Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria

Abstract

Background: New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed.

Methods: We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain).

Results: No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (C_max) of 914.2±146.5 μg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean C_max of 41.5±4.7 μg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean C_max was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 μg per milliliter.

Conclusions: In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).

Figure 1.. Enrollment, Administration of L9LS, and Controlled Human Malaria Infection.

Trial enrollment occurred from September 13 to October 25, 2021. Controlled human malaria infection occurred on October 26, 2021. All participants who received L9LS were followed for 24 weeks after administration of L9LS. Control participants were followed for 7 weeks after controlled human malaria infection (CHMI).

Figure 2.. Maximum Local and Systemic Solicited Reactogenicity.

The percentage of participants who reported a mild or moderate local or systemic symptom in the 7 days after administration of L9LS intravenously (IV) or subcutaneously (SC) is shown. After administration of L9LS, none of the participants reported systemic symptoms of myalgia or fever or the local symptom of swelling.

Figure 3.. Serum Concentrations of L9LS.

Panel A shows the geometric mean serum concentrations of L9LS with 95% confidence intervals (indicated by I bars) for each dose group after administration of a single dose of L9LS. Panel B shows the serum concentrations of L9LS over time in individual trial participants who underwent CHMI. Individual horizontal dotted lines with open circles indicate malaria infection (in one participant who received 1 mg per kilogram intravenously and in one participant who received 5 mg per kilogram subcutaneously).

Figure 4.. Predictions for Serum Concentrations after Intravenous or Subcutaneous Administration of L9LS.

Panels A and B show pharmacokinetic modeling for intravenous and subcutaneous administration of L9LS. Observed L9LS concentrations (normalized for each dose administered intravenously or subcutaneously) are overlayed for the comparison. The predicted median serum concentrations of L9LS (solid lines) and 90% prediction intervals (5th and 95th percentiles) (dashed lines) are shown. Panels C and D show the predicted median L9LS serum concentrations (solid lines) 48 weeks after administration of a single dose according to intravenous dose groups (1 mg per kilogram, 5 mg per kilogram, and 20 mg per kilogram) and the subcutaneous dose group (5 mg per kilogram) with 90% prediction intervals (5th and 95th percentiles) (dashed lines). Values were calculated on the basis of Monte Carlo simulations with the use of a population pharmacokinetic model.

Figure 5.. Parasitemia after Controlled Human Malaria Infection.

A Kaplan–Meier analysis shows the time to blood-stage parasitemia as measured by polymerase-chain-reaction analysis. Participants were monitored daily starting on day 7 after controlled human malaria infection through day 17, with a final test performed on day 21. A primary efficacy analysis performed with the use of a two-sided Barnard test comparing parasitemia among the participants who received L9LS with that among the control participants yielded a P value of less than 0.001.