Safety and Efficacy of VRC-MALMAB0100-00-AB (CIS43LS), a Human Monoclonal Antibody Against Plasmodium Falciparum, in a Dose-Escalation Trial and a Randomized, Double-Blind Trial of Adults in Mali
Phase: PHASE2
Conditions: Plasmodium Falciparum Infection, Malaria
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Abbreviated Title: Anti-malaria MAb in Mali 
FMPOS Protocol #: 2020/32/CE/FMOS/FAPH 
Version Date: October 13, 2022 
 
Title: Safety and Efficacy of VRC-MALMAB0100-00-AB (CIS43LS), a Human Monoclonal 
Antibody against Plasmodium falciparum, in a Dose-Escalation Trial and a Randomized, 
Double-Blind Trial of Adults in Mali 
 
FMPOS Principal Investigator: 
Kassoum Kayentao, MD, MPH, PhD  
Malaria Research and Training Center (MRTC) 
Faculté de Médecine Pharmacie d’Odontostomatologie (FMPOS) 
University 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 
VRC-MALMAB0100-00-AB (CIS43LS) 
Investigational New 
Drug (IND) Number 
147485 
Sponsor 
Office of Clinical Research Policy and 
Regulatory Operations (OCRPRO), Division 
of Clinical Research, NIAID 
Manufacturer 
Vaccine Research Center (VRC), NIAID 
 
Data and Safety Monitoring Board (DSMB): NIAID Intramural DSMB 
 

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Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
STUDY STAFF ROSTER 
FMPOS Investigators: 
The research activities of the following FMPOS investigators will be reviewed by:  
FMPOS Ethics Committee 
BP E302, Point G/FMPOS 
Bamako, Mali 
FWA #00001769 
FMPOS Principal Investigator: Kassoum Kayentao, MD, MPH, PhD  
MRTC, FMPOS, USTTB 
BP E302, Point G/FMPOS  
Bamako, Mali 
Phone: +223 7646 0173 
Email: kayentao@icermali.org 
Role(s): A, B, C, D, E, F 
 
FMPOS Associate Investigators: Boubacar Traore, PharmD, PhD (Senior Investigator) 
MRTC, FMPOS, USTTB 
Phone: +223 222 8109 
Email: bouba.traore@mrtcbko.org  
Role(s): A, B, C, D, E, F 
 
Aissata Ongoiba, MD, MPH 
MRTC, FMPOS, USTTB 
Phone: +223 222 8109 
Email: ongoiba@icermali.org 
Role(s): A, B, C, D, E, F 
 
Safiatou Doumbo, MD, MS 
MRTC, FMPOS, USTTB 
Phone: +223 76 03 95 24 
Email: sdoumbo@icermali.org  
Role(s): A, B, C, E, F 
 
Didier Doumtabe, PharmD, MS 
MRTC, FMPOS, USTTB 
Phone: +223 74 44 44 44 
Email: ddidier@icermali.org  
Role(s): A, B, C, E, F 
 

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Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
Abdrahamane Traore, MD 
MRTC, FMPOS, USTTB 
Phone: +223 76 49 76 58 
Email: boutraore@icermali.org 
Role(s): A, B, C, E, F 
 
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 (Senior Investigator) 
Chief, Cellular Immunology Section 
VRC, NIAID, NIH 
Phone: 301-594-8483 
Email: rseder@mail.nih.gov 
Role(s): F 
 
 

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Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
Non-NIH Employee Associate 
Investigators: 
Sara Healy, MD, MPH (Contractor) 
Medical Science & Computing, LLC 
In support of LIG, NIAID, NIH 
Phone: 206-550-6493 
Email: sarahealy@hotmail.com 
Role(s): F 
 
Anne C. Preston, RN, BS, CCRC (Contractor) 
Gap Solutions, Inc. 
In support of LIG, NIAID, NIH 
Phone: 240-669-2876 
Email: anne.preston@nih.gov 
Role(s): F 
 
Sean C. Murphy, MD, PhD 
University of Washington 
Department of Laboratory Medicine, NW120 
Box 357110 
1959 Pacific St. 
Seattle, WA 98195–7110 
Phone: 206-685-6162  
Email: murphysc@uw.edu 
Role(s): F 
 
Daniel Neafsey, PhD 
Harvard T.H. Chan School of Public Health 
665 Huntington Avenue 
Building 1, Room 711 
Boston, MA 02115 
Phone: 617-432-5404 
Email: neafsey@hsph.harvard.edu 
Role(s): F 
 
Statistician:  Zonghui Hu, PhD 
Biostatistics Research Branch, NIAID, NIH 
Phone: 240-669-5240 
Email: huzo@niaid.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 

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Version Date: October 13, 2022 
 
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):  
Shirley Jankelevich, MD (Contractor) 
Leidos Biomedical Research, Inc.  
Support to: OCRPRO, NIAID, NIH 
Phone: 301-846-7322 
Email: shirley.jankelevich@nih.gov 
 
Independent Safety Monitor (ISM): Daouda K. Minta, MD 
Point-G Hospital 
USTTB 
Phone: +223 7509 0209 
Email: minta_daouda@yahoo.fr 
 
 

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TABLE OF CONTENTS  
STATEMENT OF COMPLIANCE .............................................................................................. 11 
1 
PROTOCOL SUMMARY ..................................................................................................... 12 
1.1 
Synopsis ......................................................................................................................... 12 
1.2 
Schema ........................................................................................................................... 15 
1.3 
Schedule of Activities (SOA) ......................................................................................... 17 
1.3.1 
Dose-escalation Study ............................................................................................. 17 
1.3.2 
Efficacy Study ......................................................................................................... 19 
2 
INTRODUCTION ................................................................................................................. 22 
2.1 
Study Rationale .............................................................................................................. 22 
2.2 
Background .................................................................................................................... 22 
2.2.1 
Overview ................................................................................................................. 22 
2.2.2 
Study Product: CIS43LS ......................................................................................... 23 
2.2.3 
Laboratory Assessments of CIS43LS ..................................................................... 27 
2.3 
Risk/Benefit Assessment ................................................................................................ 28 
2.3.1 
Known Potential Risks ............................................................................................ 28 
2.3.2 
Known Potential Benefits ....................................................................................... 30 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................... 30 
3 
OBJECTIVES AND ENDPOINTS ....................................................................................... 30 
4 
STUDY DESIGN .................................................................................................................. 32 
4.1 
Overall Design................................................................................................................ 32 
4.2 
Scientific Rationale for Study Design ............................................................................ 33 
4.3 
Justification for Dose ..................................................................................................... 33 
5 
STUDY POPULATION ........................................................................................................ 34 
5.1 
Inclusion Criteria ............................................................................................................ 34 
5.2 
Exclusion Criteria ........................................................................................................... 34 
5.3 
Inclusion or Exclusion of Vulnerable Participants ......................................................... 35 
5.4 
Lifestyle Considerations ................................................................................................. 36 
5.5 
Screen Failures ............................................................................................................... 36 
5.6 
Strategies for Recruitment and Retention ...................................................................... 36 
5.6.1 
Costs ........................................................................................................................ 36 
5.6.2 
Compensation ......................................................................................................... 37 

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6 
STUDY INTERVENTION ................................................................................................... 37 
6.1 
Study Intervention Administration ................................................................................. 37 
6.1.1 
Study Intervention Description ............................................................................... 37 
6.1.2 
Dosing and Administration ..................................................................................... 37 
6.2 
Preparation/Handling/Storage/Accountability ............................................................... 39 
6.2.1 
Acquisition and Accountability .............................................................................. 39 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 39 
6.2.3 
Product Storage and Stability.................................................................................. 39 
6.2.4 
Preparation .............................................................................................................. 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................... 40 
6.3.1 
Randomization ........................................................................................................ 40 
6.3.2 
Blinding................................................................................................................... 40 
6.4 
Study Intervention Compliance ...................................................................................... 41 
6.5 
Concomitant Therapy ..................................................................................................... 41 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 41 
7.1 
Discontinuation of Study Intervention ........................................................................... 41 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 42 
7.3 
Lost to Follow-up ........................................................................................................... 42 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................. 42 
8.1 
Screening Procedures ..................................................................................................... 42 
8.2 
Efficacy Assessments ..................................................................................................... 43 
8.2.1 
Clinical Evaluations ................................................................................................ 43 
8.2.2 
Biospecimen Evaluations ........................................................................................ 44 
8.2.3 
Correlative Studies for Research/Pharmacokinetic Studies .................................... 45 
8.2.4 
Samples for Genetic/Genomic Analysis ................................................................. 45 
8.3 
Safety and Other Assessments ....................................................................................... 45 
8.4 
Safety Definitions, Management, and Sponsor Reporting ............................................. 46 
8.4.1 
Definitions............................................................................................................... 46 
8.4.2 
Documenting, Assessing, Recording, and Reporting Events ................................. 49 
8.4.3 
Withdrawal Criteria for an Individual Subject........................................................ 55 
8.4.4 
Additional Safety Oversight ................................................................................... 56 

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8.4.5 
Pausing Rules .......................................................................................................... 57 
8.4.6 
Halting Rules for the Protocol ................................................................................ 58 
8.5 
Unanticipated Problems ................................................................................................. 59 
8.5.1 
Definition of an Unanticipated Problem ................................................................. 59 
8.5.2 
Unanticipated Problem Reporting........................................................................... 59 
8.6 
ADDITIONAL REPORTING REQUIREMENTS ........................................................ 59 
8.6.1 
Reporting to the FMPOS EC .................................................................................. 59 
8.6.2 
Reporting to the NIAID Clinical Director .............................................................. 59 
8.6.3 
Reporting Protocol Deviations that Result from the COVID-19 Pandemic ........... 60 
9 
STATISTICAL CONSIDERATIONS .................................................................................. 60 
9.1 
Statistical Hypothesis ..................................................................................................... 60 
9.2 
Sample Size Determination ............................................................................................ 61 
9.2.1 
Sample Size Considerations for the Dose-Escalation Study ................................... 61 
9.2.2 
Sample Size Considerations for the Efficacy Study ............................................... 61 
9.3 
Populations for Analyses ................................................................................................ 64 
9.3.1 
Evaluable for Toxicity ............................................................................................ 64 
9.3.2 
Evaluable for Objective Response .......................................................................... 64 
9.3.3 
Evaluable Non-Target Disease Response ............................................................... 64 
9.4 
Statistical Analyses ........................................................................................................ 64 
9.4.1 
General Approach ................................................................................................... 64 
9.4.2 
Analysis of the Primary Endpoints ......................................................................... 65 
9.4.3 
Analysis of the Secondary Endpoints ..................................................................... 65 
9.4.4 
Efficacy Analyses ................................................................................................... 65 
9.4.5 
Safety Analyses ....................................................................................................... 66 
9.4.6 
Pharmacokinetics Analysis ..................................................................................... 66 
9.4.7 
Baseline Descriptive Statistics ................................................................................ 67 
9.4.8 
Planned Interim Analyses ....................................................................................... 67 
9.4.9 
Sub-group Analyses ................................................................................................ 67 
9.4.10 Tabulation of Individual Participant Data............................................................... 67 
9.4.11 Exploratory Analyses .............................................................................................. 67 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS .......................................... 67 
10.1 
Informed Consent Process .......................................................................................... 67 

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10.1.1 Consent Procedures and Documentation ................................................................ 67 
10.1.2 Consent for Minors When They Reach the Age of Majority .................................. 68 
10.1.3 Telephone Consent.................................................................................................. 68 
10.1.4 Telephone Assent .................................................................................................... 69 
10.1.5 Participation of Subjects who are/become Decisionally Impaired ......................... 69 
10.2 
Study Discontinuation and Closure ............................................................................ 69 
10.3 
Confidentiality and Privacy ........................................................................................ 69 
10.4 
Future Use of Stored Specimens and Data ................................................................. 70 
10.5 
Safety Oversight ......................................................................................................... 70 
10.6 
Clinical Monitoring .................................................................................................... 70 
10.7 
Quality Assurance and Quality Control ...................................................................... 71 
10.8 
Data Handling and Record Keeping ........................................................................... 71 
10.8.1 Data Collection and Management Responsibilities ................................................ 71 
10.8.2 Study Records Retention......................................................................................... 71 
10.9 
Protocol Deviations .................................................................................................... 71 
10.9.1 NIH Definition of Protocol Deviation .................................................................... 72 
10.10 
Publication and Data Sharing Policy .......................................................................... 72 
10.10.1 Human Data Sharing Plan ....................................................................................... 72 
10.10.2 Genomic Data Sharing Plan .................................................................................... 72 
10.11 
Collaborative Agreements .......................................................................................... 72 
10.11.1 Agreement Type...................................................................................................... 72 
10.12 
Conflict of Interest Policy........................................................................................... 72 
11 ABBREVIATIONS ............................................................................................................... 73 
12 REFERENCES ...................................................................................................................... 75 
APPENDIX A: MRTC URINE LABORATORY NORMAL VALUES ..................................... 77 
APPENDIX B: MALI ADVERSE EVENT GRADING SCALE ................................................ 78 
APPENDIX C: DOSE ESCALATION STUDY EXTENSION ................................................... 79 
APPENDIX D: PREGNANCY FOLLOW-UP ............................................................................ 81 
 
