New monoclonal antibody vaccine slashes malaria risk in children

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In a recent study published in The New England Journal of Medicine, researchers evaluated the safety and efficacy of a novel monoclonal antibody-based vaccine (L9LS) in children aged 6 to 10. The study establishes the lack of safety concerns associated with the drug in children. It highlights the antibody's ability to reduce infection risk by 70% and clinical malaria risk by 77% compared to unvaccinated placebos. These findings suggest that the vaccine could protect children too young to receive conventional chemopreventive vaccines (RTS, S/AS0, or R21/Matrix-M), potentially reducing the available reservoir of the mosquito-transmitted disease.

Study: Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria. Image Credit: Kateryna Kon / ShutterstockStudy: Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria. Image Credit: Kateryna Kon / Shutterstock

The burden of malaria in young children

Malaria is a mosquito-transmitted, blood-borne disease caused by the malarial parasite Plasmodium falciparum. It is primarily transmitted between infected humans by the bites of female Anopheles spp. mosquitoes, though instances of transmission via contaminated blood transfusions or shared infected needles have also been reported. Alarmingly, despite medical advances in the disease's prevention and treatment, the global prevalence of the disease is rapidly rising, with more than 249 million recorded infections in 2022, an increase of 5 million cases compared to the previous year (2021).

Children represent some of the most at-risk populations for malarial-associated morbidity and mortality, with more than 600,000 deaths recorded annually. The World Health Organization (WHO) recommended childhood malarial chemoprevention via the RTS, S/AS01-, and more recently, the R21/Matrix-M vaccines to address children's role as victims and reservoirs of the disease's transmission. These vaccines were previously found to be 36% and 75% effective in preventing malarial infection over 4-year and 12-month periods, respectively. Unfortunately, these drugs target children in the 5-36 months age group, with older children left largely unprotected.

L9LS – a novel anti-malarial monoclonal antibody-based vaccine

L9LS is a recently developed human IgG1 monoclonal antibody derived from the successful phase 2 clinical trial of CIS43LS, a monoclonal antibody previously shown to be effective in preventing up to 88.2% of adult malaria infections by targeting highlight conserved junctional epitopes (circumsporozoite protein) in adult P. falciparum infections (PfCSP). Produced via cell-culture expressions in genetically altered Chinese hamster ovary cell lines, L9LS has been shown to achieve more potent anti-malarial protection in phase 1 clinical trials compared to its predecessor, with four out of the five adults who received the drug effectively prevented from contracting the disease.

Encouragingly, only 5 mg per kg body weight of the novel antibody was found to be comparable in performance to 40 mg per kilogram dosages of CIS43LS in preclinical models while also being safe for administration during the 4-6 month-long malarial season. This suggests that the vaccine may also be effective in treating the hitherto vulnerable 6-10-year-old age group, hitherto found too old for R21/Martix-M interventions but too young for traditional adult-administered vaccines, albeit this hypothesis has never formally been investigated.

About the study

In the present study, researchers conducted phase 2 clinical trials in children from Toronto and Kalifabougor, Mali, hotpots of malarial endemism during the July through December season. The study sample comprised healthy adults aged 18 to 55 and children aged 6 to 10. The trial was conducted per the International Council for Harmonisation's Good Clinical Practises guidelines, reviewed by the Malian Food and Drug Administration, and sponsored by the National Institute of Allergy and Infectious Diseases.

The trial was divided into two main parts. In part A, 18 prespecified adults were administered L9LS in 300 or 600 mg dosages (injected subcutaneously) or 20 mg/kg body weight (administered intravenously; 6 individuals per intervention subgroup). Once all three trials were found to be both safe and effective in preventing adult malarial infection, 18 children were assigned to either the case (150 mg of L9LS) or placebo-controlled (saline) cohorts in a 1:1 ratio.

"Adults were followed for safety on days 1, 3, 7, 14, 21, and 28 and then monthly through 28 weeks after administration, and children on days 1, 3, 7, 14, 21, and 28 and then every 2 weeks through 28 weeks after administration."

In part B, children were randomly block-assigned to receive 150 mg of L9LS, 300 mg of L9LS, or a placebo (administered subcutaneously) in a 1:1:1 ratio. Participants' medical progress was monitored every 2 weeks for 24 weeks, during which physical examinations and microscopic evaluations of blood-smear samples were carried out.

Study findings and conclusions

A single subcutaneous dose of L9LS effectively reduced childhood malarial risk by 70% and clinical (symptomatic) malaria by 77%. Surprisingly, 150 mg of L9LS was associated with lower malarial incidence than 300 mg, though this might be explained by sporozoite infections that occurred before L9LS reached maximum serum concentrations. The vaccine was found to be safe, with mild, transient swelling at the injection site representing the only solicited adverse events (within the first seven days) and no severe side effects across the 28-week-long follow-up period.

This study establishes L9LS as a safe and effective booster therapy in the war against childhood malaria. It provides evidence to support the continued development of monoclonal antibodies as anti-malaria interventions.

Journal reference:
  • Kayentao, K., Ongoiba, A., Preston, A. C., Healy, S. A., Hu, Z., Skinner, J., Doumbo, S., Wang, J., Cisse, H., Doumtabe, D., Traore, A., Traore, H., Djiguiba, A., Li, S., Peterson, M. E., Telscher, S., Idris, A. H., Adams, W. C., McDermott, A. B., … Crompton, P. D. (2024). Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria. In New England Journal of Medicine. Massachusetts Medical Society, DOI – https://doi.org/10.1056/nejmoa2312775, https://www.nejm.org/doi/full/10.1056/NEJMoa2312775
Hugo Francisco de Souza

Written by

Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.

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