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| ID | Type | Description | Link |
|---|---|---|---|
| 000536-I |
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Background:
Malaria is a parasitic disease carried by mosquitoes in tropical areas. There is no vaccine to prevent malaria infection. If not treated right away, it can become serious or deadly. Researchers want to test a drug to prevent malaria.
Objective:
To test if the drug L9LS is safe and if it prevents malaria infection in people.
Eligibility:
Healthy adults ages 18-50 who have never had malaria.
Design:
Participants were screened with a medical history, physical exam, and blood tests.
Participants were divided into 6 groups:
All participants who received L9LS were monitored for side effects. They had 2-3 follow-up visits during the week after the drug was given, and gave blood samples. They received a thermometer to check their temperature daily for 7 days. They received a tool to measure any redness, swelling, or bruising at the injection site.
Most participants took part in the controlled human malaria infection (CHMI) or malaria challenge to find out if L9LS prevents malaria after being bitten by infected mosquitos. Participants in the group who received L9LS injected in the muscle were enrolled after CHMI and did not take part in the CHMI. Participants who received CHMI were bitten by mosquitoes carrying the malaria parasites. A cup containing mosquitoes was placed on their arm for 5 minutes. On days 7-17 after exposure, they received daily study visits to give blood samples. Those who got malaria were treated immediately. On day 21, all CHMI participants received treatment for malaria.
Participation lasted 2-6 months, depending on study group.
This was a Phase 1, open-label, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and protective efficacy of an anti-malaria human monoclonal antibody, VRC-MALMAB0114-00-AB (L9LS). The primary hypothesis was that L9LS will be safe and well tolerated when administered by either intravenous (IV),subcutaneous (SC) or intramuscular (IM) routes. The secondary objectives were that L9LS will be detectable in human sera with a definable half-life and confer protection following a controlled human malaria infection (CHMI).
The study started with enrollment into Group 1. Interim safety evaluations occurred and supported continued evaluation of L9LS prior to enrolling participants into additional dose groups. All L9LS recipients in Groups 1-4 were invited to participate in the CHMI. Group 5 participants did not receive L9LS, in order to serve as the control group for the CHMI. After CHMI, all CHMI participants were evaluated for malaria parasitemia. Participants who developed blood stage infection were treated as soon as identified per protocol criteria. Participants in Group 6 received L9LS but did not take part in the CHMI.
Study follow-up continued through 24 weeks post product administration or 8 weeks post- CHMI, whichever was the most stringent.
Study Groups:
Group 1: 5 participants - 1mg/kg IV + CHMI
Group 2: 4 participants - 5 mg/kg IV + CHMI (1 participant declined to participate in the CHMI)
Group 3: 5 participants - 5 mg/ kg SC + CHMI
Group 4: 4 participants - 20 mg/kg IV + CHMI
Group 5: 9 participants - CHMI Controls (No L9LS given; 3 back up participants were not needed so were terminated early and did not participate in the CHMI)
Group 6: 5 participants - 5 mg/kg IM
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1: L9LS (1 mg/kg IV) | Experimental | L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) |
|
| Group 2: L9LS (5 mg/kg IV) | Experimental | L9LS (5 mg/kg) administered by IV infusion (Day 0) |
|
| Group 3: L9LS (5 mg/kg SC) | Experimental | L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) |
|
| Group 4: L9LS (20 mg/kg IV) | Experimental | L9LS (20 mg/kg) administered by IV infusion (Day 0) |
|
| Group 5: CHMI Controls | Other | Control participants who did not receive L9LS and were enrolled to complete the controlled human malaria infection (CHMI) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| VRC-MALMAB0114-00-AB | Drug | VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS 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 L9LS product administration, at approximately Week 1 |
| Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of L9LS 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 L9LS product administration, at approximately Week 1 |
| Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following L9LS 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge | Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine whether IV or SC administration of L9LS mediates protection against infectious P. falciparum following CHMI | Up to 21 days after CHMI |
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INCLUSION CRITERIA:
A volunteer must have met all of the following criteria to be included:
Able and willing to complete the informed consent process
Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
Available for clinical follow-up through the last study visit
18 to 50 years of age
In good general health without clinically significant medical history
Physical examination without clinically significant findings within the 56 days prior to enrollment
Weight <= 115 kg (except Group 5)
Adequate venous access if assigned to an IV group or adequate subcutaneous tissue if assigned to an SC group
Willing to have blood samples collected, stored indefinitely, and used for research purposes
Agrees to participate in a controlled human malaria infection (CHMI) and to comply with post-CHMI follow-up requirements (except Group 6)
Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 6)
Agrees not to travel to a malaria endemic region during the entire course of study participation (except Group 6)
Laboratory Criteria within 56 days prior to enrollment:
White Blood Cell (WBC) 2,500-12,000/mm^3
WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval
Platelets = 125,000-500,000/mm^3
