Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial

Abstract

Background: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS.

Methods: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332.

Findings: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection.

Interpretation: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases.

Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Figure 1:. VRC 612 Part C Trial CONSORT Diagram.

Participants were enrolled according to dose-escalation protocol starting with the lowest dose group of 1 mg/kg IV. Of the 31 participants enrolled in Part C, 22 received one dose of CIS43LS and 8 were assigned to the control group and did not receive CIS43LS. One participant in the 10 mg/kg IV CIS43LS group withdrew consent prior to receiving CIS43LS due to a new medical diagnosis. 28 participants underwent controlled human infection in November 2021: 22 of these participants had received CIS43LS and 6 were control participants (the other 2 control participants were enrolled as back-ups and were not needed). One participant in the 10 mg/kg IV CIS43LS group withdrew consent after Controlled Human Malaria Infection (CHMI) but prior to follow-up completion due to personal reasons. All other participants completed follow-up visits. IV denotes intravenous, and SC subcutaneous route of CIS43LS administration.

Figure 2:. Maximum local and systemic solicited reactogenicity.

Percent of participants (x-axis) who reported a local or systemic symptom (y-axis) in the seven days following product administration. There were no reported local symptoms of bruising or swelling, or systemic symptoms of chills or elevated temperature for any participant following administration.

Figure 3:. Serum concentrations of CIS43LS.

Geometric mean serum concentrations with standard deviations (indicated by bars) are displayed for each study group after a single administration of CIS43LS at Day 0. The dose and route of administration for each group is specified in the key. IV denotes intravenous, and SC subcutaneous route of CIS43LS administration. Vertical dotted line indicates CHMI that occurred on November 21, 2022. Time from CIS43LS administration to the date of CHMI for all study participants was between 54 to 56 days, with the exception of one study participant in 10 mg/kg IV group which was 48 days.

Figure 4:. Parasitemia after Controlled Human Malaria Infection.

Kaplan-Meier analysis showing the time to parasitemia as measured by PCR. KP curves are provided for each arm. Note that one participant in the 10 mg/kg IV group (orange) withdrew at day 14 prior to completion of follow up. The proportion of infected subjects of all mAb treated recipients versus controls has a p value of 0·0005 by the Barnard test. Comparison of the 1 mg/kg IV recipients with controls gives p value of 0·10 with Barnard test.