A first-in-human Phase I clinical trial has found that one dose of a monoclonal antibody, designated CIS43LS, safely prevented malaria for up to nine months in people who were exposed to the malaria parasite Plasmodium falciparum. The open-label, dose-escalating two-part study is the first to demonstrate that a monoclonal antibody can prevent malaria in people, and a larger, Phase II study is now under way. CIS43LS was discovered and has been developed at the National Institutes of Health (NIH). The NIH team has now published the Phase I study findings in the New England Journal of Medicine (NEJM), in a paper titled, “A Monoclonal Antibody for Malaria Prevention.” The trial was sponsored and conducted by scientists from the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, and was funded by NIAID.
“Malaria continues to be a major cause of illness and death in many regions of the world, especially in infants and young children; therefore, new tools are needed to prevent this deadly disease,” said NIAID director Anthony S. Fauci, MD. “The results reported today suggest that a single infusion of a monoclonal antibody can protect people from malaria for at least nine months. Additional research is needed, however, to confirm and extend this finding.”
According to the World Health Organization, there were an estimated 229 million cases of malaria worldwide in 2019, resulting in an estimated 409,000 deaths, mostly in children in sub-Saharan Africa. So far, no licensed or experimental malaria vaccines provide more than 50% protection from the disease over the course of a year or longer. And, as the authors noted, “Although public health measures such as insecticide-treated bed nets and antimalarial drugs led to a 50–75% reduction in global malaria cases in the period from 2000 to 2015, the incidence of malaria is now increasing in many areas despite these interventions … Given the health and economic burden attributable to malaria, additional countermeasures are needed to better control and possibly eliminate this disease.”
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.
Laboratory and animal studies have demonstrated that antibodies can prevent malaria by neutralizing the sporozoites of P. falciparum in the skin and blood before they can infect liver cells. The NIAID trial tested whether the neutralizing monoclonal antibody 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 neutralizing antibody called CIS43. In 2018, researchers led by Robert A. Seder, MD, chief of the cellular immunology section of the VRC Immunology Laboratory, reported the isolation of 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 the antibody to extend the amount of time it would remain in the bloodstream, creating CIS43LS. “Before it was evaluated in humans, CIS43 was modified to CIS43LS by means of site-directed mutagenesis of its Fc region, which converted methionine to leucine and asparagine to serine to prolong plasma half-life through increased neonatal Fc receptor–mediated antibody recirculation,” the team wrote in their newly released NEJM paper.
Following promising results from animal studies assessing CIS43LS for malaria prevention, VRC investigators launched a Phase I dose-escalation trial clinical trial of the experimental antibody. The study participants included 40 healthy adults, aged 18–50 years, who had never had malaria or been vaccinated for the disease. The trial was led by Martin Gaudinski, MD, medical director of the VRC Clinical Trials Program, and was conducted at the NIH Clinical Center in Bethesda, MD, and the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, MD.
“The primary objectives of the trial were to evaluate the safety and initial side-effect profile of CIS43LS,” the study investigators stated. “Secondary objectives were to assess the pharmacokinetic properties and efficacy of CIS43LS in preventing malaria after controlled human malaria infection.”
During the first half of the trial, 21 participants were given one dose of CIS43LS by either an intravenous infusion or an injection under the skin. The infusions ranged from 5–40 mg/kg body weight, and the subcutaneous injections were 5 mg/kg. Investigators followed the participants for six months to determine whether the infusions and subcutaneous injections of the various doses of the experimental antibody were safe and well tolerated. In addition, the team 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 control participants 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. They are then closely monitored by medical staff for several weeks and promptly treated if they develop malaria. CHMI has been used for decades to generate information about the safety and protective effect of malaria vaccine candidates and potential antimalarial drugs.
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 1–9 months after infusion. Collectively, the data provide the first evidence that administration of an anti-malaria monoclonal antibody is safe and can prevent malaria infection in humans.
There were also no evident safety issues with the antibody administration. “In this small Phase I trial, no safety concerns associated with CIS43LS were identified after one or two intravenous administrations, as well as after subcutaneous administration,” the team noted. “There were no infusion-related reactions or dose-limiting toxic effects.”
The team said the trial offered “two major advances” for malaria prevention. First, the region of the P. falciparum circumsporozoite protein targetetd by CIS43LS supports inclusion of the same site in next-generation vaccines. Second, the trial provides what the investigators said represents a potential path forward for passive prevention against malaria. “The observation that a single administration of CIS43LS provided protection against malaria could have potentially broad clinical application, including in the seasonal control of malaria in regions in which it is endemic and in elimination campaigns.”
To build on their Phase I findings, a larger Phase II clinical trial is now underway in Mali to evaluate the safety and efficacy of CIS43LS at preventing malaria infection in adults during a six-month malaria season. The trial is being led by Peter D. Crompton, MD, chief of the Malaria Infection Biology and Immunity Section in the NIAID Laboratory of Immunogenetics, and Kassoum Kayentao, MD, MPH, PhD, a professor at the University of Sciences, Techniques, and Technologies of Bamako, Mali. NIAID is sponsoring and funding the study, from which results are expected during 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. “Passive administration of a potent monoclonal antibody that has a long half-life offers a new approach to the prevention of infection with a single administration, depending on the length of time protection is required,” the authors stated.
“Monoclonal antibodies may represent a new approach for preventing malaria in travelers, military personnel, and health care workers traveling to malaria-endemic regions,” said Seder. “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.”