There were an estimated 249 million cases of malaria worldwide in 2022. Sadly, this resulted in approximately 608,000 deaths. Most of the cases and deaths occurred in Sub-Saharan Africa, which accounted for an estimated 95% of cases and 96% of deaths.
The current standard of care is a combination of an artemisinin-based drug along with a quinine or chloroquine derivative (e.g. artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, etc.). Artesunate is a semi-synthetic derivative of artemisinin (a naturally occurring compound), modified to improve its solubility. The mechanism of action of artemisinin/artesunate against Plasmodium is still not well understood. The combination of free radical generation and inhibition of essential proteins leads to widespread cellular damage within the malaria parasite, ultimately disrupting its metabolism and resulting in its death.
The other main compound in the combination therapy is chloroquine, quinine, or a related chemical; they are weak bases that get concentrated in the acidic food vacuole of the malaria parasite. This is where the parasite digests hemoglobin from red blood cells. Hemoglobin digestion releases heme which is toxic to the malaria parasite, and so it converts heme into an inert, crystalline form called hemozoin. Both chloroquine and quinine are believed to interfere with this hemozoin formation process.
The goal of public health efforts has been not only to treat malaria, but also to prevent infection with the primary focus on developing a malaria vaccine. The good news is that significant progress has been made in recent years on this front. The World Health Organization (WHO) has recommended two vaccines, RTS,S/AS01 (Mosquirix) and R21/Matrix-M. The former is the first and currently only WHO-approved vaccine for widespread use (introduced in 2019). It has moderate efficacy (around 40% in young children), reducing malaria cases. The newer R21/Matrix-M vaccine, which received WHO recommendation in 2023, shows promise due to its higher efficacy and affordability. It has been reported to reduce symptomatic malaria cases by 75% over 12 months following a 3-dose series, with a fourth dose maintaining this efficacy.
The main mechanism by which vaccines exert their protective effects is by eliciting antibodies against the pathogen intruder. A possible alternative is to directly inject the patient with the anti-pathogen antibodies. During the first year of the Covid pandemic (2020) while the coronavirus vaccine was still undergoing clinical trials, some companies were able to quickly test and release monoclonal antibodies to treat the infection (QH). Even after the coronavirus vaccine demonstrated efficacy in the range of 90-95%, these monoclonals were used for immunocompromised individuals for which the vaccine was less efficacious.
Likewise, an effort is being made to develop monoclonal antibodies against Plasmodium as a preventive measure against malaria. L9LS is a monoclonal antibody developed by scientists at the National Institutes of Health (NIH) to prevent malaria. It is a laboratory-made version of a naturally occurring antibody called L9, derived from the blood of a volunteer who had received an investigational malaria vaccine. L9LS works by neutralizing the malaria parasites in the skin and blood before they can infect liver cells.
In a recently reported (NEJM) phase 2 trial conducted in Mali, researchers investigated the safety and effectiveness of subcutaneous administration (single dose) of the monoclonal antibody L9LS in 225 children aged 6 to 10 during a 6-month malaria season. In the randomized trial, children were inoculated with either 150 mg of L9LS, 300 mg of L9LS, or a placebo. The subjects were followed for 24 weeks with periodic blood smears for Plasmodium infection.
Over the 24-week trial period, P. falciparum infection (positive blood smear) occurred in 48% of the 150 mg L9LS group, 40% of the 300 mg L9LS group, and 81% of the placebo group (Figure 1). This translates to an efficacy of 66% for the 150 mg dose and 70% for the 300 mg dose compared to the placebo (P<0.001 for both). The efficacy calculation was based on time to infection and not just infection or not.
Using the stricter definition of clinical malaria (fever and high parasitemia), occurred in 28% of the 150 mg L9LS group, 19% of the 300 mg L9LS group, and 59% of the placebo group. This corresponds to an efficacy of 67% for the 150 mg dose and 77% for the 300 mg dose (P<0.001 for both). Importantly, there were no safety concerns with no difference in adverse events between treatment and placebo groups.
In summary, the authors of the trial concluded that the trial demonstrates that a single subcutaneous dose of L9LS can effectively prevent P. falciparum infection and clinical malaria in school-aged children (6-10 years old), offering up to 70% and 77% protection, respectively, over a 6-month malaria season. They also noted that in the 300 mg L9LS group, the efficacy could be even higher because roughly 10% of infections occurred in the first few weeks before L9LS reached peak serum concentration. Similarly with the coronavirus vaccine it took 2 weeks to reach full efficacy. A higher dose or injecting before the malaria season starts could help.
Finally they argue that L9LS could potentially complement or replace existing prevention strategies, most notably the vaccine. Interestingly, the monoclonal antibody seems to have roughly the same efficacy as the newer R21/Matrix-M vaccine while being administered with fewer doses. Both would require once a year boosting. Something to consider would be whether a combination of the vaccine and monoclonal would be more effective than each alone.
Figure 1. "Efficacy against P. falciparum Infection. Shown is the cumulative incidence of the first P. falciparum blood-stage infection during a 6-month malaria season (regardless of the presence of
symptoms) after a single subcutaneous injection of 150 mg of L9LS, 300 mg of L9LS, or placebo" (from Figure 2 of Kayentao et al. NEJM, 2024).
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