Hemoglobin within institutional normal range or accompanied by the PI or designee approval
Creatinine <= 1.1 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) <=1.25 x ULN
Negative for HIV infection by an FDA approved method of detection
Laboratory Criteria documented any time during screening, prior to enrollment:
Negative polymerase chain reaction (PCR) for malaria (except Group 6)
Negative sickle cell screening test (except Group 6)
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 6)
No evidence of increased cardiovascular disease risk; defined as >10% five-year risk by the non-laboratory method (except Group 6)
Criteria Specific to Women:
Postmenopausal for at least 1 year, post-hysterectomy or bilateral oophorectomy, or if of childbearing potential:
EXCLUSION CRITERIA:
A volunteer would have been excluded if one or more of the following conditions applied:
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| Name | Affiliation | Role |
|---|---|---|
| Richard L Wu, M.D. | National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23929949 | Background | 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. | |
| 27158907 |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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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 (aggregate) data as required in ClinicalTrials.gov.
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Healthy adults were recruited for the study at the NIH Clinical Center in Bethesda, Maryland, USA.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1: L9LS (1 mg/kg IV) | L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| FG001 | Group 2: L9LS (5 mg/kg IV) | L9LS (5 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| FG002 | Group 3: L9LS (5 mg/kg SC) | L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| FG003 | Group 4: L9LS (20 mg/kg IV) | L9LS (20 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| FG004 | Group 5: CHMI Controls | Control participants who did not receive L9LS and were enrolled to complete the controlled human malaria infection (CHMI) Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| FG005 | Group 6: L9LS (5 mg/kg IM) | L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Population included all enrolled participants. Age represents age at enrollment day. Weight represents weight from enrollment evaluation for participants who received L9LS.
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1: L9LS (1 mg/kg IV) | L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Age represents age at initial enrollment day. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS 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. | Population included all enrolled participants who received L9LS and had safety data collected via diary card (N=23). Group 5 CHMI controls did not receive L9LS. | Posted | Count of Participants | Participants | 7 days after L9LS product administration, at approximately Week 1 |
Unsolicited adverse event (AE) data collection included AEs of all severities for the L9LS and/or CHMI recipients only. Unsolicited AEs were recorded from the date of investigational product (IP) administration through the Day 28 post-product administration visit and from CHMI through the Day 28 post-CHMI visit. After and between the indicated time periods, only serious AEs (SAEs) and new chronic medical conditions were recorded as AEs through the last expected study visit at Week 24.
Solicited AEs collected through systematic assessment for L9LS recipients only and unsolicited AEs collected for L9LS and/or CHMI recipients through non-systematic assessment represent the number and percentage of participants reporting the event. A participant with multiple experiences of the same event is counted once using the event of worst severity.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group 1: L9LS (1 mg/kg IV) | L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| VRC Clinical Trials Program Leadership | Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health | 301-451-8715 | ctpleadership@mail.nih.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Dec 1, 2021 | Sep 1, 2023 | Prot_SAP_ICF_001.pdf |
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| ID | Term |
|---|---|
| D008288 | Malaria |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
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| Group 6: L9LS (5 mg/kg IM) | Experimental | L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0) |
|
|
| Plasmodium falciparum (P. falciparum) sporozoite challenge | Other | Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
|
| Day 0 through 4 weeks after L9LS 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 L9LS 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 L9LS product administration through the study participation, up to Week 24 |
| Number of Participants With New Chronic Medical Conditions Following L9LS 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 L9LS product administration through the study participation, up to Week 24 |
| Number of Participants With Abnormal Laboratory Measures of Safety Following L9LS 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 (Comprehensive Metabolic Panel (CMP) including alanine aminotransferase (ALT) and creatinine). Complete Blood Count (CBC) with differential, CMP and ALT and creatinine results were collected at different timepoints 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 L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Maximum Observed Serum Concentration (Cmax) | Serum concentrations of L9LS by dose group following a single administration. Cmax is the peak serum concentration that L9LS 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 L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Time to Reach Maximum Observed Serum Concentration (Tmax) | Tmax is the time it takes to reach Cmax of L9LS after it has been administered; it is determined based on the summary PK curve for each dose group. | Baseline through 24 weeks after L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Beta