Low-dose subcutaneous or intravenous monoclonal antibody for malaria prophylaxis

Trial design and participants

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

Eligible participants were healthy individuals between 18 and 50 years of age who had no history of malaria or received a malaria vaccine. Details of inclusion and exclusion criteria are provided in the protocol, which is available with the full text of this article at NEJM.org.

Judicial review

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 infections were conducted at the US Army Walter Reed Army Institute of Research in Silver Spring, Maryland. The NIH Institutional Review Board approved the clinical trial protocol. All participants provided written informed consent and followed Department of Health and Human Services guidelines for the protection of human subjects. The data was collected and analyzed by the Vaccine Research Center and the Walter Reed Army Institute of Research. All authors vouch for the accuracy and completeness of the data and analyses, as well as protocol compliance of the trial.

Test product

L9LS, an IgG1 monoclonal antibody produced according to current good manufacturing practices by cell culture expression in a recombinant Chinese hamster ovary cell line, consists of a purified formulation of the human L9LS glycoprotein. Processes and analytical methods were developed at the Vaccine Research Center’s Vaccine Manufacturing Program and transferred to the Vaccine Clinical Materials Program, which contracts with Leidos Biomedical Research in Frederick, Maryland, to produce current good manufacturing practices and infuse in buffered concentrations. 150 mg per milliliter.

Court proceedings

L9LS was administered intravenously over 30 minutes at doses of 1 mg/kg body weight, 5 mg/kg body weight, or 20 mg/kg body weight. Participants receiving subcutaneous injections received 5 mg per kilogram, with a total dose divided into one or two injections of no more than 2.0 mL each, depending on the participant’s weight. Most injections were abdominal, but the upper arm could be used at the discretion of the participant and clinician. Participants were observed in the clinic for 1-2 hours after receiving the L9LS.

Interim safety data reviews were conducted to assess dose-related safety concerns prior to escalation to doses of 5 mg/kg and 20 mg/kg. Unsolicited adverse events were assessed for 28 days after administration of L9LS and the modified Immune Deficiency Syndrome Section for the Severity of Adverse Events in adults and pediatric subjects with reported malaria infection.14 Serious adverse events and new chronic medical conditions were recorded for the duration of the trial.

Participants were followed for 24 weeks after L9LS administration. Control participants were followed for 7 weeks after exposure to human malaria.

Human malaria infection is controlled

Participants were exposed to hand stings anopheles stephensi infected mosquitoes P. falciparum (strain 3D7). Participants met standard infectious criteria consisting of five qualified mosquito bites with a salivary gland score of 2 or greater (scores range from 0 to 4, with higher scores indicating microscopically detectable sporozoites).15 Participants were assessed by two telephone calls within the first 7 days after a controlled human malaria infection, followed by clinic visits on days 7–17 and day 21 and parasitemia assessed by highly sensitive and specific polymerase chain reaction. Reaction (PCR) test to detect primary blood malaria infection.15-17 Day 21 was chosen as the upper limit of assessment days to minimize the risk of exposure to 2019 coronavirus disease by providing sufficient time to assess parasitemia.

Parasitaemia was defined as a positive PCR result. Participants were considered protected if parasitaemia did not develop until day 21 after controlled human malaria infection. In all participants, direct observational therapy with standard treatment of 1 g of atovaquone and 400 mg of proguanil hydrochloride for 3 consecutive days was initiated after confirmation of parasitemia or on day 21 if the participant was previously untreated.

Pharmacokinetics

Serum concentrations of L9LS were measured at prespecified time points up to 8 weeks after monoclonal antibody administration using the anti-idiotypic L9LS antibody on the Meso Scale Discovery platform as previously described.3 Pharmacokinetic analysis of L9LS concentrations was performed using compartmental and non-compartmental methods. Descriptive statistics of maximum serum concentration (Cmax) and for the moment of maximum concentration (Tmax), were calculated based on the observed data together with the concentrations on test days 28 and 56. The area under the curve was calculated using the linear trapezoidal method. Additional details on the quantification method and pharmacokinetic analysis are described in the Supplemental Methods section of the Supplementary Appendix, available at NEJM.org.

Statistical analysis

The target sample size was determined based on the probability of observing serious adverse events. Efficacy analysis included all enrolled participants with control of human malaria infection. The primary efficacy analysis was performed using a two-tailed Barnard test comparing the percentage of participants with malaria infection among those receiving L9LS with the percentage of control participants. Mean efficacy analysis was based on time to parasitaemia; Kaplan-Meier curves were presented for each group and compared using the log-rank test. To assess comparability of problem 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 corrections were made to the large number.

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