“We must expand the arsenal of interventions available to prevent malaria infection and accelerate efforts to eliminate the disease,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH. “These study results suggest that a monoclonal antibody could potentially 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.” NIAID sponsored and funded the trial, which was conducted by Peter D. Crompton, MD, MPH, and Kassoum Kayentao, MD, MPH, Ph.D. Dr. Crompton heads the Division of Malaria Infection Biology and Immunity at the NIAID Laboratory of Immunogenetics, and Dr. Kayentao is a professor at the University of Science, Technology and Technology (USTTB) in Bamako, Mali. An estimated 241 million cases of malaria occurred worldwide in 2020, according to the World Health Organization (link is external) (WHO), killing an estimated 627,000, mostly children in sub-Saharan Africa. These outbreaks involved more than 11 million pregnant women in Africa, resulting in approximately 819,000 infants with low birth weight and therefore at increased risk for 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 in 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 travelers. However, the requirement for frequent dosing of these drugs may limit compliance, and the emergence of drug resistance may also limit their utility. Therefore, there is an urgent need for novel, rapid-acting, infrequent-dose interventions that safely provide robust protection against malaria infection. Malaria is caused by Plasmodium parasites, which are transmitted to humans 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 through the bloodstream to cause disease. P. falciparum is the Plasmodium species most likely to lead to severe malaria infections, which, if not treated promptly, 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 can 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 the amount of time it would remain in circulation blood. Dr. Seder is the acting chief medical officer and deputy associate director of the NIAID Vaccine Research Center (VRC) and head of the VRC’s Division 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 P. falciparum transmission typically occurs 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 to 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 either 10 mg/kg of the antibody, 40 mg/kg, or placebo by intravenous infusion. No one knew who had been placed in which group until the end of the trial. The study team followed these people 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 efficacy 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% effective in preventing infection and the lower dose was 54.2% effective. “These first field results show 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 such an intervention can prevent malaria infection in infants, children and pregnant women,” said Sender. “We hope that monoclonal antibodies will transform malaria prevention in endemic areas.” Dr. Seder and colleagues have developed a second antimalarial monoclonal antibody, L9LS, which is much more potent than CIS43LS and therefore can be given at a lower dose as an injection under the skin (subcutaneously) rather than intravenously injection. 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 ongoing in Mali and Kenya. Additional information about the Phase 2 trial of CIS43LS is available at ClinicalTrials.gov under study identifier NCT04329104. Report: Kayentao K, Ongoiba A, Preston AC, et al. Safety and efficacy of a monoclonal antibody against malaria in Mali. N Engl J Med. 2022;0(0):null. doi: 10.1056/NEJMoa2206966 This article has been republished from the following materials. Note: material may have been edited for length and content. For more information, please contact the cited source.
