Monday, October 31, 2022
Participants in NIH clinical trials are protected by antibodies during the six-month malaria season.
A single dose of an antibody drug safely protects healthy, nonpregnant adults from malaria infection during an intense six-month malaria season in Mali, Africa, a National Institutes of Health clinical trial has found. 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 American Society of Tropical Medicine and Hygiene Annual Meeting in Seattle.
“We must expand the arsenal of interventions available to prevent malaria infection and accelerate efforts to eliminate the disease,” said Dr. Anthony S. Fauci, 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 certain geographic areas.”
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 Science, Techniques and Technology (USTTB) in Bamako, Mali.
An estimated 241 million cases of malaria occurred globally in 2020, according to the World Health Organization (WHO), resulting in an estimated 627,000 deaths, mostly among children in sub-Saharan Africa. These cases involve more than 11 million pregnant women in Africa, resulting in approximately 819,000 low birth weight infants 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 in the early years of life when given to children aged 5 to 17 months in four doses over a 20 the month. 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 adherence and the emergence of drug resistance may also limit their utility. Therefore, there is an urgent need for new, fast-acting, infrequently dosed interventions that safely provide robust protection against malaria infection.
Malaria is caused by plasmodium parasites that 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. They travel to the liver where they mature and multiply. The mature parasite then spreads through the body through the bloodstream to cause disease. P. falciparum is plasmodium species most likely to result in severe malarial infections which, if not treated promptly, may result in death.
The NIAID-USTTB phase 2 study evaluated the safety and efficacy of a single, intravenous infusion of a monoclonal antibody called CIS43LS. This antibody has previously been shown to neutralize sporozoites of P. falciparum 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 a malaria vaccine, then modified the antibody to extend the time it remained in the bloodstream. 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 included 369 healthy, non-pregnant adults aged 18 to 55 years in the rural communities of Kalifabougou and Torodo in Mali, where intensive P. falciparum transmission usually takes place from July to December each year.
The first part of the study 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 study 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 of the antibody, 40 mg/kg, or placebo by intravenous infusion. No one knew who was assigned to which group until the end of the trial. The research team followed these individuals 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 research team.
The researchers analyzed the efficacy 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) CIS43LS was 88.2% effective in preventing infection and 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 found that the high dose was 76.7% effective in preventing infection and the lower dose was 54.2% effective.
“These first field results, demonstrating that the monoclonal antibody provides a safe high level of protection against intensive malaria transmission in healthy adults, paves the way for further studies to determine whether such an intervention can prevent malaria infection in infants, children and pregnant women,” Seder, MD, said. “We hope that monoclonal antibodies will 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 therefore can be given at a lower dose as an injection under the skin (subcutaneously) instead of 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 environment. 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 CIS43LS Phase 2 trial is available at ClinicalTrials.gov under study identifier NCT04329104.
NIAID conducts and supports research—at NIH, in the United States, and around the world—to study the causes of infectious and immune-mediated diseases and to develop better means of preventing, diagnosing, and treating these diseases. News releases, fact sheets, and other materials related to NIAID are available on the NIAID website.
For the National Institutes of Health (NIH):NIH, the national agency for medical research, includes 27 institutes and centers and is part of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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K Kayentao. Testing the safety and efficacy of monoclonal antibodies against malaria in adults and children in Africa. Session 41 – Advances in the Discovery and Clinical Development of Antimalarial Monoclonal Antibodies. ASTMH 2022 Annual Meeting, Seattle. Monday, October 31, 2022 5:40 PM PT.
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