List of Tables 
Table 1. Study agent assignment and dosing by arm. ................................................................... 37 
Table 2. Standard event recording, assessment, and reporting timeframes. ................................. 50 

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Table 3. Probability (Pr) of events for different safety scenarios within an arm (n=6 or 18)....... 61 
Table 4. Power for efficacy evaluation under a 2-sided type I error rate of 0.025. ...................... 62 
Table 5. Minimum detectable difference in adverse event rate in arms receiving monoclonal 
antibody (MAb) or placebo under a 2-sided type I error rate of 0.025. ........................................ 63 
Table 6. Schedule of assessments for neonate/infant participants. ............................................... 81 
 
List of Figures 
Figure 1. Dose-escalation study flow diagram. ............................................................................ 15 
Figure 2. Efficacy study flow diagram. ........................................................................................ 16 
 
 
 

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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:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
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 FMPOS Ethics Committee 
(EC) for review and approval. Approval of both the protocol and the consent form 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 form 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 
consent form. 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
Safety and Efficacy of VRC MALMAB0100-00-AB (CIS43LS), a Human 
Monoclonal Antibody against Plasmodium falciparum, in a Dose-
Escalation Trial and a Randomized, Double-Blind Trial of Adults in Mali 
Study Description: 
A two-part phase 2 trial evaluating the safety and tolerability of one-time 
administration of CIS43LS, as well as its protective efficacy against 
naturally occurring Plasmodium falciparum (Pf) infection over a 6-month 
malaria season. The primary study hypotheses are that CIS43LS 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. 
Dose-escalation study: The first part of the study is an open-label 
dose-escalation study for safety and tolerability. Subjects will be assigned 
to 1 of 3 dose arms (N=18 total, n=6 for each dose level). Dosing will begin 
in the lowest dose arm. Once all subjects in that arm reach day 7 
post-infusion, if no safety concerns have arisen, dosing will begin at the 
subsequent dose level. This process will be repeated until subjects complete 
the third dose arm. Subjects will be followed for safety to assess adverse 
events (AEs) at study visits 1, 3, 7, 14, 21, and 28 days after administration, 
then monthly through 24 weeks after administration. Participants who 
complete participation in the dose-escalation will be offered participation in 
extension visits to collect extra bi-weekly blood samples for 
pharmacokinetic (PK) analysis and to monitor for Pf infection through the 
end of December 2021. 
After the last subject in the highest dose arm reaches day 7 safety 
follow-up, an interim safety evaluation will be performed before enrollment 
begins for the second part of the study. 
Efficacy study: The second part of the study is a randomized, double-blind, 
placebo-controlled trial (N=330 total, n=110 for each of 3 treatment arms) 
to assess safety and protective efficacy of CIS43LS and placebo. 
Subjects in the efficacy study will receive the study agent 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. 
Objectives: 
Primary Objectives:  
1. Dose escalation: To evaluate the safety and tolerability of CIS43LS 
administered intravenously (IV) at 5, 10, and 40 mg/kg in healthy 
Malian adults. 
2. Efficacy: To determine if IV administration of CIS43LS at 10 mg/kg 
and 40 mg/kg (compared to placebo) mediates protection against 
naturally occurring Pf infection in healthy Malian adults during a 
single malaria season as detected from microscopic examination of 
thick blood smear. 

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Version Date: October 13, 2022 
 
Secondary Objectives: 
1. Dose escalation: To evaluate the PK of CIS43LS at each dose level 
throughout the study. 
2. Efficacy: To determine if IV administration of CIS43LS at 10 mg/kg 
and 40 mg/kg (compared to placebo) mediates protection against 
naturally occurring Pf infection in healthy Malian adults during a 
single malaria season as detected by reverse transcription polymerase 
chain reaction (RT-PCR). 
3. Efficacy: To evaluate the PK of CIS43LS throughout the study at the 
dose of 10 mg/kg and 40 mg/kg and to correlate CIS43LS serum 
concentration with Pf infection risk.  
Endpoints: 
Primary Endpoints: 
1. Dose escalation: Incidence and severity of local and systemic AEs 
occurring within 7 days after the administration of CIS43LS.  
2. Efficacy: Pf blood stage infection as detected by microscopic 
examination of thick blood smear for 24 weeks after administration of 
CIS43LS or placebo. 
Secondary Endpoints: 
1. Dose escalation: Measurement of CIS43LS in sera of recipients.  
2. Efficacy: Pf blood stage infection as detected by RT-PCR for 
24 weeks after administration of CIS43LS or placebo.  
3. Efficacy: Measurement of CIS43LS in sera of recipients.  
Study Population: 
Healthy Malian adults (aged 18 to 55 years) residing in Kalifabougou and 
Torodo 
Phase: 
2 
Description of 
Sites/Facilities 
Enrolling Subjects: 
The MRTC clinics in Kalifabougou and Torodo. All screening, day 0 (study 
agent administration) and day 7 visits will be performed at Kalifabougou 
only. Both sites will conduct recruitment, enrollment, follow-up visits 
(other than day 7 as noted above) and unscheduled study visits. 
Description of Study 
Intervention: 
The study agent (CIS43LS or matching placebo) will be administered as a 
one-time IV infusion.  
Dose-escalation study subjects will receive 1 of 3 different dose levels; 
study agent will be administered starting with the lowest dose level: 
• 
Arm 1: 5 mg/kg IV 
• 
Arm 2: 10 mg/kg IV 
• 
Arm 3: 40 mg/kg IV 
Efficacy study subjects will be randomized 1:1:1 to receive 1 of the 
following: 
• 
Arm 1: 10 mg/kg IV 
• 
Arm 2: 40 mg/kg IV 

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Version Date: October 13, 2022 
 
• 
Arm 3: Placebo (normal saline) IV 
Study Duration: 
23 months 
Subject Duration: 
Dose-escalation study: 8 months, plus approximately 3 months optional 
extension visits  
Efficacy study: 8 months 

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1.2 
SCHEMA 
 
Figure 1. Dose-escalation study flow diagram. 
 
Screening: Obtain informed consent. Assess eligibility; obtain and document history and 
perform screening evaluations. 
Enrollment (Day -14 ±7): Total  N=18. Confirmation of eligibility; first dose of artemether-
lumefantrine; assign study identification number. 
Follow-up 1, 3, 7, 14, 
21, and 28 days later, 
then monthly through 
week 24. 
Final assessments week 
24 (day 168). 
 
Safety review when last  
Arm 1 subject reaches day 7. 
Arm 1 
n=6 
Day 0:  
Baseline 
assessments. 
5 mg/kg study agent 
infusion and 
monitoring. 
Follow-up 1, 3, 7, 14, 
21, and 28 days later, 
then monthly through 
week 24. 
Final assessments week 
24 (day 168). 
Follow-up 1, 3, 7, 14, 
21, and 28 days later, 
then monthly through 
week 24. 
Final assessments week 
24 (day 168). 
Safety review when last  
Arm 2 subject reaches day 7. 
Interim DSMB safety analysis after last Arm 3 subject 
reaches day 7, prior to first enrollment in efficacy study. 
Arm 2 
n=6 
Day 0:  
• Baseline 
assessments. 
• 10 mg/kg study agent 
infusion and 
monitoring. 
Arm 3 
n=6 
Day 0:  
• Baseline 
assessments. 
• 40 mg/kg study agent 
infusion and 
monitoring. 

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Figure 2. Efficacy study flow diagram. 
 
 
Day 0: 
Baseline assessments. 
 
 
 
 
 
 
 
 
 
 
 
Blinded study agent infusion (assigned by arm) and post-infusion monitoring. 
Screening: Obtain informed consent. Assess eligibility; obtain and document history and 
perform screening evaluations. 
Randomize 
Enrollment (Day -14 ±7): Total N=330. Confirmation of eligibility; first dose of 
artemether-lumefantrine; assign study identification number. 
Arm 3 
n=110 
Placebo 
Follow-up: 
 
Safety follow-up: Physical exam and adverse event assessment days 1 and 3, weekly 
through day 28, then once every 2 weeks through 24 weeks. 
 
Efficacy follow-up: Blood smear starting day 7, weekly through day 28, then once every 2 
weeks through 24 weeks. 
 
[Unscheduled visits as needed due to malaria or other symptoms.] 
 
Final study assessments at week 24 (day 168). 
Arm 2 
n=110 
40 mg/kg CIS43LS 
Arm 1 
n=110 
10 mg/kg CIS43LS 
 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
1.3.1 
Dose-escalation Study 
Study Day 
Screen 
Enroll 1 
0 
1 
3 
7 
14 
21 
28 
56 
84 
112 
140 
168 
Illness 
Visit 
ET 
Visit 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±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 
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 
Medical history 2 
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 
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 
Pregnancy prevention counseling 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine/serum; for 
women) 
- 
X 
X 
X 5 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
HIV, HBV, HCV 
screen 6 
SST 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
EDTA 
3 
3 
3 5 
 
3 
3 
3 
 
 
 
 
 
 
 
 
 

18 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
Study Day 
Screen 
Enroll 1 
0 
1 
3 
7 
14 
21 
28 
56 
84 
112 
140 
168 
Illness 
Visit 
ET 
Visit 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
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 
 
PK studies 
SST 
 
 
8 9 
4 
 
4 
4 
 
4 
4 
4 
4 
4 
4 
 
 
Serum storage 
SST 
 
 
8 
 
 
8 
 
 
8 
 
8 
 
 
8 
 
 
ADA 
SST 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
(X) 
 
 
(X) 
 
 
PBMC storage 
CPT 
 
 
16 
 
 
16 
 
 
 
 
 
 
 
 
 
 
Daily volume (mL) 
9 
6 
38 
4 
6 
34 
10 
0.5 
12 
4 
12 
4 
4 
12 
 
 
Cumulative volume (mL) 
9 
15 
53 
57 
63 
97 
107 
107.
5 
119.
5 
123.
5 
135.
5 
139.
5 
143.
5 
155.
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; 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. 
• Participants who complete participation in the dose-escalation will be offered participation in extension visits to collect extra bi-weekly blood samples for PK analysis and to 
monitor for Pf infection through the end of December 2021. See Appendix C for details. 
 
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. All 
artemether-lumefantrine doses will be completed prior to day 0. 
4 All other study procedures must be completed prior to study agent infusion. Subject will be monitored during and after each infusion, and vital signs will be recorded directly 
after infusion and hourly during post-infusion monitoring. The first subject in a dose arm will be monitored for at least 4 hours after completion of infusion; all other subjects will 
be monitored for at least 2 hours after completion of infusion. Prior to discharge, subject will be assessed for local reactogenicity (including pain/tenderness, swelling, redness, 
bruising, and pruritus at the site of infusion) and systemic reactogenicity (including fever, feeling unusually tired or unwell, muscle aches, headache, chills, nausea, and joint 

19 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
Study Day 
Screen 
Enroll 1 
0 
1 
3 
7 
14 
21 
28 
56 
84 
112 
140 
168 
Illness 
Visit 
ET 
Visit 
Window (days) 
-56 to -7 
-14±7 
- 
+1 
±1 
±2 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
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 infusion. For women, negative pregnancy test must be confirmed prior to infusion. Other indicated tests may be performed after infusion. 
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 can be obtained via finger prick or venipuncture. 
9 For PK, 4 mL serum will be collected prior to study agent infusion, and an additional 4 mL serum will be collected about 1 hour (±30 minutes) after the infusion. 
 
1.3.2 
Efficacy Study 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
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 

20 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
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 
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 
Pregnancy prevention 
counseling 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine/serum; 
for women) 
- 
X 
X 
X 5 
 
 
 
 
 
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 
X 
X 
0.5 
X 
0.5 
X 
0.5 
X 
0.5 
X 
0.5 
X 
0.5 
X 
X 
 
PK studies 
SST 
 
 
8 9 
4 
 
4 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
 
Serum storage 
SST 
 
 
8 
 
 
8 
 
 
8 
 
 
 
8 
 
 
 
 
 
8 
 
 
ADA 
SST 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
 
 
(X) 
 
 
 
 
 
(X) 
 
 
PBMC storage 
CPT 
 
 
16 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
 
810 
 
 
Daily volume (mL) 
9 
6 
38 
4 
6 
18 
26 
0.5 
12 
0.5 
4 
0.5 
12 
0.5 
4 
0.5 
4 
0.5 
20 
 
 
Cumulative volume 
(mL) 
9 
15 
53 
57 
63 
81 
107 
107
.5 
119
.5 
120 
124 
124
.5 
136
.5 
137 
141 
141
.5 
145
.5 
146 
166 
- 
- 

21 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
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 
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 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. 
 
