High Hopes for New Monoclonal Antibody for Malaria

A next-generation monoclonal antibody against malaria performed well for safety, efficacy, half-life duration, and ease of delivery in a phase I study. Could this be the holy grail for the eradication of the mosquito-borne disease?

Just one dose of the antimalarial antibody L9LS conferred protection to 15 out of 17 recipients challenged with controlled human malaria infection. In contrast, the six controls not receiving the treatment all showed parasitemia on PCR testing within 21 days of exposure to infected mosquitoes.

L9LS showed a serum half-life of 56 days, and pharmacokinetic modeling suggested that a dose of 5 mg/kg in children may provide protection for up to 6 to 12 months, according to the report by Robert Seder, MD, an immunologist at the NIH in Bethesda, Maryland, and colleagues of the VRC 614 study in the New England Journal of Medicine (NEJM).

"These findings may have important public health and clinical implications because they establish the potential to advance protection against malaria in regions with seasonal and perennial transmission," the investigators wrote.

"Administration of a single subcutaneous dose of a monoclonal antibody at the beginning of the transmission season could provide protection, overcome adherence issues, and potentially limit the emergence of drug-resistant strains associated with long-term use of seasonal malaria chemoprevention," they said.

Neither subcutaneous nor IV administration of L9LS was associated with safety concerns. Recipients reported symptoms (e.g., nausea, headache, and malaise) that were largely mild to moderate. One case of mild cervical lymphadenopathy occurred 9 days after administration of L9LS and resolved on its own after 29 days, according to Seder's group.

NEJM editor-in-chief Eric Rubin, MD, PhD, an infectious disease specialist at Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health in Boston, noted that L9LS follows in the footsteps of another antimalarial monoclonal antibody that had been shown in an earlier study to be not very potent, requiring large volumes delivered intravenously in an expensive and impractical process.

With the more potent L9LS, "now you can get away with giving that antibody subcutaneously by injection under the skin. It's far easier, anyone can do that. A nurse can do that, a trained aide can do that," Rubin said in a press conference.

This is relevant as Sub-Saharan Africa continues to bear a disproportionate burden of malaria. There, children under 5 years old account for approximately 80% of malaria-related deaths, according to an estimate from the World Health Organization (WHO).

Meanwhile, the WHO-recommended malaria vaccine Mosquirix offers only partial protection. Relying heavily on the host's immune status, it has a reported vaccine efficacy of less than 40% after 4 years.

"Passive administration of monoclonal antibodies can consistently provide a defined concentration at a protective titer," Seder and colleagues noted. "This approach differs from vaccines that may have variable immune priming and can be influenced by previous exposure to malaria, age, and immunocompetence, which can vary across persons."

Nevertheless, L9LS still doesn't solve the problem of the malaria parasite being able to evolve its antigen target and engage in immune escape, cautioned Johanna Daily, MD, an infectious disease specialist at Albert Einstein College of Medicine in New York City.

"The targeting of multiple antigens with vaccination and the development of a cross-reactive monoclonal antibody could address this challenge," she suggested in an editorial.

The phase I VRC 614 study was conducted by the NIH's Vaccine Research Center in late 2021. Participants were healthy U.S. adults who had never had malaria nor received a vaccine for malaria.

Those assigned L9LS received it either intravenously or subcutaneously at varying doses. Investigational and control groups subsequently underwent controlled human malaria infection -- in which they received bites on the forearm from mosquitoes carrying Plasmodium falciparum -- several weeks later at the Walter Reed Army Institute of Research.

People who developed parasitemia were treated with standard atovaquone-proguanil.

VRC 614 investigators acknowledged the small size of the study and said large field studies are needed to assess L9LS. To that end, there are two phase II trials planned: one in children in Mali and one in children in Kenya.

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