A Monoclonal Antibody for Malaria Prevention

Abstract

Background: Additional interventions are needed to reduce the morbidity and mortality caused by malaria.

Methods: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS.

Results: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection.

Conclusions: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Copyright © 2021 Massachusetts Medical Society.

Figures

Figure 1. Participants and Administration of CIS43LS.

The VRC 612 trial was conducted in two parts. Because of restrictions related to coronavirus disease 2019, the controlled human malaria infection that was originally planned for Part A was canceled, and the trial was modified. Of the 18 participants enrolled in Part B, 15 underwent controlled infection in month 10 (October 2020): 9 of these participants had received CIS43LS and 6 were control participants.

Figure 2.. Serum Concentrations of CIS43LS.

Panel A shows the mean serum concentrations of CIS43LS among participants in Part A. The geometric mean titers with standard deviations (indicated by I bars) are shown for each dose group after a single administration of CIS43LS (at week 0). The dose, route (intravenous [IV] or subcutaneous [SC]), and number of participants are specified in the key. Panel B shows the serum concentrations of CIS43LS across Parts A and B over time for individual participants who underwent controlled human malaria infection. Controlled infection in Part A had been planned for March 17, 2020, but was canceled. Participants underwent controlled infection in Part B on October 20, 2020.

Figure 3.. Predictions for Serum Concentrations after Intravenous Administration of CIS43LS.

Panels A, B, and C show the predicted median serum concentrations of CIS43LS (solid black lines) and 90% prediction intervals (5th to 95th percentiles [dashed black lines]) according to CIS43LS dose group. Values were calculated on the basis of Monte Carlo simulations with the use of a population pharmacokinetic model. The dose groups reflect administration of CIS43LS at 5 mg per kilogram of body weight (Panel A), 20 mg per kilogram (Panel B), and 40 mg per kilogram (Panel C). Observed CIS43LS concentrations (normalized for each of the respective doses) are overlayed for comparison (circles). Panel D shows the predicted median CIS43LS concentration after a hypothetical intravenous dose of 10 mg per kilogram (dashed gray line) as compared with those of the other doses used in the trial (solid lines).

Figure 4.. Parasitemia after Controlled Human Malaria Infection.

A Kaplan–Meier analysis shows the time to parasitemia as measured by polymerase-chain-reaction analysis. A log-rank test comparing parasitemia among the nine participants who received CIS43LS with that among the six control participants yielded a P value of 0.001.