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. All 
artemether-lumefantrine doses will be completed prior to day 0. 
4 All other study procedures must be completed prior to study agent infusion. Subject will be monitored during and for 60 minutes after each infusion, and vital signs will be 
recorded directly and 1 hour after infusion. Prior to discharge, subject will be assessed for local reactogenicity (including pain/tenderness, swelling, redness, bruising, and pruritus 
at the site of infusion) 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 infusion. For women, negative pregnancy test must be confirmed prior to infusion. Other indicated tests may be performed after infusion. 
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 can be obtained via finger prick or venipuncture. 
9 For PK, 4 mL serum will be collected prior to randomization and study agent infusion, and an additional 4 mL serum will be collected about 1 hour (±30 minutes) after the 
infusion. 
10This PBMC tube is optional and the subject will have the option to decline. 
 

22 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
2 
INTRODUCTION 
2.1 
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. It 
is currently being evaluated in immunization programs in sub-Saharan Africa despite having 
been found to provide only partial protection against malaria to children and infants. 2,3 
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. 
The VRC, NIAID, NIH, has developed a monoclonal antibody (MAb) called CIS43LS as a 
possible preventive therapeutic against Pf infection. CIS43LS is currently being evaluated in an 
ongoing phase 1, first-in-human study in healthy volunteers at the VRC. As a follow-up to the 
VRC study, this protocol is designed to evaluate the safety and efficacy of CIS43LS in healthy 
adults in Mali, where Pf malaria infection is endemic.  
2.2 
BACKGROUND  
2.2.1 
Overview 
The VRC, NIAID, has been investigating broadly-neutralizing human MAbs targeting a variety 
of pathogens that may be utilized in clinical applications including preventive and therapeutic 
measures. In the case of malaria, prevention by passive immunization has potential applications 
for use in travelers, military personnel, season control, and elimination campaigns in endemic 
areas. 
VRC investigators isolated a MAb, termed CIS43, from a subject immunized with an attenuated 
Pf whole-sporozoite (SPZ) vaccine (PfSPZ Vaccine [Sanaria]). The MAb was then adapted using 
site-directed mutagenesis in the Fc region, resulting in an LS mutation (CIS43LS) that has been 
found to increase product half-life in plasma, 4,5 which will be critical for optimizing its use. This 
LS modification has been applied to multiple VRC clinical MAbs and has been shown to be safe 
and significantly increase the half-life in plasma. 6, and unpublished data  
CIS43LS recognizes a unique and conserved epitope at the junction of the N- and repeat regions 
of the Pf circumsporozoite protein (CSP). In a published study in 2 different mouse models of 

23 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
malaria infection, passive immunization with CIS43 conferred high-level protection (70%-100%) 
following malaria challenge with concentrations of antibody in vivo ranging between 
10-200 μg/mL respectively. 7 Similar protection data were observed with CIS43LS 
(unpublished). These data show that CIS43LS is highly protective in vivo and suggest further 
exploration was warranted for passive prevention of malaria in humans.  
This protocol is a two-part phase 2 trial evaluating the safety and tolerability of one-time 
administration of CIS43LS in healthy Malian adults as well as its protective efficacy against 
naturally occurring Pf infection over a 6-month malaria season.  
2.2.2 
Study Product: CIS43LS 
MAb VRC-MALMAB0100-00-AB (CIS43LS) was discovered and developed by the VRC, 
NIAID, NIH. CIS43LS binds a unique and conserved epitope at the junction of the N- and repeat 
regions of the Pf CSP. The study product was manufactured under current Good Manufacturing 
Practice (GMP) by the Vaccine Clinical Materials Program (VCMP) operated under contract by 
Leidos Biomedical Research, Inc., Frederick, MD.  
2.2.2.1 Previous Human Experience  
VRC 612: A Phase 1, Dose Escalation, Open-Label Clinical Trial With Experimental Controlled 
Human Malaria Infections (CHMI) to Evaluate Safety and Protective Efficacy of an 
Anti-Malaria Human Monoclonal Antibody, VRC-MALMAB0100-00-AB (CIS43LS), in 
Healthy, Malaria-Naive Adults (NCT04206332) has completed controlled human malarial 
infection (CHMI) protective efficacy testing and remains in long-term follow-up at the VRC. 
The study is a two-part, dose-escalation, adaptive design study evaluating the safety, tolerability, 
PK, and protective efficacy of CIS43LS. Doses being evaluated range from 5 mg/kg 
subcutaneously (SC) to 40 mg/kg IV. The VRC study involves assessing protective efficacy by 
CHMI. All data from VRC 612 is interim and preliminary with final monitoring and datalock yet 
to occur. 
To date, 25 subjects have received 29 administrations of CIS43LS IV or SC, and there have been 
no SAEs attributable to CIS43LS or safety pauses. All IV infusions were well-tolerated. Of the 
12 subjects who received the highest dose, 40 mg/kg IV, 2 reported mild infusion-site pain or 
tenderness and 1 reported moderate infusion-site bruising. All systemic symptoms (headache, 
fever, malaise, joint pain, and muscle aches) were mild to moderate and self-limited. Of the 
21 subjects enrolled in Part A, the first part of the adaptive design study, 18 were scheduled to 
undergo CHMI on March 17, 2020, but the CHMI was cancelled due to the coronavirus disease 
2019 (COVID-19) pandemic. The additional 3 subjects that received CIS43LS IV were planned 
to be followed without CHMI to assess safety in the absence of CHMI. Safety follow-up was 
maintained for all 21 subjects up to August 17, 2020 following local public health guidelines and 
practices. 
Part B of the trial included Part A veteran subjects as well as newly enrolled subjects. To 
continue with Part B of this study, including CHMI, the protocol was amended to include the 
following 3 components: follow subjects after a single administration of CIS43LS in Part A, 
boost subjects who had previously received CIS43LS in Part A, and enroll new subjects for 

24 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
CIS43LS administration and/or CHMI. Part B of the trial opened to accrual in September 2020 
and included 16 subjects as follows: 
• 2 subjects who received 40 mg/kg IV in Part A received no additional product in Part B. 
• 2 subjects who received 5 mg/kg (1 SC and 1 IV) in Part A were boosted with 20 mg/kg 
IV in Part B.  
• 2 subjects who received 20 mg/kg IV in Part A were boosted with 20 mg/kg IV in Part B.  
• 4 new subjects received 40 mg/kg IV in Part B. 
• 6 CHMI control subjects who had never received CIS43LS did not receive CIS43LS in 
Part B. 
A total of 15 subjects underwent CHMI on October 20, 2020 and were followed for 21 days with 
daily polymerase chain reaction (PCR) from days 7-18. One subject who received 40 mg/kg IV 
in September 2020 did not undergo CHMI because of a concomitant, unrelated SAE that was 
unlikely to resolve by the time of challenge. Any subjects who were PCR-positive from day 7-18 
were treated with Malarone. On day 21, all remaining untreated subjects were treated with 
Malarone. Five of the 6 control subjects were PCR-positive by day 9 post-CHMI and were 
treated. The 9 CIS43LS recipients never developed parasitemia nor did they require treatment. 
Two of these subjects had received CIS43LS (40 mg/kg IV) approximately 9 months in Part A 
with no additional product in Part B prior to CHMI. The in vivo concentration of CIS43LS at the 
time of CHMI in the 9 protected subjects in the phase 1 VRC study ranged from 50-500 μg/mL. 
Thus, in this small phase 1 trial, CIS43LS was completely protective across a range of in vivo 
concentrations and provided durable protection.  
Prior clinical experience in completed and ongoing phase 1 and 2 trials of healthy adults with 
other human MAbs manufactured and formulated by the VRC that recognize pathogen-specific 
epitopes (i.e., VRC01, VRC01LS, VRC07-523LS, and MAb114) 6,8-10 are used to summarize the 
general safety risk associated with MAbs.  
Treatments with these MAbs have been generally well tolerated, with no reported deaths or 
serious adverse events (SAEs) assessed as related to the study products. Typical for MAbs, the 
predominant local reactogenicity complaint has been mild pain/tenderness, although reports of 
mild injection-site pruritus, redness and swelling have occurred at modestly higher frequencies 
with SC administration. Malaise, muscle pain, and headache have been the most frequently 
reported solicited complaints noted in the 3 days after product administration, and these have 
also been mostly transient and mild in severity. Urticaria and infusion reactions including chills, 
rigors, myalgia, headache, and/or fever have been reported after IV infusions at product doses of 
10 to 40 mg/kg; these reactions have been transient, resolved without sequelae within 24 hours of 
onset, and were treated with over-the-counter analgesics and antipyretics. 
2.2.2.2 Preclinical Experience 
To assess CIS43LS as a candidate for clinical trials, recombinant, research grade MAb was 
evaluated on binding properties, auto-reactivity, PK, 2 mouse models of in vivo protection 
following challenge, and PK studies in nonhuman primates. In mice, CIS43LS conferred 100% 
protection following mosquito bite challenge. In nonhuman primate PK studies, CIS43LS 
exhibited substantially longer half-life, both in blood and in skin biopsy samples as compared to 
CIS43 antibody without the LS mutation.  

25 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
Preclinical toxicology studies were conducted to assess safety in compliance with current Good 
Laboratory Practices (GLP) in Sprague Dawley rats using CIS43LS. The toxicology pre-clinical 
material was tested in the final formulation buffer and manufactured using the same VCMP 
manufacturing process as used to produce clinical trial material. There were no findings of 
toxicologic significance attributed to CIS43LS from the results.  
2.2.2.2.1 In vitro Studies 
Differences in the binding properties of CIS43LS and CIS43 were assessed. Binding of CIS43LS 
and CIS43 to a specific target antigen expressed on malaria parasites was determined by 
enzyme-linked immunosorbent assay (ELISA). CIS43LS and CIS43 exhibited similar binding to 
recombinant Pf circumsporozoite protein (rPfCSP). Avidity and stoichiometry of CIS43LS and 
CIS43 binding to rPfCSP were also comparable as assessed by isothermal titration calorimetry.  
CIS43LS autoreactivity was assessed using the anti-nuclear antibody (ANA) HEp2 cell staining 
system from Zeus Scientific (Branchburg, NJ). The assay was conducted according to the 
manufacturer’s instructions. Antibodies were tested at 25 and 50 mcg/mL. At 25 mcg/mL, test 
antibodies were scored in comparison to negative and positive control samples. Neither CIS43 
nor CIS43LS shows an autoreactivity signal by ANA staining. Autoreactivity was also assessed 
by an anti-cardiolipin QUANTA Lite ACA immunoglobulin (Ig) GIII ELISA (Inova 
Diagnostics, San Diego, CA). Using a similar control schema to that described for ANA HEp2 
cell staining, the assay was conducted according to the manufacturer’s instructions. 
The potential for CIS43LS, a MAb directed against Pf CSP on the surface of PfSPZ, to 
cross-react with normal human and Sprague-Dawley rat tissues was assessed in a GLP study 
(Charles River Laboratories, Inc., Frederick, MD, Study No. 20188989) by 
immunohistochemical staining of tissue cryosections with CIS43LS or appropriate controls. The 
human and rat tissue panels evaluated included all of the tissues on the “suggested list of human 
tissues to be used for immunohistochemical or cytochemical investigations of cross reactivity of 
monoclonal antibodies” in Annex I of the European Medicines Agency document “Guideline on 
Development, Production, Characterization and Specifications for Monoclonal Antibodies and 
Related Products,” adopted by the Committee for Medicinal Products for Human Use, and all of 
the tissues recommended in the US Food and Drug Administration (FDA) Center for Biologics 
Evaluation and Research document, “Points to Consider in the Manufacture and Testing of 
Monoclonal Antibody Products for Human Use.” The only difference between the 2 species in 
tissue types evaluated was tonsil; inasmuch as rats do not have tonsils, tonsil tissue was 
evaluated from humans only. To detect binding, CIS43LS was applied to cryosections of normal 
human tissues from 3 donors per human tissue, except for bladder, for which only 2 were 
available. Samples from at least 2 individual rats were evaluated except for fallopian tube, 
parathyroid, and ureter, for which only 1 was available. All tissues were incubated with test or 
control article at 2 concentrations (1 µg/mL and 10 µg/mL). As a negative control, a monoclonal 
human IgG1κ antibody, HuIgG1 (control article), with a different antigenic specificity from that 
of CIS43LS, was tested in parallel. Other controls included omission of the test or control 
articles from the assay (assay controls). At both concentrations, CIS43LS produced moderate to 
intense membrane and cytoplasmic staining of positive control HEK293 cells, which expressed 
the Pf CSP epitope targeted by CIS43LS, and did not specifically react with the negative control 
material, cryosections of negative HEK293 cells, at either staining concentration. The control 

