University of Maryland School of Medicine Researchers Found CIS43LS to be Safe, Well Tolerated in Human Challenge Trial
A monoclonal antibody treatment was found to be safe, well tolerated, and effective in protecting against malaria in a small group of healthy volunteers who were exposed to malaria in a challenge study, according to new research published in The Lancet Infectious Diseases by researchers at the University of Maryland School of Medicine (UMSOM).
“The study demonstrates the feasibility of using monoclonal antibody therapies to help prevent malarial infection and holds promise for deployment to places where the disease is endemic,” said Kirsten Lyke, MD, Professor of Medicine and Director of the Malaria Vaccine and Challenge Unit in the Center for Vaccine Development and Global Health (CVD) at UMSOM. “This may allow us to revisit malaria eradication efforts.”
There were 241 million malaria cases and 627,000 deaths reported worldwide in 2020 alone, which is a 12 percent increase from 2019. Public health experts contend new strategies are urgently needed to achieve the United Nation’s sustainable development goal of 90 percent reduction in malaria incidence and mortality by 2030. Scientists have tried for decades to develop a highly effective malaria vaccine without much success.
Monoclonal antibodies represent a promising approach to reduce malaria morbidity and mortality, and they offer a new tool for use in in preventing infection. Highly effective malaria vaccines have so far been elusive since they have not been shown to provide much protection in those who have already been infected with malaria earlier in life, but numerous trials conducted by CVD investigators show promise in this arena as well.
CVD was the first center in the world to develop controlled human malaria infection studies, providing proof of principle that live attenuated malaria vaccines protect against infection. CVD researchers conducted genome-wide studies of antimalarial drug resistance and have tested monoclonal antibodies for treating malaria. This is the first time they have tested an experimental monoclonal antibody in a challenge study in a CVD lab in Baltimore.
The new research describes the final dose selection section of a three-part clinical trial. The monoclonal antibody CIS43LS provided high levels of protection in the first two parts of the trial, in which researchers administered 20 or 40 milligrams per kilogram (mg/kg) of the monoclonal antibody via IV infusions. In the current study, 29 healthy study participants, ages 18 to 50 years – who had no prior malaria infections or vaccinations – received a single dose of CIS43LS in doses of 1, 5, or 10 mg/kg via IV infusions, or by subcutaneous injection (injected just under the skin).
Study participants were bitten by five mosquitoes infected with a Plasmodium falciparum strain of malaria about eight weeks after they were given the monoclonal antibody. A single dose of CIS43LS at 5-10 mg/kg administered subcutaneously or intravenously provided high level protection against a controlled human malaria infection with partial protection achieved at 1 mg/kg administered intravenously. Eight control participants who did not receive the monoclonal antibody all developed malaria. All participants were monitored for 24 weeks.
Immunologic studies suggest a level of protection that might extend to 6 months after administration. Furthermore, administering the monoclonal antibody subcutaneously is an easier means of delivering the dosing and allows for widespread distribution to children and adults in malaria endemic areas.
“While previous research suggests that monoclonal antibodies can be effective against malaria using higher dose IV infusions, this new study finds that the prophylactic treatment can also provide a high-level of protection with just a single injection,” said UMSOM Dean Mark T. Gladwin, MD, Vice President for Medical Affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor. “That’s a potential game changer that could provide a practical way to deploy monoclonal antibody therapies in African countries.”
Adverse events from the monoclonal antibody were mild and included pain or redness at the infusion site, headache, abdominal pain, and hypertension, which resolved within a day. The study authors said additional research is needed to explore whether CIS43LS can be used for long-term protection and to determine optimal dosage in African children. Additionally, future research should assess whether monoclonal antibodies can be safely used to protect pregnant women. Phase 2 clinical trials are underway in Mali and Kenya. The technology of monoclonal antibodies may lend an important tool towards the eradication of human malaria.
Additional coauthors on the newly published research from UMSOM include: Andrea A. Berry, MD, Associate Professor of Pediatrics and Medicine, and others in CVD’s Malaria Research Program.
This research is funded by the National Institute of Allergy and Infectious Diseases, Intramural Research Program, National Institutes of Health, ClinicalTrials.gov registration number NCT04206332.
About the University of Maryland School of Medicine
Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.3 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic, and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the U.S., and in the top 15 percent (#27) of all 192 public and private U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu
About the Center for Vaccine Development and Global Health
For over 40 years, researchers in the Center for Vaccine Development and Global Health have worked domestically and internationally to develop, test, and deploy vaccines to aid the world’s underserved populations. CVD is an academic enterprise engaged in the full range of infectious disease intervention from basic laboratory research through vaccine development, pre-clinical and clinical evaluation, large-scale pre-licensure field studies, and post-licensure assessments. CVD has worked to eliminate vaccine-preventable diseases. CVD has created and tested vaccines against cholera, typhoid fever, paratyphoid fever, non-typhoidal Salmonella disease, shigellosis (bacillary dysentery), Escherichia coli diarrhea, nosocomial pathogens, tularemia, influenza, malaria, and other infectious diseases. CVD’s research covers the broader goal of improving global health by conducting innovative, leading research in Baltimore and around the world. CVD researchers are developing new and improved ways to diagnose, prevent, treat, control, and eliminate diseases of global impact. Currently, these diseases include typhoid, Shigella, E. coli diarrhea, malaria, and other vaccine-preventable infectious diseases. CVD researchers have been involved in critical vaccine development for emerging pathogens such as Ebola and Zika. In addition, CVD’s work focuses on the ever-growing challenge of antimicrobial research.