Trial to Evaluate CIS43LS in Healthy Adults

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

Background:

People get malaria when they are bitten by an infected mosquito. Malaria can be serious and sometimes deadly. Although there are medicines to treat malaria, there is no vaccine that fully prevents infection. Researchers want to test if an experimental drug can help.

Objective:

To test the safety and effectiveness of a drug called CIS43LS that could prevent malaria infection.

Eligibility:

Healthy people ages 18-50 who have never been infected with malaria

Design:

Participants were enrolled on the basis of eligibility criteria, evaluated by clinical laboratory tests, self-reported medical history, and physical examination.

Participants received CIS43LS either infused into a vein in their arm or injected into the fat under the skin. They were monitored for side effects for up to 4 hours after they received the drug. Participants received a thermometer and recorded their temperature and symptoms every day on/with/via a diary card for 7 days after administration. The administration site was checked for redness, swelling, itching or bruising.

Participants had up to 12 follow-up visits. At follow-up visits, participants had blood drawn and were checked for health changes or problems.

Most participants who received CIS43LS took part in a Controlled Human Malaria Infection Challenge (CHMI) along with control participants who did not receive CIS43LS. During the CHMI, mosquitoes carrying the malaria parasite bit participants in a controlled setting. The participants had clinic visits every day for up to 12 days starting 7 days after the CHMI. Participants were treated right away with antimalarial medication if they tested positive for malaria. Approximately 21 days after the CHMI, participants were treated with antimalarial medication for 3 days.

The study lasted 2-6 months depending on the participant's study group.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Detailed Description

This was a multicenter, three-part, first-in-human, Phase 1, open-label, dose escalation study to evaluate the dose, safety, tolerability and protective efficacy of an anti-malaria human monoclonal antibody, VRC-MALMAB0100-00-AB (CIS43LS). The primary objective was to evaluate the safety and tolerability of CIS43LS when administered by either intravenous (IV) or subcutaneous (SC) routes. The secondary objectives were to evaluate the pharmacokinetics of CIS43LS at each dose level, determine if IV or SC administration will confer protection following a controlled human malaria infection (CHMI), and estimate the lowest protective dose of CIS43LS.

Part A: Part A evaluated the doses and routes in an open-label, dose escalation design.

Part B: Part B evaluated CIS43LS doses and routes prior to CHMI in participants previously enrolled in Part A and new Part B enrollees. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS dose intravenously. Additional participants were enrolled in Part B and received CIS43LS intravenously.

Part C: Part C evaluated CIS43LS doses and routes needed to reach a threshold of protection by assessing serum concentration prior to CHMI in a dose down design.

Study Product:

CIS43LS is a human immunoglobulin gamma-1 (IgG1) monoclonal antibody that was developed and manufactured by the National Institutes of Health (NIH) Vaccine Research Center (VRC). A recombinant Chinese hamster ovary DG44 clonal cell line14 developed by the Vaccine Production Program was transferred to the VRC pilot plant for clinical material manufacture. The study product was manufactured according to Good Manufacturing Practice at the VRC pilot plant operated by the Vaccine Clinical Materials Program, Leidos Biomedical Research (Frederick, MD, USA).

VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.

Participants:

A total of 71 participants enrolled in the study as follows:

Part A: 29 participants enrolled in Groups 1-5

Part B: 21* participants enrolled in Groups 6-10

*Out of the 21 Part B participants, 11 were newly enrolled and 10 were Part A participants who re-enrolled.

Of the 10 Part A participants who re-enrolled in Part B, 3 were back up participants who did not receive additional CIS43LS or CHMI and were terminated early because they were not needed.

Therefore, only 18 participants were actively enrolled in Part B: 11 newly enrolled and 7 Part A participants who re-enrolled.

Part C: 31 participants enrolled in Groups 11-16

Of the 71 participants enrolled, 47 participants received at least one dose of CIS43LS and 43 participants completed the CHMI.