26 
Abbreviated Title: Anti-malaria MAb in Mali 
Version Date: October 13, 2022 
 
article, HuIgG1, did not specifically react with either the positive or negative control materials, 
and there was similarly no staining of the assay control slides. The specific reactions of CIS43LS 
with the positive control cells in all staining runs, the absence of specific reactivity with the 
negative control cells, and the lack of reactivity of the control article indicated that the assay was 
sensitive, specific, and reproducible. CIS43LS produced membrane and cytoplasmic staining of 
epithelium in sebaceous glands and cytoplasmic staining of epithelium in sweat glands in the 
human skin. This staining was weak to strong in intensity and frequently observed in sebaceous 
glands and rarely or occasionally observed in sweat glands at the higher concentration of 
CIS43LS, with a reduction in the intensity of the staining at the lower concentration. No other 
staining was observed with CIS43LS in the human tissue panel. Similarly to its interaction with 
human tissue, CIS43LS weakly stained the membrane and cytoplasm of occasional to frequent 
sebaceous gland epithelium in the rat skin at the higher concentration only. No other staining was 
observed with CIS43LS in the rat tissue panel. The consonance of results between human and rat 
tissues confirm the appropriateness of the rat model for the CIS43LS toxicity study. 
2.2.2.2.2 In vivo Studies 
2.2.2.2.2.1 Protection studies in C57BL/6 mice and Rhesus macaques 
To assess protection following passive transfer of MAb, naïve C57BL/6 mice received 300 mcg 
by IV inoculation of CIS43, CIS43LS, or negative control antibody. Chimeric parasites 
comprising Plasmodium berghei (Pb) SPZ which naturally infect mice that expressed Pf CSP 
(Pb-PfCSP SPZ) were administered by 1 of 2 routes (injected by tail vein or by exposure to bites 
by infected mosquitos). In the 2 mouse challenge models, passive transfer of CIS43 and 
CIS43LS yielded nearly indistinguishable results. Administration of either CIS43 or CIS43LS 
reduced liver parasite burden by about 2 logs when challenged by IV route. Moreover, passive 
transfer of CIS43 or CIS43LS conferred 100% sterile protection in mice as assessed by 
parasitemia in blood following a natural challenge by 5 mosquito bites in the skin. This type of 
challenge is similar to what is used in the CHMI procedures at the VRC.  
To inform clinical protocol development, particularly concerning the timing of CHMI, a 20-week 
PK study was conducted in nonhuman primates (Rhesus macaques). Two animals per group 
received CIS43 or CIS43LS, administered by IV route at a dose of 10 mg/kg. CIS43LS exhibited 
substantially longer half-life, both in blood and skin biopsy samples than CIS43. In blood, 
CIS43LS maintained a titer of more than 35 mcg/mL on the last sample day (day 140). In 
contrast, CIS43 dropped to approximately 30 mcg/mL by day 49. Skin biopsy data were 
concordant.   
2.2.2.2.2.2 Toxicology Studies in Sprague Dawley Rats 
A study of repeat dosing at 10-day intervals by IV and SC administration of CIS43LS in male 
and female Sprague Dawley rats (SRI Study No. M416-19) was conducted in compliance with 
current GLP to evaluate toxicity and toxicokinetics. The test article and control (formulation 
buffer) were administered on days 1 and 11 by IV administration at doses of 0, 40, or 
400 mg/kg/day (Groups 1−3, respectively) or by SC administration at doses of 5 or 50 
mg/kg/day (Groups 4−5, respectively). Necropsies were performed on days 12 and 46. Endpoints 

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included clinical observations, body weight, food consumption, body temperature, dose site 
irritation, clinical pathology, and organ weights.   
All animals survived to their scheduled sacrifice timepoint. No test article-related changes were 
observed in clinical observations, body weights, food consumption, dose site irritation, clinical 
chemistry, coagulation, and organ weights. Body temperature was normal (≤101.0°F) for all 
males at 24 hours post-dose. Elevated body temperatures ranging from 101.1 to 102.1°F were 
seen from 1 or more females in high-dose IV or both SC treated groups for at least 24 hours after 
dosing on days 1 and/or 11. Body temperature returned to normal levels within 48 hours post-
dose. These findings are considered test article-related although reversible and at levels 
considered to be non-adverse.   
Statistically significant and dose-dependent changes in some hematology parameters were 
observed on days 12 and 46. The changes included increased platelet count (1.4-fold) and 
absolute reticulocyte count (1.2-fold) in Group 5 females, and decreased percent monocyte 
(30.6% to 32.2%) in Group 3 and 4 females on day 12. On day 46, increased absolute neutrophils 
(2.0-to 2.3-fold) in Group 3 and 4 males and decreased hemoglobin (6.1% to 7.6%) and/or 
hematocrit (5.6% to 7.6%) in all treated-group females were observed. The changes in 
neutrophils and monocytes seen after SC administration are consistent with an immune response 
and are considered test article-related although reversible and at levels considered to be non-
adverse. Without changes in red blood cell counts, the findings in platelet count, reticulocytes, 
hemoglobin, or hematocrit are not considered to be biologically meaningful or toxicologically 
adverse. In summary, no findings of toxicologic significance were attributed to CIS43LS from 
the results available as of this report. 
Taken together, these studies support the continued development of CIS43LS for clinical 
evaluation. The data confirm the predicted longer half-life effect of the LS mutation and show 
that there is no functional difference in terms of in vitro binding or in vivo protection compared 
to CIS43. No safety, efficacy, or manufacturability concerns were noted that precluded 
proceeding to further toxicology studies, GMP manufacturing, IND filing, and clinical 
investigations.   
2.2.3 
Laboratory Assessments of CIS43LS  
Some laboratory assessments in this study are designed to characterize the investigational 
product. This includes PK analysis and evaluation for anti-drug antibody (ADA) development 
after product exposure. Other assays may also be completed from stored samples at a later date.  
The 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. 
2.2.3.1 Pharmacokinetic Analysis 
Concentrations of CIS43LS will be measured by a Meso Scale Discovery LLC–based 
automation platform and similar methodology as previously described for other VRC MAb 
products. 8   
2.2.3.2 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. 8 
2.2.3.3 Measures of MAb-Mediated Protection and Parasitemia 
CIS43LS-mediated protection against naturally occurring Pf infection during a single 6-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 CIS43LS-recipients collected from day 7 through week 24 (day 168) after study agent 
administration. 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 World Health Organization 
(WHO) protocol.  
Thick blood smears will be prepared from the blood remaining in the collection device, or (at 
timepoints when no blood collection is planned) from a finger prick sample or from a small 
venipuncture sample. The smears will be examined microscopically. Thick blood smears will be 
used for diagnosis throughout the study. 
Additionally, as a secondary endpoint, Plasmodium 18S 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. 11 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. 
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 
Known Potential Risks 
Risk of CIS43LS: CIS43LS is being evaluated in an ongoing phase 1 study in healthy adult 
volunteers at the VRC to assess safety, tolerability, PK, and protective efficacy, as described in 
section 2.2.2.1. Since January 2020, 25 subjects have received CIS43LS either IV or SC, and 
there have been no SAEs assessed as related to CIS43LS and no safety pauses. All systemic 
symptoms were only mild to moderate and self-limited. Mild or moderate headache was reported 

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by 6 subjects (29%). Other solicited systemic AEs include mild myalgia (5 subjects), moderate 
malaise (1), moderate nausea (1), mild joint pain (1), and mild fever (1). There were also 
3 related unsolicited AEs that were reported (blood creatinine increase, neutropenia and 
dizziness), all of which were graded as mild. All IV infusions were well-tolerated. Of the 
12 subjects who received 40 mg/kg IV, 2 reported mild infusion-site pain or tenderness and 
1 reported moderate infusion-site bruising. The protocol and consent will be updated if new 
information about risks and side effects becomes available from the ongoing phase 1 study. 
Risks of MAb Administration: Administration of MAbs may cause immune reactions such as 
acute anaphylaxis, serum sickness, and the generation of antibodies. However, these reactions 
are rare and more often associated with MAbs targeted to human proteins or with the use of 
mouse MAbs that would have a risk of human anti-mouse antibodies. 12 In this regard, because 
CIS43LS is targeted to a parasite antigen and is a human MAb, it is expected to have a low risk 
of such side effects.  
Typically, the side effects of MAbs are mild to moderate and may include local reactions at the 
injection site (including pain, redness, bruising, swelling, 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 12; 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. 12 Most infusion-related events occur within the first 
24 hours after initiation of MAb administration. 
Published experience with human MAbs directed against cell surface targets on lymphocytes 
shows that infusion of a MAb may be associated with cytokine release, causing a reaction known 
as cytokine release syndrome (CRS). 13 CRS reactions commonly occur within the first few hours 
of infusion start and with the first MAb infusion received. This is because the cytokine release is 
associated with lysis of the cells targeted by the MAb and the burden of target cells is greatest at 
the time of the first MAb treatment. With licensed therapeutic MAbs, CRS is managed by 
temporarily stopping the infusion, administering histamine blockers and restarting the infusion at 
a slower rate. 14 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. 12 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. 15  
Participation in this study may limit a subject’s eligibility for future MAb studies.  

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Risks of Placebo Administration: There are no risks of the placebo (normal saline) other than 
infusion-related events such as headache, dizziness, and hypertension. 
Risks of Blood Drawing or IV Placement: Drawing blood via venipuncture or heel/finger stick 
or placing an IV may cause pain, bruising, and a feeling of lightheadedness or fainting. Rarely, it 
may cause infection at the site where blood is taken.  
Risks of Artemether-Lumefantrine Administration: Adverse reactions (ARs) occurring in 
more than 30% of adults are headache, anorexia, dizziness, asthenia, arthralgia, and myalgia. 
Reactions typically do not require stopping treatment. Individuals who may have any 
contraindication for the use of this drug (e.g., prolonged 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. 
A complete list of side effects and contraindications is provided in the package insert. 16  
2.3.2 
Known Potential Benefits 
Subjects in the dose-escalation study will not directly benefit from study participation, since the 
study is too early in the year to be expected to provide protection during the malaria transmission 
season. In the efficacy study, subjects may not receive direct health benefit from study 
participation. Depending on whether CIS43LS confers protective efficacy, subjects receiving a 
sufficient dose of CIS43LS may experience some protection against Pf infection 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. 
2.3.3 
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 post-vaccination 
monitoring.  
3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
1. Dose escalation: To evaluate the 
safety and tolerability of 
CIS43LS administered IV at 5, 
1. Dose escalation: Incidence and 
severity of local and systemic 
AEs occurring within 7 days after 
the administration of CIS43LS.  
1. Assessment of AEs 
is a standard 
measure of study 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
10, and 40 mg/kg in healthy 
Malian adults. 
2. Efficacy: To determine if IV 
administration of CIS43LS at 
10 mg/kg and 40 mg/kg 
(compared to placebo) mediates 
protection against naturally 
occurring Pf infection in healthy 
Malian adults during a single 
malaria season as detected from 
microscopic examination of 
thick blood smear. 
2. Efficacy: Pf blood stage infection 
as detected by microscopic 
examination of thick blood smear 
for 24 weeks after administration 
of CIS43LS or placebo. 
agent safety and 
tolerability. 
2. Blood smear is the 
gold standard for 
diagnosis of 
blood-stage Pf 
infection. 
Secondary 
 
 
1. Dose escalation: To evaluate 
the PK of CIS43LS at each 
dose level throughout the study. 
2. Efficacy: To determine if IV 
administration of CIS43LS at 
10 mg/kg and 40 mg/kg 
(compared to placebo) mediates 
protection against naturally 
occurring Pf infection in 
healthy Malian adults during a 
single malaria season as 
detected by RT-PCR. 
3. Efficacy: To evaluate the PK of 
CIS43LS throughout the study 
at the dose of 10 mg/kg and 
40 mg/kg and to correlate 
CIS43LS serum concentration 
with Pf infection risk.  
1. Dose escalation: Measurement of 
CIS43LS in sera of recipients.  
2. Efficacy: Pf blood stage infection 
as detected by RT-PCR for 
24 weeks after administration of 
CIS43LS or placebo.  
3. Efficacy: Measurement of 
CIS43LS in sera of recipients.  
1. Concentrations of 
CIS43LS in blood 
will help assess 
durability of 
CIS43LS at each 
dose level. 
2. RT-PCR is more 
sensitive than blood 
smear for detecting 
Pf blood-stage 
infection. 
3. Concentrations of 
CIS43LS in blood 
will help assess 
durability of 
CIS43LS and will 
allow for 
correlation with Pf 
infection risk. 
Tertiary/Exploratory  
 
 
1. To determine whether ADA to 
CIS43LS can be detected in 
sera of recipients at specific 
timepoints throughout the 
study. 
2. To assess for IgG1 allotypes 
and allotype-specific effects on 
CIS43LS PK.  
1. Measurement of ADA to 
CIS43LS in sera of recipients. 
2. Assessment of IgG1 allotypes and 
allotype-specific effects on 
CIS43LS PK.  
3. Characterization of the cellular 
immune response to CIS43LS. 
1. ADA to CIS43LS 
may impact the PK 
and activity of 
CIS43LS. 
2. Subject IgG1 
allotype may 
impact the PK and 
activity of 
CIS43LS.  