Half-life (T1/2b) | Beta half-life (T1/2b) is being reported for this study. Beta half-life (T1/2b) is the time required for half of the L9LS product to be eliminated from the serum. | Baseline through 24 weeks after L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL) Following IV Administration | Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each IV group. | Baseline through 24 weeks after L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL/F) Following SC or IM Administration | Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each SC and IM group. Clearance following a SC or IM administration is calculated as Clearance (CL)/Bioavailability (F). | Baseline through 24 weeks after L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss) Following IV Administration | Theoretical volume that would be necessary to contain the total amount of administered drug at the same concentration as observed in plasma. It represents the degree to which a drug is distributed in body tissue rather than the plasma and calculated based in the pharmacokinetic (PK) curve for each IV group. | Baseline through 24 weeks after L9LS product administration |
| Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss/F) Following SC or IM Administration | Theoretical volume that would be necessary to contain the total amount of administered drug at the same concentration as observed in plasma. It represents the degree to which a drug is distributed in body tissue rather than the plasma and calculated based in the PK curve for each SC and IM group. Volume of distribution at steady-state (Vss) following a SC or IM administration is calculated as Volume of distribution at steady-state (Vss)/Bioavailability (F). | Baseline through 24 weeks after L9LS product administration |
| Background |
| 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. |
| 34379916 | Background | 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. |
| 36708738 | Background | Lyke KE, Berry AA, Mason K, Idris AH, O'Callahan M, Happe M, Strom L, Berkowitz NM, Guech M, Hu Z, Castro M, Basappa M, Wang L, Low K, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Strauss KS, Joshi S, Shrestha B, Adams M, Chagas AC, Murphy JR, Stein J, Hickman S, McDougal A, Lin B, Narpala SR, Vazquez S, Serebryannyy L, McDermott A, Gaudinski MR, Capparelli EV, Coates EE, Wu RL, Ledgerwood JE, Dropulic LK, Seder RA; VRC 612 Part C Study Team. Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial. Lancet Infect Dis. 2023 May;23(5):578-588. doi: 10.1016/S1473-3099(22)00793-9. Epub 2023 Jan 25. |
| 35921449 | Result | Wu RL, Idris AH, Berkowitz NM, Happe M, Gaudinski MR, Buettner C, Strom L, Awan SF, Holman LA, Mendoza F, Gordon IJ, Hu Z, Campos Chagas A, Wang LT, Da Silva Pereira L, Francica JR, Kisalu NK, Flynn BJ, Shi W, Kong WP, O'Connell S, Plummer SH, Beck A, McDermott A, Narpala SR, Serebryannyy L, Castro M, Silva R, Imam M, Pittman I, Hickman SP, McDougal AJ, Lukoskie AE, Murphy JR, Gall JG, Carlton K, Morgan P, Seo E, Stein JA, Vazquez S, Telscher S, Capparelli EV, Coates EE, Mascola JR, Ledgerwood JE, Dropulic LK, Seder RA; VRC 614 Study Team. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria. N Engl J Med. 2022 Aug 4;387(5):397-407. doi: 10.1056/NEJMoa2203067. |
| BG001 | Group 2: L9LS (5 mg/kg IV) | L9LS (5 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| BG002 | Group 3: L9LS (5 mg/kg SC) | L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| BG003 | Group 4: L9LS (20 mg/kg IV) | L9LS (20 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| BG004 | Group 5: CHMI Controls | Control participants who did not receive L9LS and were enrolled to complete the controlled human malaria infection (CHMI) Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| BG005 | Group 6: L9LS (5 mg/kg IM) | L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. |
| BG006 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Age, Customized | Age represents age at initial enrollment day. | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Weight (kg) | Weight was collected at enrollment day for each group that received L9LS. Therefore, the overall weight calculation does not include the Group 5 control participants. | Weight was not collected for Group 5 control participants in this protocol. Per protocol, weight was only collected for participants who received L9LS. | Mean | Standard Deviation | kg |
|
| ID | Title | Description |
|---|
| OG000 | Group 1: L9LS (1 mg/kg IV) | L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| OG001 | Group 2: L9LS (5 mg/kg IV) | L9LS (5 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| OG002 | Group 3: L9LS (5 mg/kg SC) | L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| OG003 | Group 4: L9LS (20 mg/kg IV) | L9LS (20 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum |
| OG004 | Group 6: L9LS (5 mg/kg IM) | L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. |
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| Primary | Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of L9LS 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. | Population included all enrolled participants who received L9LS and had safety data collected via diary card (N=23). Group 5 CHMI controls did not receive L9LS. | Posted | Count of Participants | Participants | 7 days after L9LS product administration, at approximately Week 1 |
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| Primary | Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following L9LS 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. | Population included all enrolled participants who received L9LS and had safety data collected via clinical assessment and/or lab results (N=23). Group 5 CHMI controls did not receive L9LS. | Posted | Count of Participants | Participants | Day 0 through 4 weeks after L9LS product administration |
