORATORY ADVERSE EVENT GRADING SCALE, ADULTS 
Evaluation 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Hematology and Biochemistry Values 1, 2 
Hemoglobin (Female) – 
gm/dL 
8.0 – 9.0 
7.0 – 7.9 
6.0 – 6.9 
< 6 and/or requiring 
transfusion 
Hemoglobin (Male) – 
gm/dL 
9.5 – 10.3 
8.0 – 9.4 
6.5 – 7.9 
< 6.5 and/or requiring 
transfusion 
WBC Increase – 103/µL 
11.5 – 15.0 
15.1 – 20.0 
20.1 – 25.0 
> 25.0 
WBC Decrease – 103/µL 
2.5 – 3.3 
1.5 – 2.4 
1.0 – 1.4 
< 1.0 with fever 
Neutrophil/Granulocyte 
Decrease 3 – 103/µL 
0.80 – 1.00 
0.50 – 0.79 
< 0.50 
< 0.50 with fever 
Platelet Decrease – 103/µL 
100 – 110 
70 – 99 
25 – 69 
< 25 
Creatinine (Male) – 
µmol/L 
124.00 – 150.99 
151.00 – 176.99 
177.00 – 221.00 
> 221.00 and requires 
dialysis 
Creatinine (Female) – 
µmol/L 
107.00 – 132.99 
133.00 – 159.99 
160.00 – 216.00 
> 216.00 and requires 
dialysis 
Liver Function Tests/ALT 
– U/L 
75.0 – 150.9 
151.0 – 300.9 
301.0 – 600.0 
> 600.0 
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. 
1 The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  
2 The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as potentially life-threatening (grade 4). For example, a low sodium value that falls within a 
grade 3 parameter should be recorded as a grade 4 hyponatremia event if the subject had a new seizure associated 
with the low sodium value.  
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.40,41  
4 Values presented are for non-oral temperature reading (i.e., axillary or no-touch), which is the preferred method at 
the study site. If oral temperature is taken, the US Food and Drug Administration toxicity grading scale will be used 
to grade fever. 
 
 

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APPENDIX C: MALI LABORATORY ADVERSE EVENT GRADING SCALE, 
CHILDREN 
Hematology and 
Biochemistry Values1, 2 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially  
Life-threatening 
(Grade 4) 
Hemoglobin (Male/Female) - 
gm/dL  
7.50 – 8.40 
6.10 – 7.49 
5.00 – 6.09 
< 5.00 g/dL 
WBC Increase - 103/µL 
14.50 – 16.09 
16.10 – 20.09 
20.10 – 30.00 
>30.00 
WBC Decrease - 103/µL 
2.50 – 3.30 
1.50 – 2.49 
1.00 – 1.49 
< 1.00 with or without 
fever 
Neutrophil/Granulocyte 
Decrease3 - 103/µL 
0.75 – 0.99 
0.50 – 0.74 
< 0.50 
< 0.50 with fever 
Platelets Decreased - 103/µL 
100.0 – 120.9 
70.0 – 99.9 
25.0 – 69.9 
< 25.0 
Creatinine (Male/Female) - 
µmol/L 
95.00 – 119.99 
120.00 – 149.99 
150.00 – 200.00 
> 200.00 and requires 
dialysis 
Liver Function Tests/ALT - 
U/L 
75.0 – 150.9 
151.0 – 300.9 
301.0 – 600.0 
> 600.0 
Abbreviations: ALT, alanine transaminase; WBC, white blood cell. 
1 The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  
2 The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls 
within a grade 3 parameter should be recorded as a grade 4 hyponatremia event if the subject had a new seizure 
associated with the low sodium value.  
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. 40,41 
 
 
 

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APPENDIX D: MALI VITAL SIGNS ADVERSE EVENT GRADING SCALE, 
CHILDREN 
Vital Signs 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Temperature 
38.0 – 38.4  
  
100.4 – 101.1  
38.5 – 38.9  
  
101.2 – 102.0  
  
39.0 – 40  
  
102.1 – 104  
> 40  
  
> 104  
Tachycardia - beats 
per minute; at rest + 
calm 
121 – 135 
136 -- 150 
>150 
ER visit or 
hospitalization 
for 
arrhythmia 
Bradycardia - beats 
per minute4; at rest + 
calm 
55 -- 59 
50 – 54 
< 50 
ER visit or 
hospitalization 
for 
arrhythmia 
Hypertension (systolic) 
-mm Hg; at rest + calm 131 –  140 
141 – 150 
> 150 
ER visit or 
hospitalization 
for 
malignant 
hypertension 
Hypertension 
(diastolic) -mm Hg; at 
rest + calm 
81 – 90 
91 – 95 
> 95 
ER visit or 
hospitalization 
for 
malignant 
hypertension 
Hypotension (systolic) 
-mm Hg; at rest + calm 75 – 79 
70 – 74 
< 70 
ER visit or 
hospitalization 
for 
hypotensive 
shock 
 
 
 

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APPENDIX E: DOSE ESCALATION PEDIATRIC STUDY EXTENSION 
Study Extension Rationale 
Pediatric participants who are enrolled in the Dose Escalation study may be followed with 
additional study visits through the end of the malaria season to 1) determine whether they 
become infected with P. falciparum (as detected by RT-PCR from dried blood spots collected 
every 4 weeks), and 2) extend the PK analysis of L9LS to approximately 9 months (as 
determined by measuring the concentration of L9LS in blood samples collected every 4 weeks). 
The Pediatric Dose Escalation component of the study had 2 dose groups (150 mg of L9LS or 
placebo and 300 mg of L9LS or placebo). Following all subjects in the Pediatric Dose Escalation 
group will allow for exploratory analyses that assess the correlation between L9LS serum 
concentrations and P. falciparum infection risk over a 9-month period. Since these participants 
received study agent earlier than participants in the efficacy study, they are expected to have 
lower serum L9LS concentrations at the end of the malaria season compared to participants in 
the efficacy study, which will allow for correlations of malaria risk over a broader range of L9LS 
concentrations.  
 
Study Extension Procedures 
Pediatric participants who are enrolled in the Dose Escalation study will be offered participation 
in the extension study visits and undergo an informed consent process (see section 10.1.1.2) with 
the ICF addendum. Those that agree to participate will be enrolled and begin monthly Extension 
study visits at the MRTC clinic in Kalifabougou or Torodo. At each study visit, up to 1.0 mL of 
blood will be collected by venipuncture for blood smear, Pf RT-PCR, possible parasite 
genotyping in the case of a positive malaria parasite infection (see section 8.2.3), and 
measurement of L9LS concentrations in serum. If a participant develops symptoms of malaria or 
other symptoms, they will be asked to return for an illness visit (see section 8.2.1).  
AEs related to the blood collection procedures and all SAEs will be collected and followed 
through resolution.  
 
Participants will attend monthly study visits through Day 252, for a total of 2 monthly extension 
visits. 
 
Compensation 
Subjects will be compensated 3,000 Communauté Financière Africaine (CFA) Franc for each 
study visit for the time and inconvenience of participation. Payment will be provided in cash 
after the completion of each visit.  
 
Subjects will be provided with transportation to and from study visits but will not receive 
additional reimbursement for travel. 
 

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Additional Procedures and Processes 
Refer to main protocol sections 8-10 for additional information related to safety definitions and 
reporting, data evaluation, and human subject protection procedures.