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
3. To explore and characterize the 
cellular immune response to 
CIS43LS. 
4. To determine if the efficacy of 
CIS43LS 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 
CIS43LS.  
6. To explore the impact of 
pre-existing CSP antibodies on 
the protective efficacy and PK 
of CIS43LS. 
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 CIS43LS infusion. 
6. Pre-existing CSP-specific 
antibodies measured in sera 
collected before CIS43LS 
infusion. 
3. CIS43LS-induced 
cellular immune 
responses may be 
associated with Pf 
infection risk. 
4. CIS43LS 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 
CIS43LS.  
6. Pre-existing 
CSP-specific 
antibodies may 
impact the 
protective efficacy 
and PK of 
CIS43LS. 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a two-part, phase 2 trial evaluating the safety and tolerability of one-time administration 
of CIS43LS, as well as its protective efficacy against naturally occurring Pf infection over a 
6-month malaria season. Interim safety data from the ongoing VRC phase 1 trial of CIS43LS 
will be regularly reviewed, and if needed, the protocol and relevant study documents will be 
amended to reflect any new information. 
The primary study hypotheses are that CIS43LS will be safe and will confer protection against Pf 
infection. The study will recruit from 2 MRTC clinics, 1 in Torodo and 1 in Kalifabougou. All of 
the screening, day 0 and day 7 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 

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both typically experience intense seasonal Pf transmission from July through December each 
year. 17 Based on data collected in Kalifabougou from 2011 through 2018, 68%-90% of adults 
who are uninfected (PCR negative) before the malaria season become infected with Pf during the 
ensuing 6-month malaria season. 17  
The dose-escalation study is an open-label study for safety and tolerability. Subjects will be 
assigned to 1 of 3 dose arms. Dosing will begin in the lowest dose arm and will escalate 
sequentially as described in section 6.1.2.1. Subjects will be followed for safety to assess AEs at 
study visits 1, 3, 7, 14, 21, and 28 days after administration, then monthly for about 6 months 
after administration. Participants who complete participation in the dose-escalation will be 
offered participation in extension visits to collect extra bi-weekly blood samples for PK analysis 
and to monitor for Pf infection through the end of December 2021. 
After the final subject in the dose-escalation study reaches day 7 safety follow-up, an interim 
safety evaluation will be performed by the DSMB before enrollment begins for the efficacy 
study (section 9.4.8). 
The efficacy study is a randomized, double-blind, placebo-controlled trial (N=330 total, n=110 
for each of 3 treatment arms) to assess safety and protective efficacy of 2 dose arms and a 
placebo arm. Subjects will receive 1 dose of study agent and be followed at regular study visits 
for about 6 months. Primary study assessments include physical examination and blood 
collection for research laboratory evaluations, including assessment of protection against 
naturally occurring Pf infection over 6 months (a single malaria season). The primary endpoint is 
the absence of Pf parasites in blood smears obtained between 1 week and 6 months after study 
agent administration in recipients of CIS43LS and placebo. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This two-part study was designed to test CIS43LS in the setting of naturally occurring Pf 
infection and in a population that could potentially benefit from a novel therapeutic for malaria 
prevention. 
The efficacy study will use both randomization and a double blind 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. 
4.3 
JUSTIFICATION FOR DOSE 
The doses used in this study were selected based off preclinical data and will complement the 
data generated in the ongoing phase 1 VRC study, which tested the dose range included in this 
protocol. The doses used in the efficacy study (10 mg/kg and 40 mg/kg IV) will complement the 
data generated in the ongoing phase 1 VRC study. The 40-mg/kg dose was derived from 
1) efficacy data from the challenge studies performed in mice showing that the protective 
concentration of antibody in vivo is between 10-200 μg/mL in 2 different mouse models of 
malaria infection; and 2) PK data from nonhuman primate studies with CIS43LS 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. The addition of the 10-mg/kg 
dose was based on more recent PK data from the phase 1 VRC study. Extrapolating PK data 
from the 5-mg/kg and 20-mg/kg groups in the phase 1 VRC study, we estimate that 10 mg/kg 

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will give an in vivo concentration of approximately 90 μg/mL at 3 months (mid-malaria season) 
and approximately 30 μg/mL at 6 months (end of malaria season). The in vivo concentration of 
CIS43LS at the time of CHMI in the 9 protected subjects in the phase 1 VRC study ranged from 
50-500 μg/mL. 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
Individuals must meet all of the following criteria to be eligible for study participation: 
1. Aged ≥18 and ≤55 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. 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. 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.   
a. Reliable methods of birth control include 1 of the following: confirmed 
pharmacologic contraceptives via parenteral delivery or intrauterine or 
implantable device.  
b. 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. 
5.2 
EXCLUSION CRITERIA 
Individuals meeting any of the following criteria will be excluded from study participation: 
1. Pregnancy, as determined by a positive urine or serum beta-human choriogonadotropin 
(β-hCG) test (if female). 
2. Currently breastfeeding. 
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. 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 human immunodeficiency virus (HIV), hepatitis C virus (HCV), or 
hepatitis B virus (HBV). 

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8. Known or documented sickle cell disease by history. (Note: Known sickle cell trait is 
NOT exclusionary.) 
9. Clinically significant abnormal electrocardiogram (ECG; corrected QT interval [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 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.) 
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. Pre-existing autoimmune or antibody-mediated diseases including but not limited to: 
systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren’s 
syndrome, or autoimmune thrombocytopenia. 
17. Known immunodeficiency syndrome. 
18. Known asplenia or functional asplenia. 
19. 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. 
20. Receipt of a live vaccine within the past 4 weeks or a killed vaccine within the past 
2 weeks prior to study agent administration. 
21. Receipt of immunoglobulins and/or blood products within the past 6 months. 
22. Previous receipt of an investigational malaria vaccine in the last 5 years. 
23. Known allergies or contraindication against artemether-lumefantrine. 
24. 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. 
5.3 
INCLUSION OR EXCLUSION OF VULNERABLE PARTICIPANTS 
• Children: Children are not eligible to participate in this clinical trial because CIS43LS 
has not been previously evaluated in children to be safe. If the product is assessed as safe 
for further study, other protocols specifically designed for children may be conducted.   
• Pregnant Women: Pregnant women are excluded from this study because the effects of 
CIS43LS on pregnant women or the developing human fetus are unknown with the 
potential for teratogenic or abortifacient effects. 
• Decisionally Impaired Adults: Individuals must be able to provide consent in order to 
be eligible for participation in this study. Enrolled subjects who lose decision-making 
capability during study participation will be withdrawn (see sections 8.4.3 and 10.1.5). 

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• Illiterate Individuals: We anticipate that many individuals eligible for this study 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. 
5.4 
LIFESTYLE CONSIDERATIONS 
In addition to prohibited treatments and procedures listed in section 6.5, subjects must refrain 
from donating blood for at least 1 year after study drug administration.  
Women must not breastfeed during the study because there could be unknown risks to the child 
secondary to the mother’s receipt of the study drug.  
5.5 
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. Rescreened subjects should be 
assigned the same subject number as for the initial screening. 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Healthy adult volunteers will be selected based on the eligibility criteria described in sections 5.1 
and 5.2. The total target sample size across both study sites is 18 subjects in the dose-escalation 
study (accrual ceiling 30) and 330 subjects in the efficacy study (accrual ceiling 460). We expect 
to enroll all subjects for both parts of the study within the first 6 months of the study. Efforts will 
be made to include women in proportions similar to that of the community from which they are 
recruited. Subject selection will not be limited based on sex, race, or ethnicity. 
The study team will hold a community meeting 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.  
5.6.1 
Costs 
There are no costs associated with participation in this trial.  

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5.6.2 
Compensation 
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 (infusion). 
• 3,000 CFA Franc for all other visits. 
The total compensation amount for dose-escalation study subjects will be 48,000 CFA Franc 
(valued at approximately USD $88) and for the efficacy study subjects will be 63,000 CFA Franc 
(valued at approximately USD $115). Payment will be provided in cash after the completion of 
each visit. Subjects who participate in extension visits will receive additional compensation as 
described below (see Appendix C). 
Subjects will be provided with transportation to and from study visits but will not receive 
additional reimbursement for travel. 
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION ADMINISTRATION 
6.1.1 
Study Intervention Description 
The study intervention involves a single administration of CIS43LS or placebo to each subject. 
All study agent administration will take place at the Kalifabougou study site. 
6.1.2 
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 6.1.2.1. Procedures for 
IV infusion are described in section 6.1.2.4.  
Table 1. Study agent assignment and dosing by arm. 
Arm 
Subjects Study Agent and Dose 
Dose-escalation study 
1 
6 
5 mg/kg IV 
2 
6 
10 mg/kg IV 
3 
6 
40 mg/kg IV 
Efficacy study 
1 
110 
10 mg/kg IV 
2 
110 
40 mg/kg IV 
3 
110 
Placebo (normal saline) IV 
6.1.2.1 Dose Escalation 
In the dose-escalation study, dose escalation will proceed in 3 study arms. Enrollment will begin 
with the arm receiving the lowest of 3 dose levels of CIS43LS. Subjects enrolled in this arm will 

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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 at that dose level 
complete day 7 post-infusion, if no safety concerns have arisen, then enrollment will begin for 
the arm at the subsequent dose level. This process will be repeated to evaluate the second dose 
level prior to commencing with the highest dose level. 
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 weight-based dose to each subject, so there will be no 
dose modifications. 
6.1.2.4 Drug Administration 
Prior to study agent administration on day 0, subjects will undergo vital signs measurement, a 
targeted physical examination (as needed based on signs, reported symptoms, or interim medical 
history), and, for women, a urine pregnancy test (confirmed negative prior to administration). 
Subjects 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. 
The rate of infusion may range from 10-20 mg/kg/hr at the lowest dose level to 80-160 mg/kg/hr 
at the highest dose level. The mL/hr infusion rate may vary based on the total volume needed to 
administer a full dose. Vital signs will be monitored directly after infusion, and hourly during 
monitoring. 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-infusion observation. 
In the dose-escalation study, the first subject in each dose arm to receive a unique dose level will 
be observed for at least 4 hours following completion of initial product administration. All other 
subjects will be observed for at least 2 hours following completion of product administration. In 
the efficacy study, all subjects will be observed for at least 60 minutes following 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 infusion) and systemic reactogenicity (including fever, feeling unusually tired or unwell, 
muscle aches, headache, chills, nausea, and joint pain). Any subject who is assessed as being 
unwell or has ongoing reactogenicity symptoms will be asked to remain in the clinic until 
evaluation and discharge by a study clinician. If necessary, the subject would be referred to the 
district hospital to evaluate for safety and possible treatment. Clinicians will follow any solicited 
symptoms that are ongoing until they have resolved. 