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| Primary | 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. | Population included all participants who completed CHMI (N=23). One Group 2 participant declined to participate in the CHMI prior to the scheduled pre-CHMI visit and therefore was not enrolled in the CHMI group. Group 6 L9LS (5mg/kg IM) participants did not participate in the CHMI. | Posted | Count of Participants | Participants | Day 0 through 4 weeks after CHMI |
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| Primary | Number of Participants With Serious Adverse Events (SAEs) Following L9LS 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. | Population included all enrolled participants who received L9LS and had safety data collected via clinical assessment and/or lab results (N=23). Group 5 CHMI controls did not receive L9LS. | Posted | Count of Participants | Participants | Day 0 after L9LS product administration through the study participation, up to Week 24 |
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| Primary | Number of Participants With New Chronic Medical Conditions Following L9LS 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. | Population included all enrolled participants who received L9LS and had safety data collected via clinical assessment and/or lab results (N=23). Group 5 CHMI controls did not receive L9LS. | Posted | Count of Participants | Participants | Day 0 after L9LS product administration through the study participation, up to Week 24 |
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| Primary | Number of Participants With Abnormal Laboratory Measures of Safety Following L9LS 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 (Comprehensive Metabolic Panel (CMP) including alanine aminotransferase (ALT) and creatinine). Complete Blood Count (CBC) with differential, CMP and ALT and creatinine results were collected at different timepoints 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. | Population included all enrolled participants who received L9LS and had safety data collected via laboratory results (N=23). | Posted | Count of Participants | Participants | Day 0 through 4 weeks after L9LS product administration |
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| Secondary | Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge | Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine whether IV or SC administration of L9LS mediates protection against infectious P. falciparum following CHMI | Population included all participants who completed CHMI (N=23). One Group 2 participant declined to participate in the CHMI prior to the scheduled pre-CHMI visit and therefore was not enrolled in the CHMI group. Group 6 L9LS (5mg/kg IM) participants did not participate in the CHMI. | Posted | Count of Participants | Participants | Up to 21 days after CHMI |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Maximum Observed Serum Concentration (Cmax) | Serum concentrations of L9LS by dose group following a single administration. Cmax is the peak serum concentration that L9LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group. | Population included all participants who received L9LS (N=23). | Posted | Mean | Standard Deviation | μg/ml | Baseline through 24 weeks after L9LS product administration |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Time to Reach Maximum Observed Serum Concentration (Tmax) | Tmax is the time it takes to reach Cmax of L9LS after it has been administered; it is determined based on the summary PK curve for each dose group. | Population included all participants who received L9LS (N=23). | Posted | Mean | Standard Deviation | days | Baseline through 24 weeks after L9LS product administration |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Beta Half-life (T1/2b) | Beta half-life (T1/2b) is being reported for this study. Beta half-life (T1/2b) is the time required for half of the L9LS product to be eliminated from the serum. | Population included all participants who received L9LS (N=23). | Posted | Mean | Standard Deviation | days | Baseline through 24 weeks after L9LS product administration |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL) Following IV Administration | Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each IV group. | Population included participants who received L9LS (1 mg/kg IV, 5 mg/kg IV, and 20 mg/kg IV) intravenously (N=13). | Posted | Mean | Standard Deviation | ml/day | Baseline through 24 weeks after L9LS product administration |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL/F) Following SC or IM Administration | Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each SC and IM group. Clearance following a SC or IM administration is calculated as Clearance (CL)/Bioavailability (F). | Population included participants who received either L9LS (5 mg/kg SC and 5 mg/kg IM) subcutaneously or intramuscularly (N=10). | Posted | Mean | Standard Deviation | ml/day | Baseline through 24 weeks after L9LS product administration |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss) Following IV Administration | Theoretical volume that would be necessary to contain the total amount of administered drug at the same concentration as observed in plasma. It represents the degree to which a drug is distributed in body tissue rather than the plasma and calculated based in the pharmacokinetic (PK) curve for each IV group. | Population included participants who received L9LS (1 mg/kg IV, 5 mg/kg IV, and 20 mg/kg IV) intravenously (N=13). | Posted | Mean | Standard Deviation | Liters | Baseline through 24 weeks after L9LS product administration |
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| Secondary | Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss/F) Following SC or IM Administration | Theoretical volume that would be necessary to contain the total amount of administered drug at the same concentration as observed in plasma. It represents the degree to which a drug is distributed in body tissue rather than the plasma and calculated based in the PK curve for each SC and IM group. Volume of distribution at steady-state (Vss) following a SC or IM administration is calculated as Volume of distribution at steady-state (Vss)/Bioavailability (F). | Population included participants who received either L9LS (5 mg/kg SC and 5 mg/kg IM) subcutaneously or intramuscularly (N=10). | Posted | Mean | Standard Deviation | Liters | Baseline through 24 weeks after L9LS product administration |
