Monoclonal antibody shows effectiveness in preventing malaria infection in adults in Africa

Monoclonal antibody shows effectiveness in preventing malaria infection in adults in Africa

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, a National Institutes of Health clinical trial found. The antibody was 88.2% effective in preventing infection over 24 weeks, 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 & Hygiene Annual Meeting in Seattle.

We need to expand the arsenal of available interventions to prevent malaria infection and accelerate efforts to eradicate the disease. “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 specific geographical areas.”

Anthony S. Fauci, MD, Director, National Institute of Allergy and Infectious Diseases

NIAID sponsored and funded the study, led by Peter D. Crompton, MD, MPH, and Kassoum Kayentao, MD, MPH, Ph.D. was directed. Dr. Crompton is chief of the Malaria Infection Biology and Immunity Division in the NIAID Laboratory of Immunogenetics, and Dr. Kayentao is a professor at the University of Sciences, Techniques and Technologies (USTTB) of Bamako, Mali.

According to the World Health Organization (WHO), an estimated 241 million cases of malaria occurred worldwide in 2020, resulting in an estimated 627,000 deaths, mostly among children in sub-Saharan Africa. These cases included more than 11 million pregnant women in Africa, resulting in an estimated 819,000 newborns with low birth weight, increasing the risk of illness and death.

The only malaria vaccine currently recommended by WHO, called RTS,S (Mosquirix), provides partial protection against clinical malaria in early life when administered in four doses over 20 months to children aged 5 to 17 months. Other medications consisting of small chemical compounds that effectively prevent malaria infection are also available for infants and young children and travelers. However, the need for frequent use of these medications may limit adherence, and the emergence of drug resistance may also limit their usefulness. Therefore, there is an urgent need for new, rapid-acting, low-dose interventions that provide safe and strong 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 into the skin and bloodstream in a form called sporozoites. These migrate to the liver, where they mature and multiply. The mature parasite then spreads throughout the body via the bloodstream, causing disease. P. falciparum is the Plasmodium species most likely to cause severe malaria infections, which if not treated promptly can result in death.

The Phase 2 NIAID-USTTB trial evaluated the safety and effectiveness of a single intravenous infusion of a monoclonal antibody called CIS43LS. This antibody was previously 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 increase its residence time in the bloodstream. Dr. Seder is deputy chief medical officer and deputy director of the NIAID Vaccine Research Center (VRC) and head of the VRC's Division of Cellular Immunology.

The Phase 2 study team recruited 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 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 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 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 was assigned to 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 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 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 and the lower dose (10 mg/kg) was 75% effective in preventing infection. 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 at preventing infection and the lower dose was 54.2% effective.

“These initial 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,” Dr. Seder 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, that is much more potent than CIS43LS and can therefore be administered at a lower dose as an injection under the skin (subcutaneously) rather than as an intravenous infusion. An early 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 trials evaluating the safety and effectiveness of L9LS in infants, children and adults are underway in Mali and Kenya.

Further information about the Phase 2 study of CIS43LS is available at ClinicalTrials.gov under study identifier NCT04329104.

Source:

National Institutes of Health

References:

• Kayentao, K., et al. (2022) Sicherheit und Wirksamkeit eines monoklonalen Antikörpers gegen Malaria in Mali. Das New England Journal of Medicine. doi.org/10.1056/NEJMoa2206966.
• Wu, RL, et al. (2022) Niedrigdosierter subkutaner oder intravenöser monoklonaler Antikörper zur Vorbeugung von Malaria. Das New England Journal of Medicine. doi.org/10.1056/NEJMoa2203067.

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