Trial to Evaluate L9LS in Healthy Adults

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

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:

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

Exclusion criteria

A volunteer would have been excluded if one or more of the following conditions applied:

• Woman who is breast-feeding or planning to become pregnant during study participation
• Previous receipt of a malaria vaccine or anti-malaria monoclonal antibody
• History of malaria infection
• 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
• Hypertension that is not well controlled
• Receipt of any investigational study product within 28 days prior to enrollment/product administration (Note: SARS-CoV-2 vaccines approved by emergency use authorization are not exclusionary)
• Receipt of any live attenuated vaccines within 28 days prior to enrollment/product administration
• Receipt of any vaccine within 2 weeks prior to enrollment/product administration
• 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
• History of a splenectomy, sickle cell disease or sickle cell trait
• History of skeeter syndrome or anaphylactic response to mosquito-bites (except Group 6)
• Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 6)
• Use or planned use of any drug with antimalarial activity that would coincide with study product or CHMI (except Group 6)
• History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 6)
• Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin
• History of Sjogren's Syndrome
• History of chronic or recurrent salivary gland disorder diagnosed by a clinician (note: an isolated occurrence of parotitis, sialadenitis, sialolithiasis, or of a salivary gland tumor is not exclusionary)
• History of therapeutic head or neck radiation
• 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, infectious diseases, psychiatric disorders, heart disease, or cancer