Literature
Clinical Pearls & Morning Reports
Published November 16, 2022
How effective was CIS43LS in preventing malaria in the trial by Kayentao et al.?
Kayentao et al. conducted a phase 2 trial that assessed the safety and efficacy of a single intravenous administration of the monoclonal antibody CIS43LS against Plasmodium falciparum infection in healthy adults during intense malaria transmission over a 6-month rainy season. Read the NEJM Original Article here.
Clinical Pearls
Q: What is the status of current measures to prevent malaria infection?
A: Each year, there are 200 million to 400 million cases of malaria resulting in more than 500,000 deaths, the majority of which occur in Africa among children and are caused by P. falciparum infection. Malaria-control measures include insecticide-treated nets, early diagnosis and treatment with artemisinin-based combination therapies, and chemoprevention for high-risk groups including infants, children exposed to seasonal malaria, and pregnant women. Despite these countermeasures, progress in reducing malaria cases and deaths has stalled in recent years and is further threatened by the emergence of insecticide-resistant mosquitoes and drug-resistant parasites.
Q: What parasitic phase does CIS43LS target?
A: CIS43LS is a monoclonal antibody with an extended half-life that targets a conserved “junctional” epitope on the P. falciparum circumsporozoite protein (PfCSP). PfCSP is the major protein expressed on the surface of sporozoites, the parasite stage transmitted by mosquitoes to humans, and is required for sporozoite invasion of hepatocytes that precedes the erythrocytic stage that causes disease. Thus, targeting sporozoites to block infection is an approach for preventing malaria and onward transmission of the parasite.
Morning Report Questions
Q: How effective was CIS43LS in preventing malaria in the trial by Kayentao et al.?
A: In Part A of the trial, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. P. falciparum infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001). The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo.
Q: What were some of the limitations of the trial?
A: First, participants were healthy adults in Mali. Additional trials are needed to assess the safety and efficacy of antimalarial monoclonal antibodies in children and pregnant women across diverse transmission settings. Second, the factors underlying breakthrough infections after CIS43LS administration are unclear. Ongoing pharmacokinetic analysis will define the relationship between CIS43LS serum concentration and infection risk, and genotypic analysis will assess whether breakthrough infections are associated with mutations in the PfCSP. Third, CIS43LS was administered intravenously. The development of more potent antimalarial monoclonal antibodies is likely to be important to enable subcutaneous administration at lower doses across all ages and to reduce cost.