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10th August 2022
A malaria monoclonal antibody provides protection against controlled infection in virtually all patients according to the findings of a phase 1 clinical trial by a US research team.
Malaria is an acute, febrile illness caused by Plasmodium falciparum (P. falciparum), a unicellular protozoan parasite, spread through the bites of infected female Anopheles mosquitoes. It is an extremely common disease and the World Health Organisation has estimated that in 2020 there were 241 million cases of malaria, leading to an estimated 627,000 deaths.
While there have been huge efforts directed towards the development of a vaccine, the available data suggests that the RTS,S/AS01 candidate malaria vaccine, has an efficacy of only 36.6%. Some research has shown how antibodies can prevent malaria by neutralising sporozoites (i.e., the infectious form of Plasmodium deposited into the skin when a mosquito bites) before they infect hepatocytes in the liver.
A recognised antibody target is the P. falciparum circumsporozoite protein, that is required for parasite motility and invasion of hepatocytes and in a 2021 study, it was shown that a malaria monoclonal antibody, CIS43LS, which targets this protein, prevented malaria after controlled infection.
For the current phase 1 trial, researchers modified the CIS43LS monoclonal antibody to create a more potent agent, L9LS and described its safety, pharmacokinetics and protective efficacy in health adults who had never been infected with malaria or received a vaccine.
Study participants were given either intravenous LSL9 at doses of 1, 5 and 20 mg/kg or a subcutaneous dose of 5 mg/kg, whereas some did not receive the monoclonal antibody and served as controls. Within 2 to 6 weeks after administration of LSL9, participants were exposed to bites on the forearm from the Anopheles stephensi mosquito which had been infected with P. falciparum.
Parasitaemia (i.e., the detection of parasites in the blood) was assessed after 21 days using a PCR test and for the purposes of the study, participants were considered to be protected by LSL9, if parasitaemia did not develop at this point in time. In cases where parasitaemia did occur, individuals were treated with 1 gm atovaquone and 400 mg of proguanil for 3 days.
Malaria monoclonal antibody and parasitaemia
A total of 27 participants were enrolled with a mean age of 24.5 years (50.3% female), 18 of whom received L9LS (and 9 serving as controls) with 5 receiving the drug subcutaneously. Controlled infection was administered to 23 participants (17 given L9LS and 6 controls).
The results showed the L9LS had dose linearity with the highest mean serum concentration of 914.2 mcg/ml from the 20 mg/kg intravenous dose and the estimated overall clearance was 46.1 ml/day with a half-life of 56 days.
Parasitaemia developed in 2 of the 17 participants given L9LS and all 6 controls (p < 0.001) and did not develop in those given 5 or 20 mg of intravenous L9LS. Interestingly, protection was afforded by serum concentrations of L9LS as low as 9.2 mcg/ml.
The authors concluded that these results indicated that prevention of malaria could be achieved after a single dose of L9LS and that further studies were needed to examine the value of the drug among infants and children.
Wu RL et al. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria N Eng J Med 2022