Low-dose subcutaneous or intravenous monoclonal antibody to prevent malaria

Trial design and participants

VRC 614 was a Phase 1, open-label, escalation clinical trial. The primary objectives of the trial were to assess the safety and side effect profile of L9LS administered at intravenous doses of 1, 5, and 20 mg per kilogram of body weight and at a subcutaneous dose of 5 mg per kilogram. Secondary objectives were to assess the pharmacokinetic properties and protective efficacy of L9LS after controlled human malaria infection approximately 2 to 6 weeks after participants received L9LS.

Eligible participants were healthy adults between the ages of 18 and 50 who had not had malaria or received a previous malaria vaccine. Full details of the inclusion and exclusion criteria are provided in the protocol, available with the full text of this article at NEJM.org.

test supervision

The trial was designed, funded, and conducted by the Center for Vaccine Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), at the NIH Clinical Center in Bethesda, Maryland. Controlled human malaria infection was carried out at the US Army facility at the Walter Reed Army Research Institute in Silver Spring, Maryland. The NIH Institutional Review Board approved the clinical trial protocol. All participants gave their written informed consent and the trial followed the Department of Health and Human Services guidelines for the protection of human research participants. The data was collected and analyzed by the Vaccine Research Center and the Walter Reed Army Research Institute. All authors guarantee the accuracy and integrity of the data and analysis and the adherence of the trial to the protocol.

test product

L9LS, a human IgG1 monoclonal antibody that was produced in accordance with current good manufacturing practices by cell culture expression in a recombinant Chinese hamster ovary cell line, consists of formulated and purified L9LS glycoprotein. Analytical processes and methods were developed at the Vaccine Research Center’s Vaccine Production Program and transferred to the Vaccine Clinical Materials Program, operated under contract to Leidos Biomedical Research in Frederick, Maryland, for current best practice production manufacturing and packaging in a buffered formulation at a concentration of 150 mg per milliliter.

Test Procedures

L9LS was administered intravenously over a 30-minute period at a dose of 1 mg per kilogram of body weight, 5 mg per kilogram, or 20 mg per kilogram. Participants receiving subcutaneous injections received 5 mg per kilogram, with the total dose divided into one or two injections, not to exceed 2.0 mL each, depending on the participant’s weight. Most of the injections were abdominal, but the participant and doctor could use the upper arm if they preferred. Participants were observed in the clinic for 1 to 2 hours after L9LS administration.

Interim safety data reviews were conducted to assess any dose-related safety concerns before escalation to 5 mg per kilogram and 20 mg per kilogram doses. Unsolicited adverse events were recorded for 28 days after L9LS administration and controlled human malaria infection and were graded according to a modified Division of Acquired Immunodeficiency Syndrome table for grading the severity of adverse events in adults. and kids.14 Serious adverse events and new chronic medical conditions were recorded throughout the duration of the trial.

Participants were followed for 24 weeks after L9LS administration. Control participants were followed for 7 weeks after controlled human malaria infection.

Controlled human malaria infection

Participants were exposed to bites to the forearm of Anopheles stephensi mosquitoes infected with Pfalciparum (3D7 strain). Participants met standard criteria for infectivity consisting of five rated mosquito bites with a salivary gland score of 2 or more (scores range from 0 to 4, with higher scores indicating more sporozoites observed microscopically).fifteen Participants were assessed by means of two telephone calls in the first 7 days after controlled human malaria infection, followed by clinic visits on days 7 to 17 and day 21 to assess parasitaemia with a highly sensitive polymerase chain. and specific. reaction test (PCR) to detect early-stage malaria infection in blood.15-17 Day 21 was chosen as the upper end of the testing day range to minimize the risk of exposure to coronavirus disease 2019 while ensuring sufficient time to test for parasitaemia.

Parasitaemia was defined as a single positive PCR result. Participants were considered protected if parasitaemia did not develop until day 21 after controlled human malaria infection. Directly observed therapy with standard treatment of atovaquone 1 g and proguanil hydrochloride 400 mg for 3 consecutive days was started in all participants, either on confirmation of parasitaemia or on day 21 if the participant had not yet been treated.

Pharmacokinetics

Serum concentrations of L9LS were quantified using an anti-idiotype L9LS antibody on the Meso Scale Discovery platform, as described above, at prespecified time points up to 8 weeks after monoclonal antibody administration.3 Pharmacokinetic analysis of L9LS concentrations was performed with compartmental and non-compartmental approaches. Descriptive statistics of the maximum serum concentration (Cmaximum) and for the time of maximum concentration (Tmaximum), together with the concentrations on days 28 and 56 of the trial, were calculated based on the observed data. The area under the curve was calculated using the linear trapezoid method. Additional details of the quantitation method and pharmacokinetic analysis are described in the Supplementary Methods section in the Supplementary Appendix, available at NEJM.org.

Statistic analysis

The target sample size was determined based on the probability of observing serious adverse events. The efficacy analysis included all enrolled participants who underwent controlled human malaria infection. The main efficacy analysis was performed using a two-sided Barnard’s test comparing the percentage of participants who had malaria infection among those who had received L9LS with the percentage among control participants. Secondary efficacy analysis was based on time to parasitaemia; Kaplan-Meier curves for each group were provided and compared using a log-rank test. To assess challenge comparability between treatment and control groups, median and interquartile ranges of salivary gland scores were reported for each group. Due to the exploratory nature of the trial, no adjustment for multiplicity was made.

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