Monday 31 October 2022
Participants in the NIH clinical trial protected antibodies during the six-month malaria season.
One dose of an antibody drug safely protected healthy, non-pregnant adults from malaria infection during an intense six-month malaria season in Mali, Africa, according to a National Institutes of Health clinical study. 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 American Society of Tropical Medicine & Hygiene 2022 Annual Meeting in Seattle.
“We need to 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. “The results of these studies 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, led by Peter D. Crompton, MD, MPH, and Kassoum Kayentao, MD, MPH, Ph.D. Dr. Crompton is Head of the Malaria Infection Biology and Immunity Section in the Immunogenetics Laboratory NIAID and Dr. Kayentao is a professor at the University of Sciences, Techniques and Technologies (USTTB) in Bamako, Mali.
According to the World Health Organization (WHO), around 241 million cases of malaria occurred worldwide in 2020, causing around 627,000 deaths, mainly in children in sub-Saharan Africa. These cases included more than 11 million pregnant women in Africa, resulting in approximately 819,000 newborns 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 5-17 months in four doses over a period of 20 months. Other medications consisting of small chemical compounds that effectively prevent malaria infection are also available for infants and young children, as well as for travelers. The need to administer these drugs frequently may limit adherence, however, and the emergence of drug resistance may also limit their usefulness. Therefore, there is an urgent need for new, fast-acting and rarely dosed interventions that safely 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 parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply. Then the mature parasite spreads throughout the body through the bloodstream causing disease. P. falciparum and the Plasmodium species that are more likely to cause severe malaria infections which, if not treated promptly, can lead to death.
The Phase 2 NIAID-USTTB study evaluated the safety and efficacy of a one-time intravenous infusion of a monoclonal antibody called CIS43LS. It has previously been shown that this antibody neutralizes sporozoites of P. falciparum in the skin and blood before they could infect liver cells. Researchers led by Robert A. Seder, MD, isolated a natural form of this antibody from the blood of a volunteer who had received an experimental malaria vaccine and then modified the antibody to extend the length of time it would remain. into the bloodstream. Dr. Seder is the interim chief medical officer and interim associate director of the NIAID Vaccine Research Center (VRC) and chief of the cellular immunology section of the VRC.
The study team for the Phase 2 study enrolled 369 healthy, non-pregnant adults aged 18 to 55 in the rural communities of Kalifabougou and Torodo in Mali, where intense activity P. falciparum transmission generally takes place from July to December of 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 – administered by intravenous infusion in 18 study participants, with six participants per level of dose. 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 effectiveness of two different doses of CIS43LS compared to a placebo. Three hundred and thirty participants were randomly assigned to receive 10 mg / kg of antibody, 40 mg / kg, or a placebo by intravenous infusion. Nobody knew who was assigned to which group until the trial was over. The study team followed these individuals for 24 weeks, testing their blood P. falciparum weekly for the first 28 days and every two weeks thereafter. Any participant who developed symptomatic malaria during the study received standard treatment from the study team.
The researchers analyzed the effectiveness of CIS43LS in two ways. Based on the first time P. falciparum infection over the 24-week study period, the high dose (40 mg / kg) of CIS43LS was 88.2% effective in preventing infection and the lowest 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 it found that the high dose was 76.7% in preventing infections and the lowest dose was 54.2% effective.
“These first field results showing 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 Dr. Seder said. “We hope monoclonal antibodies transform malaria prevention in endemic regions.”
Dr. Seder and colleagues developed a second antimalarial monoclonal antibody, L9LS, which is much more potent than CIS43LS and therefore can be given in a smaller dose as a subcutaneous (subcutaneous) injection rather than an intravenous infusion. An early stage NIAID study 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 studies are ongoing in Mali and Kenya to evaluate the safety and efficacy of L9LS in infants, children and adults.
More information on the CIS43LS phase 2 study 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. Press releases, fact sheets and other NIAID-related material are available on the NIAID website.
Information on the National Institutes of Health (NIH):NIH, the nation’s medical research agency, comprises 27 institutes and centers and is a component of the United States Department of Health and Human Services. NIH is the leading federal agency that conducts and supports basic, clinical and translational medical research and is studying the causes, treatments, and cures for common and rare diseases. For more information on NIH and its programs, visit www.nih.gov.
NIH … Turning Discovery into Health®
K Kayentao. To test the safety and efficacy of anti-malaria monoclonal antibodies in African adults and children. Session 41 – Advances in the discovery and clinical development of anti-malaria monoclonal antibodies. ASTMH 2022 Annual Meeting, Seattle. Monday, October 31, 2022. 5:40 pm Pacific time.
K Kayentao et al. Safety and efficacy of a monoclonal antibody against malaria in Mali. The New England Journal of Medicine DOI: 10.1056 / NEJMoa2206966 (2022).
RL Wu et al. Low dose subcutaneous or intravenous monoclonal antibody to prevent malaria. The New England Journal of Medicine DOI: 10.1056 / NEJMoa2203067 (2022).