Monoclonal antibody prevents malaria in small trial


Wednesday, 18 August, 2021


Monoclonal antibody prevents malaria in small trial

One dose of a new monoclonal antibody discovered and developed at the US National Institutes of Health safely prevented malaria for up to nine months in people who were exposed to the malaria parasite. The small, carefully monitored clinical trial was conducted by scientists from the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), with the findings published in The New England Journal of Medicine.

Malaria is caused by Plasmodium parasites, which are transmitted to people through the bite of an infected mosquito. The mosquito injects the parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply. Then the mature parasite spreads throughout the body via the bloodstream to cause illness. P. falciparum is the Plasmodium species most likely to result in severe malaria infections, which, if not promptly treated, may lead to death. So far, no licensed or experimental malaria vaccine that has completed Phase 3 testing provides more than 50% protection from the disease over the course of a year or longer.

Laboratory and animal studies have demonstrated that antibodies can prevent malaria by neutralising the sporozoites of P. falciparum in the skin and blood before they can infect liver cells. The NIAID trial tested whether a neutralising monoclonal antibody called CIS43LS could safely provide a high level of protection from malaria in adults following careful, voluntary, laboratory-based exposure to infected mosquitos in the United States.

CIS43LS was derived from a naturally occurring neutralising antibody called CIS43. Researchers led by Dr Robert A Seder, Chief of the Cellular Immunology Section of the VRC Immunology Laboratory, isolated CIS43 from the blood of a volunteer who had received an investigational malaria vaccine. The scientists found that CIS43 binds to a unique site on a parasite surface protein that is important for facilitating malaria infection and is the same on all variants of P. falciparum sporozoites worldwide. The researchers subsequently modified this antibody to extend the amount of time it would remain in the bloodstream, creating CIS43LS.

After animal studies of CIS43LS for malaria prevention yielded promising results, VRC investigators launched a Phase 1 clinical trial of the experimental antibody with 40 healthy adults aged 18 to 50 years who had never had malaria or been vaccinated for the disease. During the first half of the trial, the study team gave 21 participants one dose of CIS43LS by either an intravenous infusion or an injection under the skin. The infusions ranged from 5 to 40 mg/kg of body weight, and the subcutaneous injections were 5 mg/kg. Investigators followed the participants for six months to learn whether the infusions and subcutaneous injections of the various doses of the experimental antibody were safe and well tolerated. In addition, they measured the amount of CIS43LS in the blood to determine its durability over time.

In the second half of the trial, six participants who had received an intravenous infusion during the first half of the trial continued to participate. Four of these participants received a second antibody infusion while the other two did not. In addition, four new participants joined the study and received a single intravenous infusion of CIS43LS. Another seven people joined the study as controls who did not receive the antibody.

All participants in the second half of the trial provided informed consent to be exposed to the malaria parasite in what is known as a controlled human malaria infection (CHMI). In this procedure, volunteers are exposed to P. falciparum through bites of infected mosquitos in a carefully controlled setting, then are closely monitored by medical staff for several weeks and promptly treated if they develop malaria. Nine participants who had received CIS43LS and six participants who served as controls voluntarily underwent CHMI and were closely monitored for 21 days. Within that period, none of the nine participants who had received CIS43LS developed malaria, but five of the six controls did. The participants with malaria received standard therapy to eliminate the infection.

Among the nine participants who received CIS43LS and were protected, seven underwent CHMI approximately four weeks after their infusion. The other two participants had received their sole infusion during the first half of the study and were infected approximately nine months later. These results indicate that just one dose of the experimental antibody can prevent malaria for one to nine months after infusion. Collectively, these data provide evidence that administration of an antimalaria monoclonal antibody is safe and can prevent malaria infection in humans.

To build on this finding, a larger Phase 2 clinical trial is underway in Mali to evaluate the safety and efficacy of CIS43LS at preventing malaria infection in adults during a six-month malaria season, with results expected in early 2022. In addition, VRC scientists are conducting further research on CIS43LS in the United States to determine the lowest dose that protects people from malaria infection.

“Monoclonal antibodies may represent a new approach for preventing malaria in travellers, military personnel and healthcare workers traveling to malaria-endemic regions,” Dr Seder said. “Further research will determine whether monoclonal antibodies can also be used for the seasonal control of malaria in Africa and ultimately for malaria-elimination campaigns.”

Image caption: Colourised electron micrograph showing malaria parasite (right, blue) attaching to a human red blood cell. The inset shows a detail of the attachment point at higher magnification. Image credit: NIAID.

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