Trial to Evaluate CIS43LS in Healthy Adults

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.

• INCLUSION CRITERIA:

• 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 (for all groups except Groups 5, 10, and 16) and < 100 kg for Group 15
• 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 4B)
• Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 4B)
• Agrees not to travel to a malaria endemic region during the entire course of study participation

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 prior to enrollment:

• Negative sickle cell screening test
• Negative troponin test (except Group 4B)
• 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)
• 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:

• 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:

• Woman who is breast-feeding or planning to become pregnant during study participation
• Previous receipt of a malaria vaccine
• History of malaria infection
• History of severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) defined per FDA guidance
• Active SARS-CoV-2 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 (note: Emergency Use Authorization Coronavirus Disease 2019 (COVID-19) vaccine is not exclusionary)
• Receipt of any live attenuated vaccines within 28 days prior to enrollment
• 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 4B)
• Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 4B)
• Use or planned use of any drug, including antibiotics, with antimalarial activity within 4 weeks prior to CHMI
• History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 4B)
• 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)
• 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