A single dose of the antibody safely protected healthy, nonpregnant adults from malaria infection during an intense six-month malaria season in Mali, Africa, a National Institutes of Health clinical trial found. The effectiveness of the antibody in preventing infection over a 24-week period was 88.2%, demonstrating for the first time that monoclonal antibodies can prevent malaria infection in endemic regions. These results were published today in New England Journal of Medicine and presented at the 2022 American Society for Tropical Medicine and Hygiene Annual Meeting in Seattle.

“We need to expand the arsenal of available preventive measures malaria infection and accelerate efforts to eradicate 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 monoclonal antibodies can potentially to complement other measures to protect travelers and vulnerable groups such as infants, children and pregnant women from seasonal malaria and to help eliminate malaria in defined geographic areas.’

The trial was led by Peter D. Crompton, MD, MPH, and Kassoum Kayentao, MD, MPH, Ph.D. Dr. Crompton is Chief of the Division of Malaria Infection Biology and Immunity at NIAID’s Laboratory of Immunogenetics, and Dr. Kayentao is a professor at the University of Science, Technology and Technology (USTTB) in Bamako, Mali.

The World Health Organization (WHO) estimates that 241 million cases of malaria were reported worldwide in 2020, resulting in approximately 627,000 deaths, mostly among children in sub-Saharan Africa. These cases involved more than 11 million pregnant women in Africa, resulting in an estimated 819,000 infants with low birth weight and thus at increased risk of morbidity and mortality.

The only malaria vaccine currently recommended by WHO, called RTS,S (Mosquirix), provides partial protection against clinical malaria in the first years of life when given to children aged 5 to 17 months in four doses over 20 months. Other drugs that consist of small chemical compounds that effectively prevent malaria infection also available for babies and toddlers, as well as travelers. Requiring frequent administration of these drugs may limit adherence, but the emergence of drug resistance may also limit their usefulness. Thus, 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. Mosquitoes introduce parasites in a form called sporozoites into the skin and blood. They go to the liver, where they mature and reproduce. The mature parasite then spreads throughout the body through the bloodstream, causing disease. P. falciparum is the species of Plasmodium most likely to cause severe malarial infections that, 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 the natural form of this antibody from the blood of a volunteer who had received an experimental malaria vaccine, then modified the antibody to extend the time it remained in the blood. Dr. Seder is the Acting Chief Medical Officer and Acting Associate Director of the NIAID Vaccine Research Center (VRC) and Chief of the VRC Division of Cellular Immunology.

The research team for the phase 2 trial enrolled 369 healthy, non-pregnant adults aged 18 to 55 years in the rural communities of Kalifabougou and Tarada in Mali, where intense transmission of P. falciparum typically occurs between July and 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 – administered by intravenous infusion to 18 study participants, with six participants per dose level. The research 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 efficacy of two different doses of CIS43LS compared to placebo. Three hundred and thirty participants were randomly assigned to receive either 10 mg/kg antibody, 40 mg/kg, or placebo by intravenous infusion. Until the end of the trial, no one knew who was assigned to which group. The research team followed these people for 24 weeks, testing their blood for P. falciparum weekly for the first 28 days and every two weeks thereafter. 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 over the 24-week study period, the high dose (40 mg/kg) of CIS43LS was 88.2% effective in preventing infection, while the lower dose (10 mg/kg) was 75% effective . . Analysis of the proportion of participants infected with P. falciparum at any time during the 24-week study period showed that the high dose was 76.7% effective in preventing infection, while the low dose was 54.2% effective.

“These first field results, demonstrating that monoclonal antibodies safely provide high levels of protection against intensive malaria transmission in healthy adults, pave the way for further research to determine whether such an intervention can prevent malaria in infants, children and pregnant women.” – Dr. Said Seder. “We hope that monoclonal antibodies will revolutionize 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 at a lower dose as an injection under the skin (subcutaneously) rather than by intravenous infusion. Early Phase NIAID L9LS Trials in the United States Show Antibodies to be Safe and Prevent malaria infection for 21 days in 15 of 17 healthy adults exposed to P. falciparum under carefully controlled conditions. Two larger NIAID-funded phase 2 trials are underway in Mali and Kenya, evaluating the safety and efficacy of L9LS in infants, children, and adults.