A dose of an antibody drug safely protected healthy, non-pregnant adults from malaria infection during an intense six-month malaria season in Mali, Africa, a clinical trial from the National Institute of Health. The antibody was up to 88.2% effective in preventing infection over a 24-week period, demonstrating for the first time that a monoclonal antibody can prevent malaria infection in an endemic region. These findings were published today in The New England Journal of Medicine and presented at the 2022 annual meeting of the American Society of Tropical Medicine and Hygiene in Seattle.
We must expand the arsenal of interventions available to prevent malaria infection and accelerate efforts to eliminate the disease. These study results suggest that a monoclonal antibody could complement other measures to protect travelers and vulnerable groups, such as infants, children and pregnant women, from seasonal malaria and help eliminate malaria from defined geographic areas.”
Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases
NIAID sponsored and funded the trial, which was led by Peter D. Crompton, MD, MPH, and Kassoum Kayentao, MD, MPH, Ph.D. Dr. Crompton is chief of the Malaria Infection Biology and Immunity Section at NIAID’s Immunogenetics Laboratory, and Dr. Kayentao is a professor at the University of Sciences, Techniques and Technologies (USTTB) in Bamako, Mali.
An estimated 241 million cases of malaria occurred worldwide in 2020, according to the World Health Organization (WHO), resulting in approximately 627,000 deaths, most of them in children in sub-Saharan Africa. These cases involved more than 11 million pregnant women in Africa, resulting in an estimated 819,000 babies with low birth weight and therefore at increased risk of disease and death.
The only malaria vaccine currently recommended by WHO, called RTS,S (Mosquirix), provides partial protection against clinical malaria during the first years of life when given to children aged 5 to 17 months in four doses for a period of 20 months. Other drugs consisting of small chemical compounds that effectively prevent malaria infection are also available for infants and young children, as well as for travelers. The requirement for frequent dosing of these drugs may limit adherence, and the emergence of drug resistance may also limit their usefulness. . Therefore, there is an urgent need for novel, rapid-acting, infrequently dosed interventions that provide strong protection against malaria infection.
Malaria is caused by Plasmodium parasites, which are transmitted to people through the bite of an infected mosquito. The mosquito injects the parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply. The mature parasite then spreads throughout the body via the bloodstream to cause disease. P. falciparum is the Plasmodium species most likely to cause severe malaria infections, which, if not treated quickly, can lead to death.
The NIAID-USTTB Phase 2 trial evaluated the safety and efficacy of a single intravenous infusion of a monoclonal antibody called CIS43LS. This antibody has previously been shown to neutralize P. falciparum sporozoites in the skin and blood before they could infect liver cells. Researchers led by Robert A. Seder, MD, isolated a naturally occurring form of this antibody from the blood of a volunteer who had received an investigational malaria vaccine and then modified the antibody to extend how long it would remain in the bloodstream. Dr. Seder is the acting medical director and acting associate director of the NIAID Vaccine Research Center (VRC) and chief of the VRC’s Section of Cellular Immunology.
The study team for the Phase 2 trial enrolled 369 healthy, non-pregnant adults aged 18 to 55 years in the rural communities of Kalifabougou and Torodo in Mali, where intense transmission of P. falciparum typically takes place from July to December each year.
The first part of the trial evaluated the safety of three different doses of CIS43LS: 5 milligrams per kilogram of body weight, 10 mg/kg and 40 mg/kg, given by intravenous infusion in 18 study participants, with six participants per dose level. The study team followed these participants for 24 weeks and found that the antibody infusions were safe and well tolerated.
The second part of the trial evaluated the effectiveness of two different doses of CIS43LS compared to a placebo. Three hundred and thirty participants were randomly assigned to receive 10 mg/kg antibody, 40 mg/kg, or a placebo by intravenous infusion. No one knew who was assigned to which group until the end of the trial. The study team followed these individuals for 24 weeks, testing their blood for P. falciparum weekly for the first 28 days and then every two weeks. Any participant who developed symptomatic malaria during the trial received standard treatment from the study team.
The researchers analyzed the effectiveness of CIS43LS in two ways. Based on time to first P. falciparum infection during the 24-week study period, the high dose (40 mg/kg) of CIS43LS was 88.2% effective in preventing infection and the lower dose (10 mg/kg) was 75% effective. . An analysis of the proportion of participants infected with P. falciparum at any time during the 24-week study period found that the high dose was 76.7% to prevent infection and the lowest dose was 54.2 effective %
“These first field results demonstrating that a monoclonal antibody safely provides high-level protection against intense malaria transmission in healthy adults pave the way for further studies to determine whether this intervention can prevent infection of the malaria in infants, children and pregnant women,” said Dr. said Seder. “We expect monoclonal antibodies to transform malaria prevention in endemic regions.”
Dr. Seder and colleagues have developed a second antimalarial monoclonal antibody, L9LS, which is much more potent than CIS43LS and can therefore be given in a smaller dose as an injection under the skin (subcutaneous), rather than by intravenous infusion. An early-phase NIAID trial of L9LS in the United States found that the antibody was safe and prevented malaria infection for 21 days in 15 of 17 healthy adults exposed to P. falciparum in a carefully controlled setting. Two larger NIAID-sponsored Phase 2 trials evaluating the safety and efficacy of L9LS in infants, children, and adults are underway in Mali and Kenya.
Additional information about the phase 2 trial of CIS43LS is available at ClinicalTrials.gov under study identifier NCT04329104.
Source:
National Institutes of Health
Journal references:
- Kayentao, K., et al. (2022) Safety and efficacy of a monoclonal antibody against malaria in Mali. The New England Journal of Medicine. doi.org/10.1056/NEJMoa2206966.
- Wu, RL, et al. (2022) Low-dose subcutaneous or intravenous monoclonal antibody to prevent malaria. The New England Journal of Medicine. doi.org/10.1056/NEJMoa2203067.