L9LS antibody safe and highly protective against malaria, finds study

Phase I human challenge study shows a single subcutaneous injection of the monoclonal antibody L9LS provides at least short-term protection against malaria.

A single injection of the investigational L9LS monoclonal antibody (mAb) has been found to be safe and highly protective in US adults exposed to the malaria parasite. The results of the Phase I US National Institutes of Health (NIH) study were published in The New England Journal of Medicine.

In 2020, the World Health Organization (WHO) estimated that 240 million people had malaria, the mosquito-borne disease spread by Plasmodium parasites, and that it caused about 627,000 deaths. A disproportionate burden of malarial disease is seen in Sub-Saharan Africa, where children under five years of age account for approximately 80 percent of all malaria deaths. A vaccine to prevent malaria is now available; however, its variable efficacy underscores the need for new interventions that offer high-level protection against disease. 

Scientists from NIH’s Vaccine Research Center (VRC), developed L9LS, a laboratory-made version of a naturally occurring malaria parasite neutralising antibody called L9, derived from the blood of a volunteer who had received an investigational malaria vaccine. These scientists also led the Phase I clinical trial 

L9LS is similar to a candidate anti-malarial antibody called CIS43LS that the VRC developed and found to be highly protective in a small trial when administered by the intravenous route, but L9LS is two to three times more potent. Increasing the potency allowed for subcutaneous injection, a more cost-effective and feasible route of administration than intravenous infusion. 

The Phase I study (NCT05019729) was conducted from 13 September to 16 November 2021, at the NIH Clinical Center in Bethesda, Maryland, and the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Maryland. The trial involved 18 volunteer participants receiving various doses of L9LS subcutaneously or intravenously. After tolerating the injection and experiencing no safety concerns, the participants allowed mosquitoes carrying the malaria parasite to bite their forearm five times, starting from two to six weeks after receiving the mAb candidate. This took place in a carefully controlled setting, known as controlled human malaria infection (CHMI). As part of this approach, which has been used for decades in malaria research, medical staffers closely monitor participants and provide proper treatment if they become infected.

L9LS fully protected 15 of 17 (88 percent) participants from malaria infection during the 21-day challenge period. All volunteers in the control group that underwent CHMI, but did not receive L9LS, became infected and were promptly treated without complications. Encouragingly, four of the five participants who received a low, subcutaneous dose of the mAb were protected from malaria.

“This is the first demonstration that a monoclonal antibody can provide protection when given by the subcutaneous route, with important implications for widespread clinical use and reaching the goal of eliminating malaria,” stated Dr Robert Seder, chief of the Cellular Immunology Section in the VRC, who led the development of L9LS. “We look forward to results in larger field studies that will help establish an effective dose.” 

Additional clinical trials evaluating if L9LS can prevent malaria over six to 12 months against seasonal and perennial transmission are underway in infants and children in Mali and Kenya, where malaria is endemic.

“These early clinical trial results demonstrating that a monoclonal antibody administered subcutaneously can protect people from malaria are highly encouraging,” added NIAID Director Dr Anthony Fauci. “A one-time intervention that protects against malaria for six months to a year could significantly reduce morbidity and mortality among children in malaria-endemic regions and offer an effective preventive tool for health care workers, military personnel and travellers to these areas.”

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