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14th November 2022
The malarial monoclonal antibody CIS43LS has shown a high level of efficacy after 6 months against plasmodium falciparum during the malaria season in Mali according to the findings of a study by researchers from the Mali Malaria mAb trial team.
Malaria is caused by four members of the plasmodium species including Plasmodium falciparum, P. vivax, P. ovale, and P. malariae and is transmitted after being bitten by an infective female Anopheles mosquito producing a febrile illness. Malaria is an extremely common infection and which, according to the World Health Organization (WHO), led to 241 million cases in 2020 (up from 227 million in 2019) and an estimated 627 000 deaths.
The infection disproportionately affects individuals on the African continent and WHO estimates that in 2020, 95% of all malaria cases and 96% of deaths occurred within the region with children under 5 years of age accounting for about 80% of all malaria deaths.
As well as vaccines, a malarial monoclonal antibody, CIS43LS has been developed and which targets the circumsporozoite protein which covers the surface of the infecting sporozoites and has a critical role in sporozoite development in the mosquito, and invasion of hepatocytes necessary for initiation of malaria infection. CIS43LS binds with the circumsporozoite protein, inhibiting its action and is therefore highly effective for passive prevention of malaria. In a phase 1 trial, administration of CIS43LS to adults who had never had malaria infection or vaccination, prevented malaria after controlled infection.
Based on these early and positive findings, researchers undertook a phase 2 trial to assess the efficacy and safety of CIS43LS in healthy adults in Mali during a 6-month malaria season. After an initial dose ranging study, individuals were randomised 1:1:1 to receive CIS43LS doses of either 10 mg/kg/bodyweight, 40 mg or placebo.
The primary efficacy endpoint was the first detection of P. falciparum infection in blood smear examination, and which was checked every 2 weeks for a total of 24 weeks. Prior to the study, all participants were given artemether–lumefantrine for treatment of any existing malarial infection.
Malarial monoclonal antibody efficacy
A total of 330 individuals with a median age of 34.6 years (43% female) were equally randomised to either 10, 40 mg/kg dose of CIS43LS or placebo. At enrolment, plasmodium infection was still present in 12.7% of those receiving 10 mg, 7.3% in the 40 mg group and a similar proportion of placebo participants.
The primary efficacy, i.e., P. falciparum infection, was seen in 35.5% of those receiving 10 mg, 18.2% in the 40 mg group but in 78.2% of placebo participants. At 6 months the efficacy of the 40 mg/kg dose (compared to placebo) was 88.2% and 75% for the 10 mg dose and both comparisons were statistically significant.
In terms of safety, the risk of a moderate headache was 3.3 times as high with the 40 mg/kg dose compared to placebo.
The authors concluded that CIS43LS was effective over a 6-month malaria season and without any evidence of safety concerns.
Citation
Kayentoa K et al. Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali. N Engl J Med 2022
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.
Citation
Wu RL et al. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria N Eng J Med 2022
11th August 2021
Malaria is caused by the Plasmodium falciparum parasite and is spread to humans after being bitten by an infected female Anopheles mosquito. Malaria is extremely common and according to data from the World Health Organisation, in 2019, there were an estimated 229 million cases of malaria across the world and approximately 409,000 deaths. Symptoms of malaria include non-specific flu-like illness with fever, sweats and chills. Although malaria is endemic in sub-Saharan Africa and South East Asia, the disease still occurs in those who have returned from travelling to malaria areas. For example, in 2018, there were 1683 cases of imported malaria in the UK and this figure has remained remarkably constant over the past 10 years. An important first step in the management of travellers is a malaria screen to identify those with the condition. According to UK guidelines published in 2016, the best diagnostic procedure is examination of thick and thin blood films by an expert to detect the presence of the malarial parasite. Moreover, the guidelines also recognise that malaria can also be accurately diagnosed using rapid diagnostic tests (RDTs). In fact, a Cochrane review concluded that RDTs have a high sensitivity such that these can replace or extent the access of diagnostic services for uncomplicated plasmodium falciparum (P. falciparum) malaria. Guidance from the Haematology Task Force, has recommended that if the initial malaria screen is negative despite a strong clinical suspicion of infection, the films should be repeated after 12 to 24 hours and again after 24 hours. Nevertheless, this requires the patient to return to a hospital for repeat testing and it cannot be guaranteed that someone likely to be infected will return to a hospital. Thus, in order to optimise the malaria screen process to ensure that patients are successfully identified and using a combination of thin film and RDTs, a team from the Emergency Department, Manchester University, Manchester, UK, undertook a retrospective analysis of the value of this single malaria screen consisting of a RDT and a thin film over a 5-year period.
Findings
The study included a complete malaria screen, i.e., thin film and RDT, for 1331 unique patients with an average age of 30.6 years (51.3% male). A total of 104 positive tests were identified from the screening of which 103 were for single malarial species (74 P. falciparum, 23 P. vivax, 6 P. ovale and one mixed infection). This gave a background malaria prevalence of 5.6% for P. falciparum and 7.8% for any species. Using this approach, the authors calculated the sensitivity for the detection of P. falciparum as 100% and the specificity was 99.4%. For the detection of any malaria species, the sensitivity was 99% and the specificity 99.5%.
The authors concluded that a single malaria screen using a combination of a thin film and a RDT is likely to be sufficient to identify P. falciparum in the returning traveller, avoiding the need for a return visit when the initial film is negative. They also called for further work to confirm the value of this approach.
Citation
Reynard C et al. A diagnostic evaluation of single screen testing for malaria in the returning traveller: A large retrospective cohort study. Acad Emerg Med 2021
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