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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 
Acquisition and Accountability 
Acquisition: CIS43LS 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. The placebo product will either be 
purchased in the US and shipped to Mali at ambient temperature or purchased in Mali. 
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. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
VRC-MALMAB0100-00-AB (CIS43LS) is a sterile buffered solution that is filled into 
single-dose vials. The placebo product (used in the efficacy study) will be sterile isotonic (0.9%) 
normal saline. Both CIS43LS and placebo are clear liquids and are indistinguishable from one 
another. The products will be prepared by an unblinded pharmacist and placed in a standard IV 
infusion bag when preparing for administration.  
Vials of CIS43LS 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.  
6.2.3 
Product Storage and Stability 
CIS43LS: CIS43LS vials should be stored frozen at −35°C to −15°C in a qualified, 
continuously-monitored, temperature-controlled freezer. 18 The site pharmacist must promptly 
report any storage temperature excursions outside of the normal allowance for the storage device 
to the manufacturer (VRC). The affected product must be quarantined in a separate area under 
protocol-specific temperature ranges until further notice from the manufacturer. If the excursion 
results in thawed material, DO NOT REFREEZE; store the thawed, vialed material at 2°C to 
8°C.  
Provide the following information regarding the excursion to the manufacturer: lot number, fill 
volume and number of vials affected; temperature range and length of excursion, including data 
log reports; handling of materials post excursion (e.g., transfer to alternate storage, including 
times); visual inspection data of the materials (e.g., did the materials appear to have remained 
frozen, were vials cracked, etc.). The manufacturer will notify the site pharmacist if continued 
clinical use of the product is acceptable. 

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Prior to preparation for 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. Prior to preparation for 
administration in the IV bag, vials should be gently swirled for approximately 30 seconds while 
avoiding foaming. DO NOT SHAKE THE VIAL. 18  
After product preparation in an IV bag, the prepared CIS43LS may be stored at 2°C to 8°C for a 
maximum of 24 hours and/or at ambient temperature (15°C to 32°C) for a maximum of 4 hours 
total including the infusion time. Product may not be stored in direct sunlight. 18  
Placebo: Normal saline will be stored at room temperature in a controlled room per product 
standards.  
6.2.4 
Preparation 
For each IV infusion order, the subject’s weight, dose level, and study arm code will be included 
in the pharmacy order. To prepare an IV infusion, the pharmacist will do the following:  
• For subjects assigned to CIS43LS:  
1) Calculate the total milligrams of CIS43LS 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 the necessary amount of CIS43LS. 
4) Add this volume to a 150 mL capacity, partial fill, 100 mL bag of normal saline 
using sterile compounding techniques to maintain sterility.  
• For subjects assigned to placebo: 
1) Obtain a 100 mL bag of normal saline for administration. 
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.  
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
6.3.1 
Randomization 
In the efficacy study, subjects will be randomized to 1 of 3 treatment arms, including 2 CIS43LS 
arms and a placebo arm. Randomization lists will be generated by the study statistician, and the 
randomization code list will be maintained by a designated pharmacist at the study site where the 
study intervention will take place. 
Randomization is further described in section 9.4.1. 
6.3.2 
Blinding 
The efficacy study will be conducted with a double blind. The subjects, the clinical staff, and the 
study team will be blinded to study treatment allocation. The pharmacy team at the study site 

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where administration is taking place will be unblinded, and they are responsible for maintaining 
security of study treatment assignments.  
Data will remain blinded until the last subject completes the final study visit. 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. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention administration will be documented by study staff. 
6.5 
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 within 2 weeks of study agent administration. 
• 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.  
• Antimalarials and antibiotics with known antimalarial activity. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
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 

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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. 
7.2 
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. 
7.3 
LOST TO FOLLOW-UP 
A subject will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
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 and reschedule the missed visit within 7 days, 
counsel the subject on the importance of maintaining the assigned visit schedule, and 
ascertain if the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (where possible, 3 telephone calls). These contact 
attempts should be documented in the subject’s medical record or study file.  
• Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
SCREENING PROCEDURES 
Screening will be performed at the Kalifabougou study site. The study staff will explain the 
study to the prospective subject, complete the study comprehension examination and obtain 
consent (section 10.1), and assess eligibility. Consent will be obtained before any study-related 
procedures are performed.  
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 and 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). 

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• For women, serum β-hCG pregnancy test. 
• Blood collection via venipuncture for screening evaluations: 
o HIV tests: 2 rapid diagnostic tests (RDTs), plus 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. 
o Complete blood count (CBC) with differential. 
o ALT. 
o Cr. 
• Pregnancy prevention confirmation and counseling. 
• Pre- and post-test HIV counseling. 
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 5.5, 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; at this time, the subject will be assigned a unique study 
identification number in the clinical database. 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. The identification number will 
link subject samples and data collected throughout the study. 
8.2 
EFFICACY ASSESSMENTS 
8.2.1 
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 

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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 (4 tablets twice daily for 3 days) to clear any possible Pf 
blood-stage infection prior to study agent administration. 
Randomization Procedures: Randomization for the efficacy study is described in sections 6.3.1 
and 9.4.1. 
Study Agent Administration and Monitoring: Study agent infusion 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 fingerprick or 
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 adults 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.  
8.2.2 
Biospecimen Evaluations 
Blood will be collected under this protocol by the following methods: 
• Venipuncture will be performed with single-use needles. Venous blood samples will be 
used as follows: 
o Safety evaluations described in section 8.3. 
o Shipment to the research 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 PfRT-PCR if unable to obtain ample sample 
from finger prick 
• Fingerprick will be performed using single-use disposable lancets. Fingerprick blood 
samples will be used as follows: 
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 adult 
research subjects by the NIH Clinical Center: no more than 10.5 mL/kg or 550 mL (whichever is 
smaller) over an 8-week period. 
The collection schedule, volumes, and test tubes are presented in section 1.3. 

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8.2.3 
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 2.2.3.3) to identify Pf infection for the primary endpoint. This evaluation will be 
performed centrally in the laboratory in Bamako. 
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 CIS43LS 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 CIS43LS-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 9.4.11). This evaluation will be 
performed by Dr. Daniel Neafsey at the Harvard School of Public Health. 
8.2.4 
Samples for Genetic/Genomic Analysis  
8.2.4.1 Description of the scope of genetic/genomic analysis 
Genetic testing performed in this protocol will be limited to analyzing the genetic material of 
infection-inducing parasites in blood samples. No human genetic analyses will be performed. 
8.2.4.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Privacy and confidentiality of medical information and biological samples is described in 
section 10.3. 
8.2.4.3 Management of Results 
As no human genetic analyses will be performed in this protocol, no genetic results will be 
returned to subjects. 
8.2.4.4 Genetic counseling 
Not applicable. 
8.3 
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. 

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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 infusion, 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: Women will have a serum pregnancy test at screening and urine tests at 
enrollment, day 0 (confirmed negative prior to administration of the study agent), and monthly 
through the final study visit. 
Pregnancy Prevention Counseling: Female subjects will be counseled on the importance of not 
becoming pregnant during study participation and on acceptable methods of contraception. 
8.4 
SAFETY DEFINITIONS, MANAGEMENT, AND SPONSOR REPORTING 
8.4.1 
Definitions 
Adverse Event: An AE is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or not 
considered related to the research. 
Adverse Reaction: An AR means any AE caused (see “Causality” below) by a study agent. ARs 
are a subset of all suspected adverse reactions (SARs; defined below) where there is reason to 
conclude that the study agent caused the event. 
Suspected Adverse Reaction: SAR means any AE for which there is a reasonable possibility 
that the study agent caused the AE. 
Per US FDA guidance:   
For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to 
suggest a causal (see “Causality” below) relationship between the study agent and the AE. A 
SAR implies a lesser degree of certainty about causality than an AR, which means any AE 
caused by a study agent. 
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. 

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• 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 
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. 

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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. 
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 

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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. 
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. 
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). 
8.4.2 
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: MALI ADVERSE EVENT GRADING SCALE. 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 

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NOTE: A subject death should always be reported as grade 5. 
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 creatinine) 
• 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 
Unlikely Related 
• does not have a reasonable temporal relationship 

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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.  
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. 

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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  
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 
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. 

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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, 
independent safety monitor (ISM), and DSMB: 
• Sample collection will continue (including participation in extension visits described in 
Appendix C) per guidelines below: 
o Only proceed with blood draw if subject’s hemoglobin value is ≥ 8.0 
gm/dL (assessed via finger prick). 
o PK samples (4 mL) will be collected according to the regular study 
schedule (Day 1, Day 7, Day 14, Day 28, Day 56, Day 84, Day 112, Day 
140 and Day 168), plus optional extension visits. 
o The finger prick 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 PfRT-PCR. A 
venipuncture (up to 0.5 mL) may also be performed if the investigators 
believe that a finger prick would not provide a sufficient volume of blood 
to prepare dried blood spots for the PfRT-PCR assay.   
o Serum storage samples will not be drawn if a subject becomes pregnant. 

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• Continue to follow for safety for the duration of the pregnancy and for a period of up to 
12 months (per investigator discretion) following delivery for assessment of the neonate 
(see Appendix D). 
• 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. 
8.4.3 
Withdrawal Criteria for an Individual Subject 
An individual subject will be withdrawn from the study for any of the following: 
• An individual subject’s decision. (The investigator should attempt to determine the 
reason for the subject’s decision.) 
• 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 to provide informed consent. 
o Withdraws permission to have blood samples or data stored for future research. 
• 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 5.5), 
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 

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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.  
All subjects exposed to study agents MUST be included in the safety dataset. 
8.4.4 
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. 
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.  

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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 9.4.8). 
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.  
8.4.5 
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. 

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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 
A subject who does not resume study agent/intervention/treatment will continue to be followed 
for protocol-specified safety assessments or as clinically indicated, whichever is more 
conservative. 
8.4.6 
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, FMPOS 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. 

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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 
Subjects who do not resume study agent/study intervention will continue to be followed for 
protocol-specified safety assessments or as clinically indicated, whichever is more conservative. 
8.5 
UNANTICIPATED PROBLEMS 
8.5.1 
Definition of an Unanticipated Problem 
The definition of a UP is provided in section 8.4.1. 
8.5.2 
 Unanticipated Problem Reporting  
The investigator will report UPs to the FMPOS EC according to NIH Human Research 
Protection Program (HRPP) Policy 801, as described in section 8.6.1. 
8.6 
ADDITIONAL REPORTING REQUIREMENTS 
8.6.1 
Reporting to the FMPOS EC 
Non-compliance and other reportable events will be reported to the FMPOS 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. 
• 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 
Office of Human Subjects Research Protections (OHSRP) 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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8.6.2 
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. 
8.6.3 
Reporting Protocol Deviations that Result from the COVID-19 Pandemic  
The following addresses the reporting requirements to the FMPOS 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 FMPOS EC as well as the NIH reporting requirements. 
Investigators may modify the protocol without prospective FMPOS 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 FMPOS 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 FMPOS 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 FMPOS 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 
9.1 
STATISTICAL HYPOTHESIS 
The hypotheses are that CIS43LS 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 safety and efficacy of CIS43LS compared 
to placebo. 
Primary Endpoints: 
• Dose escalation: Incidence and severity of local and systemic AEs occurring within 
7 days after the administration of CIS43LS  
• Efficacy: Pf blood stage infection as detected by microscopic examination of thick blood 
smear for 24 weeks after administration of CIS43LS or placebo 

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Secondary Endpoints: 
• Dose escalation: Measurement of CIS43LS in sera of recipients  
• Efficacy: Pf blood stage infection as detected by RT-PCR for 24 weeks after 
administration of CIS43LS or placebo  
• Efficacy: Measurement of CIS43LS in sera of recipients  
9.2 
SAMPLE SIZE DETERMINATION 
9.2.1 
Sample Size Considerations for the Dose-Escalation Study 
The ability of the study to identify safety events can be expressed in terms of the probability of 
observing 1 or more event of interest (e.g., AEs) within each arm. With the sample size n=6 in 
each arm, there is over a 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 n=18 over 
3 dose arms, there is over a 90% chance to observe at least 1 AE if the true rate is no less than 
0.121 and over a 90% chance of observing no AE if the true rate is no more than 0.005. 
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 (Pr) of events for different safety scenarios within an arm (n=6 or 18). 
True event 
rate 
n=6 
n=18 
Pr(0) 
Pr(>1) 
Pr(0) 
Pr(>1) 
0.005 
0.970 
0.000 
0.914 
0.004 
0.01 
0.941 
0.001 
0.835 
0.014 
0.02 
0.886 
0.006 
0.695 
0.050 
0.035 
0.808 
0.017 
0.527 
0.130 
0.05 
0.735 
0.033 
0.397 
0.226 
0.1 
0.531 
0.114 
0.150 
0.550 
0.15 
0.377 
0.224 
0.054 
0.776 
0.2 
0.262 
0.345 
0.018 
0.901 
0.3 
0.118 
0.580 
0.002 
0.986 
9.2.2 
Sample Size Considerations for the Efficacy Study 
The efficacy study is designed to evaluate protective efficacy (PE) of CIS43LS at each dose by 
testing the null hypothesis,  

