Trial Outcomes & Findings for L9LS MAb in Malian Infants (NCT NCT06461026)

327 participants were screened to participate in the study * 96 screen failure * 40 were backup * 11 participants withdrew prior to start of study * 180 participants were randomized One participant did not receive three doses of the R21/Matrix-MTM vaccine but completed the study

L9LS MAb in Malian Infants

Number of participants with local adverse events occurring within 7 days after administration of L9LS or placebo intervention. Local reactogenicity included pain/tenderness, swelling, redness, bruising, and pruritus at the site of infusion. Adverse events were captured by Investigator examination and history from participants.

The severity of local AEs was graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Clinical Trials. Grade 1: Pain = does not interfere with activity; Tenderness = mild discomfort to touch; Erythema/Redness = 2.5-5 cm; Induration/Swelling = 2.5-5 cm and does not interfere with activity Grade 2: Pain = Repeated use of non-narcotic pain reliever \> 24 hours or interferes with daily activity; Tenderness=Discomfort with movement; Erythema/Redness = 5.1-10 cm; Induration/Swelling = 5.1-10 cm and interferes with activity Grade 3: Pain = Any use of narcotic pain reliever or prevents daily activity; Tenderness = Significant discomfort at rest; Erythema/Redness = \> 10 cm; Induration/Swelling = \> 10 cm or prevents daily activity Grade 4: Pain = Emergency room (ER) visit or hospitalization; Tenderness = ER visit or hospitalization; Erythema/Redness = Necrosis or exfoliative dermatitis; induration/Swelling = Necrosis Grade 5: Death

Number of participants with local adverse events occurring within 7 days after administration of L9LS or placebo intervention. Systemic reactogenicity events included fever, feeling unusually tired or unwell, muscle aches, headache, chills, nausea, and joint pain. Adverse events were captured by Investigator examination and history from participants.

The severity of systemic AEs after the administration of L9LS or placebo was assessed using the grading scale below: Grade 1: Fever = 37.5\^oC-37.9\^oC; Fatigue, Headache, Myalgia = No interference with activity; Nausea = no interference with activity or 1-2 episodes/hour Grade 2: Fever = 38\^oC-38.4\^oC; Fatigue, Myalgia = Some interference with activity; Headache = Repeated use of non-narcotic pain reliever \> 24 hours or some interference with activity; Nausea = Some interference with activity or \> 2 episodes/24 hours Grade 3: Fever = 38.5\^oC-39.5\^oC; Fatigue = Prevents daily activity; Headache =Significant; any use of narcotic pain reliever or prevents daily activity; Myalgia =Significant; prevents daily activity; Nausea = Prevents daily activity, requires outpatient intravenous hydration Grade 4: Fever = \> 39.5\^oC; Fatigue, Headache, Myalgia = Emergency room (ER) visit or hospitalization; Nausea = ER visit or hospitalization for hypotensive shock Grade 5: Death

Number of participants with Adverse events of special interest (AESIs), which is described as hypersensitivity reaction within seven days of receiving each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196). Adverse events of special interest (AESIs) are study-specific events that are of particular concern due to population, study intervention, class effect, etc. A Type III hypersensitivity reaction associated with the administration of the R21/Matrix-MTM vaccine are characterized by symptoms such as fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea.

The severity of adverse events of special interest (AESIs) occurring within 7 days after administration of each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196) was graded using the table below. Participants with multiple episodes of same adverse event across grades were counted separately according to adverse event grade. Grade 1: Mild signs and symptoms Grade 2: Moderate signs and symptoms AND intervention indicated (e.g., antihistamines) Grade 3: Severe signs and symptoms AND higher level intervention indicated (e.g., steroids or IV fluids) Grade 4: Life-threatening consequences (e.g., requiring pressor or ventilator support)

The antibody response to the R21/Matrix-M was assessed as the total anti-Asn-Ala-Asn-Pro (anti-NANP) immunoglobulin G (IgG) ((anti-NANP IgG)) antibody titers. The total IgG anti-NANP antibody titers was measured by electrochemiluminescence immunoassay (ECLIA), using the Meso Scale Discovery LLC-based automation platform on serum samples collected 28 days (day 224) and 84 days (day 280) after the third dose of R21/Matrix-MTM vaccination. Outcomes analyzed as concentration of antibody titers of the polyclonal antibody response in a serum sample. Concentration is expressed in arbitrary units per milliliter (AU/mL), which are assigned based on a sample's relative binding as compared to an established serum reference standard.

Maximum total plasma concentration (Cmax) following a dose of 150 mg L9LS. Serum was collected on days 0, 7, 28, 84, 140, 196, and 280 after the administration of L9LS. Cmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles post dose. Analysis was done to determine each participant's maximum observed concentration based on all available data points and cumulative output was calculated as the central tendency and dispersion metric based on the observed maximum concentrations.

Time to maximum total plasma concentration (Tmax) following a dose of 150 mg or 300 mg L9LS. Serum was collected on days 0, 7, 28, 84, 140, 196, \& 280 after administration of L9LS. Tmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles. Analysis was done to determine the time (in days) at which the maximum observed concentration was achieved for each participant and cumulative output was calculated as the central tendency and dispersion metric based on the observed time of maximum concentration.

Plasma area under the concentration time curve (AUC) for L9LS from day 0 to day 168. Data for day 168 was interpolated using observed concentrations. Non-compartmental analysis was performed using the linear-up/log-down trapezoidal rule with the PKNCA package in R.

The area under the concentration time curve from day 0 to the last observed concentration (in days) was calculated using the linear-up/log-down trapezoidal rule by non-compartmental analysis with the PKNCA package in R.

The area under the concentration time curve (AUC) from day 0 to infinity, extrapolated from the last observed concentration, was calculated using the linear-up/log-down trapezoidal rule by non-compartmental analysis with the PKNCA package in R.

The terminal half-life was determined by non-compartmental analysis using the PKNCA package in R, which fits the natural logarithm of concentration by time using a minimum of four observed data points in the terminal phase, not including the maximum total plasma concentration (Cmax).

Number of participants with Plasmodium falciparum (Pf) blood stage infection defined as blood smear-positive for Pf was assessed by microscopic examination of thick blood smear collected at various time points (day 7, 28, 84, 140, 196, 224, and 280) from participants from day 7 through day 280 after administration of L9LS or placebo. Analysis was done as number of participants who had at least one positive blood smear.