Subcutaneous or low-dose intravenous monoclonal antibody to prevent malaria
Trial design and participants
VRC 614 was a Phase 1, open-label, dose-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 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 never had malaria or received a malaria vaccine. Full details of inclusion and exclusion criteria are provided in the protocol, available with the full text of this article on NEJM.org.
Supervision of trials
The trial was designed, funded and conducted by the Vaccine Research Center, 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 conducted at US Army facilities at the Walter Reed Army Research Institute in Silver Spring, Maryland. The NIH Institutional Review Board approved the clinical trial protocol. All participants provided written informed consent and the trial followed Department of Health and Human Services guidelines for the protection of human participants in research. 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 analyzes and for the trial’s adherence to protocol.
L9LS, a human IgG1 monoclonal antibody that was produced according to current good manufacturing practices by cell culture expression in a recombinant Chinese hamster ovary cell line, consists of purified and formulated L9LS glycoprotein. Processes and analytical methods were developed at the Vaccine Research Center’s Vaccine Production Program and transferred to the Vaccine Clinical Materials Program, operated under contract with Leidos Biomedical Research in Frederick, Maryland, for production and implementation. in a vial of current good manufacturing practice in a buffered formulation at a concentration of 150 mg per milliliter.
L9LS was administered intravenously over 30 minutes at a dose of 1 mg per kilogram body weight, 5 mg per kilogram, or 20 mg per kilogram. Participants who received subcutaneous injections received 5 mg per kilogram, with the total dose divided into one or two injections, not exceeding 2.0 ml each, depending on the weight of the participant. Most injections were abdominal, but the upper arm could be used if the participant and clinician preferred. Participants were observed in the clinic for 1-2 hours after L9LS administration.
Interim safety data reviews were conducted to assess any dose-related safety issues prior to escalation to doses of 5 mg per kilogram and 20 mg per kilogram. Unsolicited adverse events were recorded for 28 days after L9LS administration and controlled human malaria infection and were categorized according to a modified Acquired Immune Deficiency Syndrome Division table for adverse event severity classification in adults and children.14 Serious adverse events and new chronic medical conditions were recorded throughout the trial.
Participants were followed for 24 weeks after L9LS administration. Control participants were followed for 7 weeks after controlled human malaria infection.
Human malaria infection controlled
Participants were exposed to bite wounds on the forearm of Anopheles stephensi mosquitoes infected with P. falciparum (strain 3D7). Participants met standard infectivity criteria consisting of five qualifying mosquito bites with a salivary gland score of 2 or greater (scores range from 0 to 4, with higher scores indicating more sporozoites observed under the microscope).15 Participants were assessed with two phone calls within the first 7 days of controlled human malaria infection, followed by clinic visits on days 7-17 and day 21 to assess parasitaemia with a highly sensitive polymerase chain and specific. reaction test (PCR) to detect early malaria infection in the blood stage.15-17 Day 21 was chosen as the upper end of the assessment day range to minimize the risk of exposure to coronavirus disease 2019 while ensuring sufficient time to assess 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 a standard course of 1 g atovaquone and 400 mg proguanil hydrochloride for 3 consecutive days was initiated in all participants either upon confirmation of parasitaemia or on day 21 if the participant did not. had not already been processed.
Serum L9LS concentrations were quantified using an anti-idiotype L9LS antibody on the Meso Scale Discovery platform, as previously described, at predefined time points up to 8 weeks after antibody administration. monoclonal.3 Pharmacokinetic analysis of L9LS concentrations was performed with compartmental and non-compartmental approaches. Descriptive statistics of maximum serum concentration (Cmaximum) and for the time of maximum concentration (Tmaximum), as well as the concentrations on test days 28 and 56, were calculated on the basis of the observed data. The area under the curve was calculated using the linear trapezium method. Additional details on the quantitation method and pharmacokinetic analysis are described in the Additional Methods section of the Supplementary Appendix, available at NEJM.org.
The target sample size was determined based on the probability of observing serious adverse events. The efficacy analysis included all enrolled participants who experienced controlled human malaria infection. The primary efficacy analysis was performed using a two-tailed Barnard test in which the percentage of participants who had malaria infection among those who received L9LS was compared to the percentage among control participants. Secondary efficacy analysis was based on time to parasitaemia; Kaplan-Meier curves were provided for each group and compared using a log-rank test. To assess the comparability of provocation 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 was made for multiplicity.