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H0: protective efficacy ≤ 0%, 
versus the alternative hypothesis,  
H1: protective efficacy > 0%,  
where PE is 1 minus the ratio of the infection rate under CIS43LS over the infection rate under 
placebo. 
The sample size considerations are based on the power of rejecting H0 over a range of possible 
protective efficacy and infection rates under placebo. Assuming a drop-out rate of 10%, Table 4 
presents the power under a 2-sided significance level of 0.025. With 110 subjects enrolled in 
each arm, the trial has at least 80% power in each comparison to claim protective efficacy of 
CIS43LS if the underlying efficacy is greater than or equal to 0.5 and the infection rate under 
placebo is no less than 0.4.  
Table 4. Power for efficacy evaluation under a 2-sided type I error rate of 0.025. 
Sample size per 
arm 
Infection rate 
under placebo 
Protective 
efficacy 
Power 
 
100 
0.4 
0.4 
52 
0.4 
0.5 
76 
0.4 
0.6 
92 
0.5 
0.4 
69 
0.5 
0.5 
90 
0.5 
0.6 
98 
0.6 
0.4 
84 
0.6 
0.5 
97 
0.6 
0.6 
100 
0.7 
0.4 
95 
0.7 
0.5 
100 
0.7 
0.6 
100 
110 
 
0.4 
0.4 
57 
0.4 
0.5 
80 
0.4 
0.6 
94 
0.5 
0.4 
74 
0.5 
0.5 
93 
0.5 
0.6 
99 
0.6 
0.4 
88 
0.6 
0.5 
98 
0.6 
0.6 
100 
0.7 
0.4 
96 
0.7 
0.5 
100 
0.7 
0.6 
100 

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Sample size per 
arm 
Infection rate 
under placebo 
Protective 
efficacy 
Power 
 
120 
0.4 
0.4 
61 
0.4 
0.5 
84 
0.4 
0.6 
96 
0.5 
0.4 
78 
0.5 
0.5 
95 
0.5 
0.6 
99 
0.6 
0.4 
91 
0.6 
0.5 
99 
0.6 
0.6 
100 
0.7 
0.4 
98 
0.7 
0.5 
100 
0.7 
0.6 
100 
 
Table 5 presents the minimum detectable difference between a CIS43LS arm and a placebo arm 
in terms of the AE rate based on a two-sided proportion test with type I error rate of 0.025.  
Table 5. Minimum detectable difference in adverse event rate in arms receiving monoclonal 
antibody (MAb) or placebo under a 2-sided type I error rate of 0.025. 
Sample 
size within 
each arm 
(#) 
Event rate 
(in placebo) 
(%) 
Detectable with 80% power 
Detectable with 90% power 
Difference 
(%) 
Event rate 
(in MAb) 
(%) 
Difference 
(%) 
Event rate 
(in MAb) 
(%) 
100 
0.1 
9.1 
9.2 
11.6 
11.7 
0.5 
9.8 
10.3 
12.3 
12.8 
1.0 
10.5 
11.5 
13.0 
14.0 
2.0 
11.6 
13.6 
14.2 
16.2 
5.0 
14.1 
19.1 
16.8 
21.8 
110 
0.1 
8.4 
8.5 
10.6 
10.7 
0.5 
9.0 
9.5 
11.3 
11.8 
1.0 
9.7 
10.7 
12.0 
13 
2.0 
10.8 
12.8 
13.2 
15.2 
5.0 
13.2 
18.2 
15.7 
20.7 
120 
0.1 
7.7 
7.8 
9.8 
9.9 
0.5 
8.4 
8.9 
10.5 
11.0 
1.0 
9.0 
10.0 
11.2 
12.2 
2.0 
10.2 
12.2 
12.3 
14.3 

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Sample 
size within 
each arm 
(#) 
Event rate 
(in placebo) 
(%) 
Detectable with 80% power 
Detectable with 90% power 
Difference 
(%) 
Event rate 
(in MAb) 
(%) 
Difference 
(%) 
Event rate 
(in MAb) 
(%) 
5.0 
12.5 
17.5 
14.9 
19.9 
 
9.3 
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.  
• 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 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 intervention received.  
9.3.1 
Evaluable for Toxicity  
All subjects will be evaluable for toxicity from the time of their first treatment with CIS43LS or 
placebo. 
9.3.2 
Evaluable for Objective Response  
Not applicable. 
9.3.3 
Evaluable Non-Target Disease Response 
Not applicable. 
9.4 
STATISTICAL ANALYSES 
9.4.1 
General Approach 
In general, descriptive statistics will be tabulated by treatment arm for endpoints of interest. This 
will include point estimates (mean, geometric mean, median, or proportions) and their respective 
95% confidence intervals. Formal comparisons will use standard methods, contingency tables for 
categorical variables, t-tests for comparing means if data follow a normal distribution or 
geometric means if data after log transformation follow a normal distribution, or nonparametric 
analogs for comparing medians. Unless specified in the subsequent sections, comparisons will be 
two-sided with type I error rate of 0.05. 

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Missing data will be considered as “missing completely at random” provided missing data is 
modest (e.g., <10%). We will examine the “missing completely at random” assumption if 
missing data is more than 10%. If the assumption does not hold, missing data will be handled 
under the “missing at random” assumption (that is, missingness depends only on observed 
variables) via methods such as multiple imputation and inverse propensity weighting. To handle 
the possibility of “missing not at random,” a sensitivity analysis will be performed by imputing 
missing binary observations with the observed proportion in the opposite arm. A secondary 
sensitivity analysis will be considered by imputing missing binary observations as failures.  
Randomization: In the efficacy study, randomization will be 1:1:1 allocation to the 2 CIS43LS 
arms and the placebo arm. To limit the number of dropouts before vaccination, randomization 
and CIS43LS administration will occur as close in time as possible. 
9.4.2 
Analysis of the Primary Endpoints 
Analysis for the primary endpoint for safety and tolerability is described in section 9.4.5. 
Analysis for the primary efficacy endpoint, protective efficacy with Pf infection determined by 
blood smear, is described in section 9.4.4. 
9.4.3 
Analysis of the Secondary Endpoints 
Analysis of the secondary efficacy endpoint, with Pf infection determined by RT-PCR, is 
described in section 9.4.4. 
Analyses of the secondary endpoints for the PK of CIS43LS and the association of CIS43LS 
concentration with Pf infection risk are described in section 9.4.6. 
9.4.4 
Efficacy Analyses 
The primary efficacy endpoint (efficacy study primary endpoint) is the incidence of malaria 
infection defined as blood smear–positive Pf infection through 24 weeks after administration. 
The secondary efficacy endpoint is the incidence of malaria infection as determined by RT-PCR. 
The efficacy analyses will be MITT.  
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.  
The secondary efficacy analysis will be based on the proportion of infection. The proportions of 
infection will be estimated for each arm and compared across arms based on Kaplan-Meier 
estimates along with 95% confidence intervals via R package “bpcp.” This estimation accounts 

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for right censoring and the comparison should be equivalent to Fisher’s exact test in case of no 
censoring. Though not accounting for interval censoring, the Kaplan-Meier estimates are 
appropriate as the interest is on infection at 24 weeks only.  
The Holm method will be adopted to address the issue of multiplicity in comparing the 2 dose 
arms against the placebo. 
The above analyses will apply to both the primary and the secondary efficacy endpoints.  
9.4.5 
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.   
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 AEs will be summarized by dose arm along with the exact 
95% confidence intervals of the AE rate. For subjects experiencing more than 1 AE, the subjects 
will be counted once under the event of highest severity.  
In the efficacy study, comparisons between the dose arms and the control arm will be 
additionally performed in terms of the proportions of solicited AEs, related AEs, and SAEs.  
In the rare case of subjects receiving a regimen different from assignment, a per-protocol 
analysis will be performed as a secondary analysis, which will include subjects according to the 
product they actually receive in the study.     
9.4.6 
Pharmacokinetics Analysis 
PK analysis will be carried out for subjects in the dose-escalation study and the efficacy study 
with blood samples collected at defined timepoints as listed in section 1.3. The following PK 
analysis will be performed as needed.  
Individual Subject PK Analysis: A non-compartmental (NC) PK analysis will be performed on 
the CIS43LS 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 CIS43LS concentration falls below the quantitative limit (QL) of the 
assay, the sample with concentration below the QL will be assigned a CIS43LS 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 CIS43LS 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.  

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Population PK Analyses: Based on preclinical PK results for CIS43LS 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. 19  
To assess the association of CIS43LS concentration with protection, we will perform a Cox 
proportional hazards regression for the time to the first infection with CIS43LS concentration as 
a time-varying covariate. A logistic regression analysis will be additionally performed to model 
the infection rate as a function of CIS43LS concentration via the method of generalized 
estimating equation to account for repeated measures.  
9.4.7 
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.  
9.4.8 
Planned Interim Analyses 
One interim safety analysis will be performed when safety data are available from the 
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. 
9.4.9 
Sub-group Analyses 
Not applicable. 
9.4.10 
Tabulation of Individual Participant Data 
Safety data will be presented by line listing and tables at the individual level, as described in 
section 9.4.5. 
9.4.11 
Exploratory Analyses 
To explore the impact of CIS43LS 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 CIS43LS footprint.  

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10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 
INFORMED CONSENT PROCESS 
10.1.1 
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 5.6. Following the process of Diallo and colleagues, 20 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.   
Discussions during the community permission process will address the need for both a husband 
and wife to agree to avoid pregnancy for the specified period if a wife chooses to volunteer for 
the study. 
10.1.1.2 Individual Informed Consent 
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 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 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 subject 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. Individuals who agree to participate 
will sign or fingerprint (if illiterate) the consent form.  
Also, a study comprehension examination will be conducted to make sure that the study is 
understood by the potential subjects 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 is mandatory to enroll. 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 individual whose comprehension is 
questionable, regardless of score, may be excluded from enrollment. 

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10.1.2 
Consent for Minors When They Reach the Age of Majority  
Not applicable. 
10.1.3 
Telephone Consent  
Not applicable. 
10.1.4 
Telephone Assent 
Not applicable. 
10.1.5 
Participation of Subjects who are/become Decisionally Impaired 
Adults unable to give consent are excluded from enrolling in the protocol. However, reconsent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because subjects might not benefit from research 
participation (section 2.3.3), subjects who lose the ability to consent during participation will be 
withdrawn. 
10.2 
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. 
10.3 
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 FMPOS 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 

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research subjects, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to subjects. 
Samples and data will be collected and stored under this protocol. All of the stored study 
research samples are labeled by a code that only the investigators can link to the subject. 
Samples are stored in secure research laboratories in locked freezers with limited access at the 
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 FMPOS 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. 
10.4 
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. 
10.5 
SAFETY OVERSIGHT 
Safety oversight is described in section 8.4.4. 
10.6 
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. 
10.7 
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 standard operating 
procedures. 
10.8 
DATA HANDLING AND RECORD KEEPING 
10.8.1 
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. 
10.8.2 
Study Records Retention 
The investigator is responsible for retaining all essential documents listed in the ICH GCP 
guidelines. Study records will be maintained by the principal investigator according to the 
timelines specified in 21 CFR 312.62 or a minimum of 7 years, and in compliance with 
institutional, EC, state, and federal medical records retention requirements, whichever is longest. 
All stored records will be kept confidential to the extent required by federal, state, and local law.  
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 

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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. 
10.9 
PROTOCOL DEVIATIONS 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations to the FMPOS EC 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. 
10.9.1 
NIH Definition of Protocol Deviation 
The definition of a protocol deviation is provided in section 8.4.1.  
10.10 PUBLICATION AND DATA SHARING POLICY 
10.10.1 
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. 
Data will be shared at the time of publication or shortly thereafter. 
10.10.2 
Genomic Data Sharing Plan 
Not applicable. 