Of the 47 participants who received CIS43LS, 4 participants who received a dose in Part A were also enrolled in Part B and received a second dose as follows:

• one participant received a 5 mg/kg IV dose in Part A and 20 mg/kg IV dose in Part B,
• one participant received a 5 mg/kg SC dose in Part A and 20 mg/kg IV dose in Part B, and
• two participants received a 20 mg/kg IV dose in Part A and Part B.

Therefore, a total of 51 doses of CIS43LS were administered to 47 participants as follows:

• 7 doses of 1 mg/kg IV
• 8 doses of 5 mg/kg SC
• 8 doses of 5 mg/kg IV
• 3 doses of 10 mg/kg IV
• 4 doses of 10 mg/kg SC
• 9 doses of 20 mg/kg IV and
• 12 doses of 40 mg/kg IV

Study Duration:

Participants who received CIS43LS were followed for up to 24 weeks after product administration. Control participants were followed through 7 weeks after CHMI.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201-1595
      • University of Maryland Baltimore, Center for Vaccine Development
    • Bethesda, Maryland, United States, 20814
      • VRC Clinic, NIH Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

• INCLUSION CRITERIA:

  1. Able and willing to complete the informed consent process
  2. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
  3. Available for clinical follow-up through the last study visit
  4. 18 to 50 years of age
  5. In good general health without clinically significant medical history
  6. Physical examination without clinically significant findings within the 56 days prior to enrollment
  7. Weight <= 115 kg (for all groups except Groups 5, 10, and 16) and < 100 kg for Group 15
  8. Adequate venous access if assigned to an IV group or adequate subcutaneous tissue if assigned to an SC group
  9. Willing to have blood samples collected, stored indefinitely, and used for research purposes
  10. Agrees to participate in a controlled human malaria infection (CHMI) and to comply with post-CHMI follow-up requirements (except Group 4B)
  11. Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 4B)

  12. Agrees not to travel to a malaria endemic region during the entire course of study participation

      Laboratory Criteria within 56 days prior to enrollment:

  13. White Blood Cell (WBC) 2,500-12,000/mm^3
  14. WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval
  15. Platelets = 125,000 - 500,000/mm^3
  16. Hemoglobin within institutional normal range or accompanied by the PI or designee approval
  17. Creatinine <= 1.1 x upper limit of normal (ULN)
  18. Alanine aminotransferase (ALT) <= 1.25 x ULN

  19. Negative for HIV infection by an FDA approved method of detection

      Laboratory Criteria documented any time prior to enrollment:

  20. Negative sickle cell screening test
  21. Negative troponin test (except Group 4B)
  22. Electrocardiogram (ECG) without clinically significant abnormalities (examples may include: pathologic Q waves, significant ST-T wave changes, left ventricular hypertrophy, any non-sinus rhythm excluding isolated premature atrial contractions, right or left bundle branch block, advanced A-V heart block). ECG abnormalities determined by a cardiologist to be clinically insignificant as related to study participation do not preclude study enrollment (except Group 4B)

  23. No evidence of increased cardiovascular disease risk; defined as >10% five-year risk by the non-laboratory method (except Group 4B)

      Criteria Specific to Women:

  24. Postmenopausal for at least 1 year, post-hysterectomy or bilateral oophorectomy, or if of childbearing potential:

      1. Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on day of enrollment, and prior to product administration and CHMI, and
      2. Agrees to use an effective means of birth control through the duration of study participation

• EXCLUSION CRITERIA:

  1. Woman who is breast-feeding or planning to become pregnant during study participation
  2. Previous receipt of a malaria vaccine
  3. History of malaria infection
  4. History of severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) defined per FDA guidance
  5. Active SARS-CoV-2 infection
  6. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study
  7. Hypertension that is not well controlled
  8. Receipt of any investigational study product within 28 days prior to enrollment (note: Emergency Use Authorization Coronavirus Disease 2019 (COVID-19) vaccine is not exclusionary)
  9. Receipt of any live attenuated vaccines within 28 days prior to enrollment
  10. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with intramuscular injections or blood draws
  11. History of a splenectomy, sickle cell disease or sickle cell trait
  12. History of skeeter syndrome or anaphylactic response to mosquito-bites (except Group 4B)
  13. Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 4B)
  14. Use or planned use of any drug, including antibiotics, with antimalarial activity within 4 weeks prior to CHMI
  15. History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 4B)
  16. Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin (except Group 4B)
  17. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