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| 0 |
| 5 |
| 0 |
| 5 |
| 4 |
| 5 |
| EG001 | Group 2: L9LS (5 mg/kg IV) | L9LS (5 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum | 0 | 4 | 0 | 4 | 3 | 4 |
| EG002 | Group 3: L9LS (5 mg/kg SC) | L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum | 0 | 5 | 0 | 5 | 5 | 5 |
| EG003 | Group 4: L9LS (20 mg/kg IV) | L9LS (20 mg/kg) administered by IV infusion (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum | 0 | 4 | 0 | 4 | 0 | 4 |
| EG004 | Group 5: CHMI Controls | Control participants who did not receive L9LS and were enrolled to complete the controlled human malaria infection (CHMI) Plasmodium falciparum (P. falciparum) sporozoite challenge: Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum | 0 | 6 | 0 | 6 | 1 | 6 |
| EG005 | Group 6: L9LS (5 mg/kg IM) | L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0) VRC-MALMAB0114-00-AB: VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein. | 0 | 5 | 0 | 5 | 2 | 5 |
| Constipation | Gastrointestinal disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Upper Respiratory Tract Infection | Infections and infestations | MedDRA 25.0 | Non-systematic Assessment |
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| Viral Infection | Infections and infestations | MedDRA 25.0 | Non-systematic Assessment |
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| Alanine Aminotransferase Increased | Investigations | MedDRA 25.0 | Non-systematic Assessment |
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| Blood Creatinine Increased | Investigations | MedDRA 25.0 | Non-systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Folliculitis | Infections and infestations | MedDRA 25.0 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Neuropathy Peripheral | Nervous system disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Laryngeal Pain | Respiratory, thoracic and mediastinal disorders | MedDRA 25.0 | Non-systematic Assessment |
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| Administration site pain | General disorders | MedDRA 25.0 | Systematic Assessment |
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| Administration site pruritus | General disorders | MedDRA 25.0 | Systematic Assessment |
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| Administration site erythema | General disorders | MedDRA 25.0 | Systematic Assessment |
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| Administration site bruise | General disorders | MedDRA 25.0 | Systematic Assessment |
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| Malaise | General disorders | MedDRA 25.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 25.0 | Systematic Assessment |
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| Chills | General disorders | MedDRA 25.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 25.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 25.0 | Systematic Assessment |
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Not provided
Not provided
Not provided
| D000079426 |
| Vector Borne Diseases |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Mild |
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| Moderate |
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| Severe |
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| Mild |
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| Moderate |
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| Severe |
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| Mild |
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| Moderate |
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| Severe |
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| Mild |
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| Moderate |
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| Severe |
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| Mild |
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| Moderate |
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| Severe |
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| Mild |
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| Moderate |
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| Severe |
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| Muscle Aches |
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| Headache |
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| Chills |
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| Nausea |
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| Joint Pain |
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| Temperature (Fever) |
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| Any Systemic Symptom |
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| Unrelated to Study Product |
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| Total Number of Participants who had One or More Non-Serious Unsolicited AE after L9LS |
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| Unrelated to CHMI |
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| Total Number of Participants who had One or More Non-Serious Unsolicited AE after CHMI |
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| Creatinine |
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| Number of Participants with one or more Abnormal Laboratory Results AE Related to Study Product |
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| Number of Participants with one or more Abnormal Laboratory Results AE Unrelated to Study Product |
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| Total Number of Participants who had Any Abnormal Laboratory Results Reported as AEs |
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