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10.11 COLLABORATIVE AGREEMENTS  
10.11.1 
Agreement Type 
Not applicable. 
10.12 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 and manage 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 
ANA 
Anti-nuclear antibody 
AR 
Adverse reaction 
AUC 
Area under the curve 
β-hCG 
Beta-human choriogonadotropin 
Cave 
Time-weighted average concentrations 
CBC 
Complete blood count 
CFA 
Communauté Financière Africaine 
CFR 
Code of Federal Regulations 
CHMI 
Controlled human malaria infection 
CIS43LS 
VRC-MALMAB0100-00-AB 
CL 
Clearance 
Cmax 
Maximum concentration 
CONSORT Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
CPT 
Cell preparation tube 
Cr 
Creatinine 
CRF 
Case report form 
CRS 
Cytokine release syndrome 
CSO 
Clinical Safety Office 
CSP 
Circumsporozoite protein 
CTM 
Clinical Trials Monitoring 
DSMB 
Data and safety monitoring board 
EC 
Ethics committee 
ECG 
Electrocardiogram 

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EDTA 
Ethylenediaminetetraacetic acid 
ELISA 
Enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
FMPOS 
Faculté de Médecine Pharmacie d’Odontostomatologie 
GCP 
Good clinical practice 
GLP 
Good laboratory practices 
GMP 
Good manufacturing practices 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPF 
High power field 
HRPP 
Human Research Protection Program 
ICH 
International Council on Harmonisation  
Ig 
Immunoglobulin 
IND 
Investigational new drug 
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 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH  
National Institutes of Health 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
OHSRP 
Office of Human Subjects Research Protections 
Pb 
Plasmodium berghei 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
Pf 
Plasmodium falciparum 
PK 
Pharmacokinetics 
Pr 
Probability 
Q 
Intercompartmental clearance 
QL 
Quantitative limit 
QTc 
QT interval, corrected 
RBC 
Red blood cell 
RDT 
Rapid diagnostic test 
REDCap 
Research Electronic Data Capture 
REF 
Reportable Event Form 
rPfCSP 
Recombinant Plasmodium falciparum circumsporozoite protein 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 

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SAR 
Suspected adverse reaction 
SC 
Subcutaneous(ly) 
SERF 
Safety Expedited Report Form 
SMM 
Sponsor medical monitor 
SOA 
Schedule of Activities 
SOP 
Standard operating procedure 
SPZ 
Sporozoite 
SRCP 
Safety review and communications plan 
SST 
Serum-separating tube 
SUSAR 
Serious and unexpected suspected adverse reaction 
Tmax 
Time of maximum concentration 
UP 
Unanticipated problem 
UPnonAE 
Unanticipated problem that is not an adverse event 
US 
United States 
USTTB 
University of Science, Techniques and Technologies of Bamako 
VCMP 
Vaccine Clinical Materials Program 
Vd1, Vd2 
Volumes of distribution 
Vdss 
Total volume of distribution at steady-state 
VRC 
Vaccine Research Center 
WBC 
White blood cell 
WHO 
World Health Organization 
 
12 REFERENCES 
1. 
WHO. World Malaria Report 2018. 2018. 
2. 
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in 
infants and children in Africa: final results of a phase 3, individually randomised, 
controlled trial. Lancet. 2015;386(9988):31-45. 
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. 
2017;13(9):2098-2101. 
4. 
Zalevsky J, Chamberlain AK, Horton HM, et al. Enhanced antibody half-life improves in 
vivo activity. Nat Biotechnol. 2010;28(2):157-159. 
5. 
Ko SY, Pegu A, Rudicell RS, et al. Enhanced neonatal Fc receptor function improves 
protection against primate SHIV infection. Nature. 2014;514(7524):642-645. 
6. 
Gaudinski MR, Coates EE, Houser KV, et al. Safety and pharmacokinetics of the Fc-
modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical 
trial in healthy adults. Plos Med. 2018;15(1):e1002493. 
7. 
Kisalu NK, Idris AH, Weidle C, et al. A human monoclonal antibody prevents malaria 
infection by targeting a new site of vulnerability on the parasite. Nat Med. 
2018;24(4):408-416. 

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8. 
Ledgerwood JE, Coates EE, Yamshchikov G, et al. Safety, pharmacokinetics and 
neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in 
healthy adults. Clin Exp Immunol. 2015. 
9. 
Gaudinski MR, Houser KV, Doria-Rose NA, et al. Safety and pharmacokinetics of 
broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a 
phase 1 dose-escalation clinical trial. Lancet HIV. 2019;6(10):e667-e679. 
10. 
Gaudinski MR, Coates EE, Novik L, et al. Safety, tolerability, pharmacokinetics, and 
immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus 
glycoprotein (VRC 608): an open-label phase 1 study. Lancet. 2019;393(10174):889-898. 
11. 
US Food and Drug Administration. Biomarker Qualification Decision Letter 
DDTBMQ000044, October 12 2018. Silver Spring, MD: US Food and Drug 
Administration;2018. 
12. 
Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The safety and side effects 
of monoclonal antibodies. Nat Rev Drug Discov. 2010;9(4):325-338. 
13. 
Bugelski PJ, Achuthanandam R, Capocasale RJ, Treacy G, Bouman-Thio E. Monoclonal 
antibody-induced cytokine-release syndrome. Expert Rev Clin Immunol. 2009;5(5):499-
521. 
14. 
Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clin J Oncol 
Nurs. 2010;14(2):E10-21. 
15. 
Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 
2010;105(4):259-273. 
16. 
Coartem (artemether and lumefantrine) tablets [package insert]. East Hanover, NJ: 
Novartis; 2019. 
17. 
Tran TM, Li S, Doumbo S, et al. An intensive longitudinal cohort study of Malian 
children and adults reveals no evidence of acquired immunity to Plasmodium falciparum 
infection. Clin Infect Dis. 2013;57(1):40-47. 
18. 
CIS43LS [investigator's brochure]. Bethesda, MD: NIAID Vaccine Research Center; 
2019. 
19. 
Gibaldi M, Perrier D. Pharmacokinetics. New York, NY: Marcel Dekker, Inc.; 1975. 
20. 
Diallo DA, Doumbo OK, Plowe CV, Wellems TE, Emanuel EJ, Hurst SA. Community 
permission for medical research in developing countries. Clin Infect Dis. 2005;41(2):255-
259. 
21. 
Bain BJ. Ethnic and sex differences in the total and differential white cell count and 
platelet count. J Clin Pathol. 1996;49(8):664-666. 
22. 
Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute 
neutrophil count? J Lab Clin Med. 1999;133(1):15-22. 
 
 
 

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APPENDIX A: MRTC URINE LABORATORY NORMAL VALUES 
Urine Dip/Urinalysis 
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). 
 
 

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APPENDIX B: MALI ADVERSE EVENT GRADING SCALE 
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 – 215.99 
> 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. 21,22 
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: DOSE ESCALATION STUDY EXTENSION 
Study Extension Rationale 
Subjects who completed 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 2 weeks), and 2) to 
extend the PK analysis of CIS43LS to approximately 9 months (as determined by measuring the 
concentration of CIS43LS in blood samples collected every 4 weeks). The Dose Escalation 
component of the study had 3 dose groups (5 mg/kg, 10 mg/kg, and 40 mg/kg of CIS43LS), 
while the Efficacy component of the study only had 2 CIS43LS dose groups (10 mg/kg and 40 
mg/kg). Following all subjects in the Dose Escalation group (including those who received 5 
mg/kg of CIS43LS) will provide insight into the potential protective efficacy of a broader range 
of CIS43LS doses. Extending the PK analysis of subjects in the Dose Escalation group out to a 
total of 9 months will provide valuable information on the PK of CIS43LS in all 3 dose groups (5 
mg/kg, 10 mg/kg, and 40 mg/kg) and will allow for exploratory analyses that assess the 
correlation between CIS43LS concentrations in blood and P. falciparum infection risk over a 9-
month period.  
Study Extension Procedures 
Participants who completed the Dose Escalation study will be offered participation in the 
extension study visits and undergo an informed consent process (see section 10.1). Those who 
agree to participate will sign the extension consent and have a screening hemoglobin test. Those 
with hemoglobin <7 g/dL (<8 g/dL for pregnant women) will be excluded from participating in 
the Extension visits; those with hemoglobin ≥7 g/dL (≥8 g/dL for pregnant women) will be 
enrolled and begin bi-weekly Extension study visits at the MRTC clinic in Kalifabougou. At 
each study visit, up to 4.5 mL of blood will be collected by fingerprick or venipuncture for blood 
smear, Pf RT-PCR, and PK studies, as well as possible parasite genotyping in the case of a 
positive malaria parasite infection (see section 8.2.3). 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). 
During the final extension visit, an additional 8mL CPT tube will be collected for PBMC 
storage, unless the subject declines. 
AEs related to the blood collection procedures and all SAEs will be collected and followed 
through resolution.  
Participants will attend bi-weekly study visits through a common end date of December 31, 
2021, at which point all participants will be completed with study participation.  
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. 
 
 

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APPENDIX D: PREGNANCY FOLLOW-UP 
Pregnancy Follow-up Rationale 
If a woman becomes pregnant during study participation, we will follow her for safety for the 
duration of the pregnancy and for 12 months following delivery for assessment of the neonate. In 
addition to the procedures described in section 8.4.2.3.4, we will perform additional research 
procedures to collect information regarding the delivery outcome and the health of the 
neonate/infant and mother over the months following delivery. This will allow an initial 
assessment of PK values after delivery as well as the effects of the investigational agent on 
pregnancy course and outcome, and infant health. 
Pregnancy Follow-up Procedures 
Participants who become pregnant during the study will be offered participation in the pregnancy 
follow-up phase and undergo an informed consent process (see section 10.1). Women who agree 
to participate will sign the pregnancy follow-up consent and will undergo the following 
assessments at the time of delivery: 
• Hemoglobin measure using HemoCue 
• Peripheral malaria test (RDT, blood smear, filter paper) 
• Placental malaria using blood smear, filter paper 
• Placental malaria histology 
• PK blood draw 
• AE assessment 
• Breast milk to measure CIS43LS concentrations 
After delivery, we will collect a breast milk sample at each of the scheduled infant visits 
described below. 
At the infant follow-up visits during months 6, 9, and 12, 4 mL of blood will also be collected 
from the mother for detection of malaria and for PK analysis. 
The neonate/infant and mother will undergo research assessments according to Table 6. 
Table 6. Schedule of assessments for mother and neonate/infant participants. 
Study Month 
Month 0/ 
Delivery 
3 
6 
9 
12 
Illness 
Visit 
ET Visit 
Window (days) 
+7 
±7 
±7 
±7 
±7 
Clinical Procedures/Evaluations 
Heel/finger stick 
(infant) 
X 
X 
X 
X 
X 
X 
X 
Cord blood collection 
X 
 
 
 
 
 
 

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Study Month 
Month 0/ 
Delivery 
3 
6 
9 
12 
Illness 
Visit 
ET Visit 
Window (days) 
+7 
±7 
±7 
±7 
±7 
Weight 
(infant) 
X 
X 
X 
X 
X 
X 
X 
Ballard assessment 
(infant) 
X 
 
 
 
 
 
 
Apgar 
(infant) 
X 
 
 
 
 
 
 
Length 
(infant) 
X 
X 
X 
X 
X 
X 
X 
Head circumference 
(infant) 
X 
X 
X 
X 
X 
X 
X 
Neurological assessment 
(infant) 
 
X 
X 
X 
X 
X 
X 
Vaccination/EPI review a 
(infant) 
 
X 
X 
X 
X 
X 
X 
AE assessment 
(mother and infant) 
X 
X 
X 
X 
X 
X 
X 
Breast milk sample 
(collected from mother) 
X 
X 
X 
X 
X 
 
X 
Venous blood 
(collected from mother) 
 
 
4 mL 
4 mL 
4 mL 
4 mL 
4 mL 
Laboratory Evaluations 
Test 
Tube 
(infant blood volume) 
PK (heel/ 
finger stick) 
SST  
50 uL 
50 uL 
50 uL 
50 uL 
50 uL 
 
50 uL 
PK (cord 
blood) 
SST 
X 
 
 
 
 
 
 
Malaria blood 
smear/RDT b 
N/A 
(X) 
(X) 
(X) 
(X) 
(X) 
3 to 4 
drops 
(X) 
Hemoglobin 
N/A 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 

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Abbreviations: AE, adverse event; ET, early termination; EPI, Expanded Programme of Immunization; PK, 
pharmacokinetics; RDT, rapid diagnostic test. 
(X) indicates that no additional blood will be drawn; the test will be performed from blood collected for another 
evaluation listed. 
a Record vaccination information from EPI card. 
b Only performed if enough blood is available. 
 
The month 12 visit will be the final study visit for participants; participation will be complete 
after this timepoint. 
For both women and children, any AEs related to the blood collection procedures and all SAEs 
will be followed through resolution.  
Compensation 
Subjects will be compensated 3,000 Communauté Financière Africaine (CFA) Franc for each 
study visit for the time and inconvenience of participation. Mothers and neonates/newborns will 
each receive compensation for study visits. Payment will be provided in cash after the 
completion of each visit. The parent/guardian will receive the payments for the neonate/infant 
participants. 
Subjects will be provided with transportation to and from study visits but will not receive 
additional reimbursement for travel. 
Additional Procedures and Processes 
Refer to main protocol sections 2.3.1, 8, and 10 for additional information related to risks, safety 
definitions and reporting, and human subject protection procedures.