17

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A, Group 1: CIS43LS (5 mg/kg IV); CIS43LS (5 mg/kg) administered by intravenous (IV) infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS
Experimental: Part A, Group 2: CIS43LS (5 mg/kg SC); CIS43LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS
Experimental: Part A, Group 3: CIS43LS (20 mg/kg IV); CIS43LS (20 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS
Experimental: Part A, Group 4A: CIS43LS (40 mg/kg IV); CIS43LS (40 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS
Experimental: Part A, Group 4B: CIS43LS (40 mg/kg IV); CIS43LS (40 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS
No Intervention: Part A, Group 5: CHMI Controls; Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI); however, Group 5 did not undergo CHMI because of restrictions related to coronavirus disease 2019 (COVID-19)
Experimental: Part B, Group 6: CIS43LS (5 mg/kg SC); CIS43LS (5 mg/kg) administered by SC injection (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part B, Group 7: CIS43LS (20 mg/kg IV); CIS43LS (20 mg/kg) administered by IV infusion (Day 0) Part B, Group 7 participants included participants previously enrolled in Part A who received either 5 mg/kg IV (1), 5 mg/kg SC (1) or 20 mg/kg IV (2) in the first part of the study and newly enrolled Part B participants	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Other: Part B, Group 8: CHMI [CIS43LS (40 mg/kg IV) in Part A]; Part B, Group 8 participants included participants previously enrolled in Part A who received CIS43LS (40 mg/kg IV) in the first part of the study but did not receive CIS43LS in Part B of the study. Group 8 participants were enrolled to complete the controlled human malaria infection (CHMI).	Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part B, Group 9: CIS43LS (40 mg/kg IV); CIS43LS (40 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Other: Part B, Group 10: CHMI Controls; Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI)	Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part C, Group 11: CIS43LS (1 mg/kg IV); CIS43LS (1 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part C, Group 12: CIS43LS (5 mg/kg IV); CIS43LS (5 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part C, Group 13: CIS43LS (5 mg/kg SC); CIS43LS (5 mg/kg) administered by SC injection (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part C, Group 14: CIS43LS (10 mg/kg IV); CIS43LS (10 mg/kg) administered by IV infusion (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Experimental: Part C, Group 15: CIS43LS (10 mg/kg SC); CIS43LS (10 mg/kg) administered by SC injection (Day 0)	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.; Other Names: CIS43LS; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).
Other: Part C, Group 16: CHMI Controls; Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI)	Other: Plasmodium falciparum (P. falciparum) sporozoite challenge; Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration	Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.	7 days after CIS43LS product administration, at approximately Week 1
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration	Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.	7 days after CIS43LS product administration, at approximately Week 1
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following CIS43LS Product Administration	Unsolicited adverse event (AE) data collection included AEs of all severities from the date of product administration through the Day 28 post-product administration visit. At other time periods between study product administration and when greater than 4 weeks after the study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that required ongoing medical management (reported as a separate outcome) were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.	Day 0 through 4 weeks after CIS43LS product administration
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Controlled Human Malaria Infection (CHMI)	Unsolicited adverse event (AE) data collection included AEs of all severities from CHMI through the Day 28 post-CHMI visit. The relationship between an AE and CHMI was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.	Day 0 through 4 weeks after CHMI
Number of Participants With Serious Adverse Events (SAEs) Following CIS43LS Product Administration	SAEs were recorded from receipt of first study product administration through the last expected study visit at Week 24. The relationship between a SAE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.	Day 0 after CIS43LS product administration through the study participation, up to Week 24
