The National Institutes of Health (NIH) announces single injection of monoclonal antibody against the Plasmodium mosquito-borne parasite prevented malaria throughout 9 month phase 1 trial.
The NIH has announced development of a long-acting monoclonal antibody (MAB) against the mosquito-borne Plasmodium parasite by its Vaccine Research Center (VRC) at the National institute of Allergy and Infectious Diseases (NIAID); and phase 1 trial findings of its safety and efficacy in preventing malaria after controlled infection.
"Malaria continues to be a major cause of illness and death in many regions of the world, especially in infants and young children; therefore, new tools are needed to prevent this deadly disease," NIAID Director Anthony Fauci, MD, stated.
Malaria vaccines that have completed phase 3 testing provide no more than 50% protection from the disease over the course of a year or longer, according to the NIH announcement.
"The results reported today suggest that a single infusion of a monoclonal antibody can protect people from malaria for at least 9 months," Fauci indicated. "Additional research is needed, however, to confirm and extend this finding."
Robert Seder, MD, chief, Cellular Immunology Section of the VRC Immunology Laboratory, and colleagues developed the MAB, CIS43LS, by modifying the antibody CIS43 isolated from blood of a volunteer participating in a malaria vaccine trial. The investigators determined that CIS43 binds to a novel site of vulnerability on the circumsporozoite protein on the surface of P falciparum, which is distinct from previously targeted, and is present across P falciparum isolates.The circumsporozoite protein is critical to motility of the parasite, and successful antigenic binding can neutralize its capacity to invade hepatocytes, continue its lifecycle and fulminate malaria.
The phase 1, first-in-human trial of CIS43L, led by Martin Gaudinski, MD, Medical Director, VRC Clinical Trials Program, was conducted in two stages; with stage 1 establishing safety of different dosages, and stage 2 testing efficacy of a single dose to prevent malaria in participants receiving controlled infection. The controlled human malaria infection (CHMI), which has previously been used to test anti-malaria drug and vaccine candidates, involves exposure of the forearm to 5 bites from Anopheles stephensi mosquitoes infected with P falciparum, frequent outpatient monitoring, and directly observed treatment at the time of confirmed parasitemia.
In stage 1, 25 healthy participants who never had malaria received CIS43LS subcutaneously or intravenously at a dose of either 5mg/kg, 20mg/kg or 40mg/kg, with elevated doses administered to participants after observation of those who had received lower doses. Four of the 25 received an additional dose of 20mg/kg.The investigators found dose-dependent increases in CIS43LS serum concentration with a half-life of 56 days, and without safety concerns.
Noting that the 56 day half-life is longer than the average 21-day physiologic half-life of human IgG, Gaudinski and colleagues suggest,"CIS43LS displayed a pharmacokinetic profile aligned with potential clinical use across a variety of settings."
In the second stage, 9 of these participants underwent CHMI, along with 6 volunteers who did not receive the MAB to serve as controls.The investigators reported that none of the 9 participants who received CIS43LS had parasitemia through 21 days after CHMI, compared with 5 of 6 control participants who did contract parasitemia.Two of the participants exposed to CHMI who had received 40mg/kg of CIS43LS were negative for parasitemia at 36 weeks.
"Monoclonal antibodies may represent a new approach for preventing malaria in travelers, military personnel and health care workers traveling to malaria-endemic regions," Seder commented.
Concurring with Fauci on the importance of expanding testing, and anticipating results from a phase 2 trial that is underway, Seder added, "further research will determine whether monoclonal antibodies can also be used for the seasonal control of malaria in Africa and ultimately for malaria-elimination campaigns."
The phase 2 trial of CIS43LS is being conducted in a real-world setting during the six-month malaria high season in Mali. That trial is under the direction of Peter Crompton, MD, MPH, chief of the Malaria Infection Biology and Immunity Section in the NIAID Laboratory of Immunogenetics, and Kassoum Kayentao, MD, MPH, PhD, University of Sciences, Techniques and Technologies of Mamako, Mali. Their results are anticipated by early 2022, according to the NIH announcement,