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Scientists find potential new malaria blocker in CIS43
A monoclonal antibody identified in the blood of individuals vaccinated for malaria could offer a new, more effective target for preventing infection with the tropical disease. This discovery is the result of joint work between scientists at the National Institutes of Health (NIH) and the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center. The study was published in Nature Medicine, with the work led by Dr. Marie Pancera, a Fred Hutch structural biologist and co-senior author of the study, and Dr. Robert A. Seder of the NIH.
Malaria results from the Plasmodium parasite and is transmitted via mosquitos, specifically infected female Anopheles mosquitos. According to the World Health Organization (WHO), there were approximately 216 million cases of malaria across 91 countries in 2016, 5 million more cases than seen in 2015. Deaths due to malaria totaled 445,000 in 2016, and the disease was estimated to cost $2.7 billion in funding for control and elimination efforts. While deaths from malaria were down slightly in 2016 compared to 2015--a decrease of 1,000 deaths--new options are sorely needed, particularly given the issue of resistance to antimalarial drugs.
At present, only a single malaria vaccine candidate has made it to Phase 3 clinical trials. The candidate in question, RTS,S, has been shown to protect only about a third of children, but even with that limited effectiveness, a pilot introduction with continued evaluation is expected to take place this year in certain areas of Kenya, Ghana and Malawi.
The focus of this newest work was the identification of a unique binding site on circumsporozoite (CSP), a protein found on the surface of the malaria parasite. The antibody in question is known as CIS43. It's thought that, provided it has similar efficacy in humans, that it could offer protection from malaria for up to six months—a vast improvement over existing preventative malarial drugs, which have to be taken daily.
The team started their work with a batch of individuals who had been immunized with PfSPZ, an experimental malaria vaccine developed by Sanaria Inc. and comprised of whole, weakened malaria parasites. By testing the blood of the inoculated participants, Seder and his team identified the antibody CIS43 as being more protective than any other antibody they examined. The monoclonal antibody “conferred high-level, sterile protection in two different mouse models of malaria infection,” the authors reported in their study.
Pancera was the one to describe the molecular structure of the CIS43 antibody and detail the sites where it binds to portions of the malaria parasite’s surface. A virologist who at the time was working in the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, she is also studying HIV.
“The whole scientific field has learned from all the work that has been done in HIV — learning from infected people or vaccinated people, trying to understand their immune response, and then using that information for a vaccine,” Pancera said.
What they found, as noted in the Nature Medicine paper, was that “The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif.”
“The group used excellent structural and biophysical methods to analyze the binding of the antibody to the protein target in order to explain the antibodies’ neutralizing capacity,” commented Dr. Sean Murphy of the Seattle-based Center for Infectious Disease Research, who designed the diagnostic tool used in the study.
“This is a big deal because neutralizing monoclonal antibodies have transformed the approach to HIV, and the possibility exists that they will do the same for malaria,” he added.
While this has so far only been tested in animal models, the hope at the NIH is to evaluate this antibody in clinical trials in humans in 2019.
This is not the only malaria research out of the NIH so far this year. At the end of March, the NIH shared research results that could potentially explain why iron can occasionally exacerbate malaria infection. An NIH research team discovered that extra iron interferes with the protein ferroportin, which prevents toxic levels of iron from building up in red blood cells and protects those cells from malaria infection. In addition, they found that a mutant form of ferroportin exists that presents in African populations and seems to have protective characteristics against malaria.
According to the researchers, red blood cells utilize ferroportin as a kind of maintenance crew to remove excess iron, a food source for malaria parasites. When ferroportin was removed from erythroid cells (red blood cells and their precursor cells) in mice, iron levels rose to the point of toxicity, stressing the cells and shortening their life spans. A lack of ferroportin also resulted in more parasites and poorer outcomes in mice vs. those with intact ferroportin.
This work also included the identification of a hormone known as hepcidin, which regulates ferroportin in erythroid cells. Hepcidin lowers ferroportin levels in erythroblasts (precursors to red blood cells) and binds to ferroportin to prevent iron from being removed from cells.
A ferroportin mutation called Q248H was discovered as well, as were its protective effects against malaria. The team was led by Dr. De-Liang Zhang, who remarked in a press release that the team will continue evaluating ferroportin, the noted mutation and its potential use in combating malaria.