Number of Participants With New Chronic Medical Conditions Following CIS43LS Product Administration	New chronic medical conditions that required ongoing medical management were recorded from receipt of first study product administration through the last expected study visit at Week 24. The relationship between a new chronic medical condition and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.	Day 0 after CIS43LS product administration through the study participation, up to Week 24
Number of Participants With Abnormal Laboratory Measures of Safety Following CIS43LS Product Administration	Abnormal laboratory results recorded as unsolicited adverse events (AEs) are summarized. Safety lab parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV) platelets, and white blood cell (WBC), red blood cell (RBC), neutrophil, lymphocyte, monocyte, eosinophil and basophil counts) and chemistry (alanine aminotransferase (ALT) and creatinine). Complete Blood Count (CBC) with differential and Chemistry (ALT and creatinine) results were collected at different timepoints in Parts A, B and C throughout the study per the protocol's schedule of evaluations. Institutional laboratory normal ranges as well as the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 were used.	Day 0 through 4 weeks after CIS43LS product administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part A and Part B)	Serum concentrations of CIS43LS by dose group following a single administration. Cmax is the peak serum concentration that CIS43LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group. After subcutaneous injection, Cmax could not be fully calculated because of COVID-19-related interruptions in sample collection.	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part C)	Serum concentrations of CIS43LS by dose group following a single administration. Cmax is the peak serum concentration that CIS43LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group.	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part A and Part B)	Tmax is the time it takes to reach Cmax of CIS43LS after it has been administered; it is determined based on the summary PK curve for each dose group.	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part C)	Tmax is the time it takes to reach Cmax of CIS43LS after it has been administered; it is determined based on the summary PK curve for each dose group.	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Beta Half-life (T1/2b) - (Part A and Part B)	Beta half-life (T1/2b) is being reported for this study. Beta half-life (T1/2b) is the time required for half of the CIS43LS product to be eliminated from the serum. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall beta half-life and bootstrap 90% confidence intervals (CIs).	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Beta Half-life (T1/2b) - (Part C)	Beta half-life (T1/2b) is the time required for half of the CIS43LS product to be eliminated from the serum. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall beta half-life and bootstrap 95% confidence intervals (CIs).	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Clearance Rate - (Part A and Part B)	Rate of CIS43LS elimination divided by the plasma CIS43LS concentration; determined based on the summary pharmacokinetic (PK) curve for each study group. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall clearance and bootstrap 90% confidence intervals (CIs).	Baseline through 24 weeks after CIS43LS product administration
Pharmacokinetic (PK) Parameters of CIS43LS: Clearance Rate - (Part C)	Rate of CIS43LS elimination divided by the plasma CIS43LS concentration; determined based on the summary pharmacokinetic (PK) curve for each study group. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall clearance and bootstrap 95% confidence intervals (CIs).	Baseline through 24 weeks after CIS43LS product administration
Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge (Part B)	Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine whether IV or SC administration of CIS43LS mediates protection against infectious P. falciparum following CHMI	Up to 21 days after CHMI
Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge (Part C)	Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine the lowest dose of CIS43LS administered IV and SC that confers protection against infectious P. falciparum following CHMI in Part C of the study	Up to 21 days after CHMI

