PROVIDENCE, R.I. – Rhode Island Hospital researchers have discovered a protein that is essential for malaria-causing parasites to escape from inside red blood cells. Antibodies to this protein trap the parasite inside these red blood cells. This protein could lead to the development of a vaccine that would prevent the progression of Plasmodium falciparum malaria, which kills one child every 15 seconds each year in Sub-Saharan Africa and Southeast Asia, according to new research by Jonathan Kurtis, M.D., Ph.D., and colleagues, published in the May 23 issue of journal Science.
"This research really began in 2002 when our colleagues from the National Institutes of Health, led by Patrick Duffy and Michal Fried, enrolled a birth cohort of children in Tanzania," said Kurtis, director of the Center for International Health Research at Rhode Island Hospital, and the study's principal investigator. "Six years ago we began using these samples to identify novel vaccine candidates and now it's coming full circle. While a portion of this research was conducted in mice, the actual vaccine discovery experiments were performed using human samples, thus we believe the results will effectively translate to humans."
In the mouse experiments, researchers conducted five independent vaccine trials in which mice were vaccinated with the novel antigen, which they have designated as Schizont Egress Antigen-1 (PfSEA-1) or control. All mice were then challenged with malaria parasites. In all five experiments, vaccinated mice had lower levels of malaria parasites and survived longer than the unvaccinated mice.
"When my post-doctoral fellow Dipak Raj discovered that antibodies to this protein, PfSEA-1, effectively trapped the malaria-causing parasite within the red blood cells, it was truly a moment of discovery,'" Kurtis said. "Many researchers are trying to find ways to develop a malaria vaccine by preventing the parasite from entering the red blood cell, and here we found a way to block it from leaving the cell once it has entered. If it's trapped in the red blood cell, it can't go anywhere… it can't do any further damage."
The researcher then measured antibodies to PfSEA-1 in the entire Tanzanian birth cohort of 785 children. Surprisingly, among children with antibodies to PfSEA-1, there were zero cases of severe malaria. To generalize their results, researchers then went back to a serum bank they had collected from 140 children in Kenya in 1997. They found that individuals with antibodies to PfSEA-1 had 50 percent lower parasitemia than individuals without these antibodies during a high transmission season.
"We still have additional trials ahead of us, first in another animal model, but we hope to begin Phase I trials in humans very soon," Kurtis said. "Our findings support PfSEA-1 as a potential vaccine candidate, and we are confident that by partnering with our colleagues at the National Institutes of Health and other researchers focused on vaccines to prevent the parasites from entering red blood cells, we can approach the parasite from all angles, which could help us develop a truly effective vaccine to prevent this infectious disease that kills millions of children every year."
Scientists at Rhode Island Hospital/Brown University led the discovery of PfSEA-1 and scientists at NIAID led the epidemiological studies in endemic areas, with contribution of scientists at Harvard Medical School and the University of Washington, which was partially supported by NIAID grants R01-AI52059 and R01-AI076353.
ARTICLE: DK Raj et al. Antibodies to PfSEA-1 block parasite egress from RBCs and protect against malaria infection. Science. DOI: 10.1126/science.1254417 (2014).
This work was supported by grants from the US National Institutes of Health (R01-AI076353 to Kurtis, R01-AI52059-to Duffy); Intramural Research Program of the NIAID-NIH; the Bill & Melinda Gates Foundation grant awarded to Duffy (1364); grants from the NIH awarded to Jeffrey Dvorin of Boston Children's Hospital (R01-AI102907 and DP2-AI112219); and an internal Lifespan Hospital System Research Pilot Award Grant to Kurtis. Kurtis' principal affiliation is Rhode Island Hospital, a member hospital of the Lifespan health system in Rhode Island. He also has an academic appointment at The Warren Alpert Medical School of Brown University, Department of Pathology and Laboratory Medicine. Other researchers include Dipak K. Raj, Christian Nixon, Christina Nixon, Sunthorn Pond-Tor, Lauren Pischel, Ailin Lu, Ling Cheng and Emily McDonald, all of the Center for International Health Research at Rhode Island Hospital; Hai-Wei Wu, Ian Michelow and Jennifer Friedman of the Center for International Health Research, and the Department of Pediatrics at Rhode Island Hospital; Grant Jolly and Solomon Conteh of the Department of Pathology and Laboratory Medicine at Rhode Island Hospital, all are affiliated with the Alpert Medical School of Brown University; Jeffrey Dvorin, Christen DiPetrillo and Sabrina Absalon of the Division of Infectious Diseases at Boston Children's Hospital and Harvard Medical School; Sarah Holte of the Fred Hutchinson Cancer Research Cener Program in Biostatistics and Biomathematics at University of Washington Seattle; and Michal Fried and Patrick Duffy of the Laboratory of Malaria Immunology and Vaccinology at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.
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Founded in 1863, Rhode Island Hospital in Providence, R.I., is a private, not-for-profit hospital and is the principal teaching hospital of The Warren Alpert Medical School of Brown University. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Last year, Rhode Island Hospital received more than $55 million in external research funding. It is also home to Hasbro Children's Hospital, the state's only facility dedicated to pediatric care. For more information on Rhode Island Hospital, visit http://www.rhodeislandhospital.org, follow us on Twitter @RIHospital or like us on Facebook http://www.facebook.com/rhodeislandhospitalpage.