The only vaccine currently recommended by the WHO is RTS,S (Mosquirix), and although other vaccines are in development, this has traditionally proven to be a difficult area. Although drugs to prevent malaria are available for infants, young children, and travelers, the requirement for frequent dosing can be problematic while the urgency of drug resistance can also limit their usefulness.
“Thus, there is an urgent need for novel, rapid-acting, low-dose interventions that safely provide robust protection against malaria infection,” says the US National Institutes of Health, which conducted the clinical trial of the new monoclonal antibody.
Targeting malaria at the early stage of development
The Institute hopes that the monoclonal antibody CIS43LS can offer a new solution. Phase 2 data has been published in The New England Journal of Medicine recently and presented at the 2022 American Society of Tropical Medicine & Hygiene Annual Meeting in Seattle: finding that CIS43LS “protected against P. falciparum infection during a 6-month malaria season with no obvious safety concerns “.
According to the WHO, there were around 241 million cases of malaria worldwide in 2020, resulting in around 627,000 deaths, mostly among children in sub-Saharan Africa. These cases affected more than 11 million pregnant women in Africa, resulting in an estimated 819,000 newborn babies with low birth weight and therefore at increased risk of illness and death.
Malaria is caused by Plasmodiumparasites, which are transmitted by mosquitoes. One of the challenges in developing the arsenal against malaria is to target the right stage in the life cycle of the sporozoites injected into the body.
Researchers led by Robert A. Seder, MD (Acting Chief Medical Officer and Acting Associate Director of the NIAID Vaccine Research Center (VRC) and Head of the Cellular Immunology Section of the VRC) have isolated a naturally occurring form of an antibody antimalarial from the blood of a volunteer who had received an experimental malaria vaccine, then modified the antibody to extend the length of time it would stay in the bloodstream.
Preclinical trials had already shown the potential of CIS43LS to neutralize these sporozoites in the blood before they infect liver cells: this is where they normally mature, multiply and spread throughout the body, causing diseases.
Now, the phase 2 study has shown the antibody remained effective in humans for the 24 weeks of the study – roughly the length of the malaria season.
The phase 2 trial recruited 369 healthy, non-pregnant adults, ages 18 to 55, from the rural communities of Kalifabougou and Torodo in Mali, where an intense P. falciparumTransmission usually 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 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 either 10 mg/kg antibody, 40 mg/kg, or placebo by intravenous infusion. The study 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.
Investigators analyzed the effectiveness of CIS43LS in two ways. Based on the time of the premiere P. falciparumOver 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. falciparumAt any time during the 24-week study period, the high dose was 76.7% effective in preventing infection and the lower dose was 54.2% effective.
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 Biology and Immunity Section of the malaria infection from the NIAID Immunogenetics Laboratory, and Dr. Kayentao is a professor at the University of Sciences, Techniques and Technologies (USTTB) in Bamako, Mali.
“These early field results demonstrating that a monoclonal antibody safely provides high-level protection against intense malaria transmission in healthy adults paves the way for further studies to determine if such an intervention can prevent malaria. ‘malaria infection in infants, children and pregnant women’,said Dr. Seder. “We hope monoclonal antibodies will transform malaria prevention in endemic regions.”
Dr. Seder and his colleagues have developed a second antimalarial monoclonal antibody, L9LS, which is much more potent than CIS43LS and can therefore be administered at a lower dose subcutaneously rather than by intravenous infusion.
An early phase NIAID trial of L9LS in the United States foundthat the antibody was safe and prevented malaria infection for 21 days in 15 out of 17 healthy adults exposed to P. falciparumin a carefully controlled environment. Two larger, NIAID-sponsored Phase 2 trials evaluating the safety and efficacy of L9LS in infants, children, and adults are ongoing. maliand Kenya.
“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), which is part of the NIH. “These study results [for CIS43LS] suggest that a monoclonal antibody could potentially complement other measures to protect travelers and vulnerable groups such as infants, children and pregnant women against seasonal malaria and help eliminate malaria in defined geographic areas.
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