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Director: Clinical Trials Program Leadership:ctpleadership@mail.nih.gov, VRC, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Publications and helpful links

General Publications

• Seder RA, Chang LJ, Enama ME, Zephir KL, Sarwar UN, Gordon IJ, Holman LA, James ER, Billingsley PF, Gunasekera A, Richman A, Chakravarty S, Manoj A, Velmurugan S, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, Plummer SH, Hendel CS, Novik L, Costner PJ, Mendoza FH, Saunders JG, Nason MC, Richardson JH, Murphy J, Davidson SA, Richie TL, Sedegah M, Sutamihardja A, Fahle GA, Lyke KE, Laurens MB, Roederer M, Tewari K, Epstein JE, Sim BK, Ledgerwood JE, Graham BS, Hoffman SL; VRC 312 Study Team. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013 Sep 20;341(6152):1359-65. doi: 10.1126/science.1241800. Epub 2013 Aug 8.
• Ishizuka AS, Lyke KE, DeZure A, Berry AA, Richie TL, Mendoza FH, Enama ME, Gordon IJ, Chang LJ, Sarwar UN, Zephir KL, Holman LA, James ER, Billingsley PF, Gunasekera A, Chakravarty S, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, K C N, Murshedkar T, DeCederfelt H, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Laurens MB, Plowe CV, Flynn B, Whalen WR, Todd JP, Noor J, Rao S, Sierra-Davidson K, Lynn GM, Epstein JE, Kemp MA, Fahle GA, Mikolajczak SA, Fishbaugher M, Sack BK, Kappe SH, Davidson SA, Garver LS, Bjorkstrom NK, Nason MC, Graham BS, Roederer M, Sim BK, Hoffman SL, Ledgerwood JE, Seder RA. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat Med. 2016 Jun;22(6):614-23. doi: 10.1038/nm.4110. Epub 2016 May 9. Erratum In: Nat Med. 2016 Jun 7;22(6):692.
• Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, Holman LA, Gordon IJ, Chen GL, Carter C, Nason M, Sitar S, Yamshchikov G, Berkowitz N, Andrews C, Vazquez S, Laurencot C, Misasi J, Arnold F, Carlton K, Lawlor H, Gall J, Bailer RT, McDermott A, Capparelli E, Koup RA, Mascola JR, Graham BS, Sullivan NJ, Ledgerwood JE; VRC 608 Study team. 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 Mar 2;393(10174):889-898. doi: 10.1016/S0140-6736(19)30036-4. Epub 2019 Jan 24. Erratum In: Lancet. 2020 May 30;395(10238):1694.
• Kayentao K, Ongoiba A, Preston AC, Healy SA, Doumbo S, Doumtabe D, Traore A, Traore H, Djiguiba A, Li S, Peterson ME, Telscher S, Idris AH, Kisalu NK, Carlton K, Serebryannyy L, Narpala S, McDermott AB, Gaudinski M, Traore S, Cisse H, Keita M, Skinner J, Hu Z, Zeguime A, Ouattara A, Doucoure M, Dolo A, Djimde A, Traore B, Seder RA, Crompton PD; Mali Malaria mAb Trial Team. Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali. N Engl J Med. 2022 Nov 17;387(20):1833-1842. doi: 10.1056/NEJMoa2206966. Epub 2022 Oct 31.
• Gaudinski MR, Berkowitz NM, Idris AH, Coates EE, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Hu Z, Campos Chagas A, O'Connell S, Basappa M, Douek N, Narpala SR, Barry CR, Widge AT, Hicks R, Awan SF, Wu RL, Hickman S, Wycuff D, Stein JA, Case C, Evans BP, Carlton K, Gall JG, Vazquez S, Flach B, Chen GL, Francica JR, Flynn BJ, Kisalu NK, Capparelli EV, McDermott A, Mascola JR, Ledgerwood JE, Seder RA; VRC 612 Study Team. A Monoclonal Antibody for Malaria Prevention. N Engl J Med. 2021 Aug 26;385(9):803-814. doi: 10.1056/NEJMoa2034031. Epub 2021 Aug 11.
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Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2020
• Primary Completion (Actual): February 28, 2022
• Study Completion (Actual): February 28, 2022

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 19, 2019
• First Posted (Actual): December 20, 2019

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 13, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Mosquito; Prevention and Control; Parasitemia; Passive Immunization; Malaria Challenge; Controlled Human Malaria Infection (CHMI)
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: 200017; 20-I-0017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) is not shared because it has limited value in a small phase 1 trial of healthy volunteers. We instead report non-IPD data as required in ClinicalTrials.gov.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No