Experience design and participants
VRC 614 was a Phase I, open-label, dose-escalation clinical trial. The primary objectives of the trial were to evaluate the safety and side effects of L9LS given at intravenous doses of 1, 5 and 20 mg per kg of body weight and at a subcutaneous dose of 5 mg per kg. Secondary objectives were to evaluate 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 18 and 50 years of age who had never had malaria or had received a malaria vaccine. Full details of the inclusion and exclusion criteria are provided in the protocol, which is available with the full text of this article at NEJM.org.
The trial was designed, funded and conducted by the Center for Vaccine Research, the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health (NIH) at the NIH Clinical Center in Bethesda, Maryland. Controlled human malaria infections were conducted at a US Army facility at the Walter Reed Military Research Institute in Silver Spring, Maryland. The National Institutes of Health 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 to protect human research participants. Data were collected and analyzed by the Center for Vaccine Research and Walter Reed Army Research Institute. All authors undertake the accuracy and completeness of the data and analyzes and adherence of the experiment to the protocol.
L9LS, a human IgG1 monoclonal antibody produced according to current Good Manufacturing Practices by expressing cell culture in a recombinant Chinese hamster ovary cell line, is composed of a purified synthesized L9LS glycoprotein. The analytical processes and methods have been developed in the Vaccine Research Center’s Vaccine Production Program and transferred to the Vaccine Clinical Materials Program, which operates under contract with Leidos Biomedical Research in Frederick, Maryland, to produce cGMP and packaged in a concentration buffered formulation. 150 mg per milliliter.
L9LS was administered intravenously over 30 minutes at a dose of 1 mg per kg of body weight, 5 mg per kg, or 20 mg per kg. Participants who received subcutaneous injections received 5 mg per kg, with the total dose divided into one or two injections, not exceeding 2.0 mL each, depending on the participant’s weight. Most injections were abdominal, but the upper arm may be used if preferred by the participant and clinicians. Participants were observed in the clinic for one to two hours after taking L9LS.
Interim safety data reviews were conducted to assess any dose-related safety concerns prior to escalation to doses of 5 mg per kg and 20 mg per kg. Unwanted adverse events were recorded 28 days after administration of L9LS and controlled human malaria infection and were classified according to a modified section of the acquired immunodeficiency syndrome table to classify the severity of adverse events in adults and children.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 up for 7 weeks after infection with controlled human malaria.
Control of human malaria infection
Participants were exposed to roosters on the forearm of Anopheles Stephensi infected mosquito Plasmodium falciparum (3D dynasty7). Participants fulfilled standard infection criteria consisting of five eligible mosquito bites with a salivary gland score of 2 or more (scores ranged from 0 to 4, with higher scores indicating more microscopically observed spores).15th Participants were assessed by two phone calls in the first 7 days after infection with controlled human malaria, followed by visits in the clinic on days 7–17 and on day 21 for parasitaemia evaluation using a specific and highly sensitive polymerase chain. Polymerase chain reaction (PCR) test for early blood-stage malaria infection.15-17 Day 21 was chosen as the upper end of the pool of evaluation days in order to reduce the risk of exposure to MERS-CoV 2019 while ensuring adequate time for evaluation of parasitemia in the blood.
The parasitemia was defined as a single positive PCR result. Participants were considered protected if parasitemia did not develop during day 21 after controlled human malaria infection. Direct observational treatment was started with standard treatment of 1 g of atovaquone and 400 mg of proguanil hydrochloride for 3 consecutive days in all participants either when parasites were confirmed in the blood or on day 21 if the participant had not already been treated.
Serum L9LS concentrations were quantified using the autologous anti-L9LS antibody on the Meso Scale Discovery platform, as described previously, at predetermined time points up to 8 weeks after monoclonal antibody administration.3 Pharmacokinetic analysis of L9LS concentrations was performed with both partial and non-partial approaches. Descriptive statistics of maximum serum concentration (C .).the above) and maximum concentration time (T .).the above), along with the concentrations on experiment days 28 and 56, were calculated based on the observed data. The area under the curve was calculated using the linear trapezoid method. Additional details of the method for quantification and pharmacokinetic analysis are described in the Supplementary Methods section of the Supplementary Appendix, available at NEJM.org.
The target sample size was determined on the basis of the probability of observing serious adverse events. The efficacy analysis included all enrolled participants who underwent a controlled human malaria infection. Primary efficacy analysis was performed using Bernard’s two-sided test in which the percentage of participants with malaria infection among those who received L9LS was compared with the percentage among control participants. Secondary efficacy analysis was based on the time required for infiltration. Kaplan-Meier curves were presented for each group and compared using the rank scoring test. To assess the comparability of the challenge between the treatment and control groups, the mean and interquartile ranges of salivary gland scores were reported for each group. Because of the exploratory nature of the trial, no adjustment for plurality was made.
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