The World Health Organization (WHO) recently announced that it had approved 15 additional rapid diagnostic tests (RDTs) for malaria, bringing the total number that meet its performance criteria to 37. WHO considers rapid tests a major breakthrough in malaria control, as they enable health workers to accurately diagnose malaria in people living in remote rural areas, where most malaria cases occur.
Twenty-five years ago, the concept of a malaria RDT was considered scientifically questionable. Many malaria experts doubted that RDTs could be as effective as using a microscope to visualize malaria parasites in blood smears. However, a discovery made in NIAID laboratories helped change this perception.
Innovation Leads to First Malaria RDT
During the mid 1980s, NIAID scientists Russell Howard, Ph.D., and Thomas Wellems, M.D., Ph.D., identified and characterized a unique protein called Pf HRP-2, found in abundance in the deadliest malaria parasite, Plasmodium falciparum. They cloned and sequenced the gene that encodes Pf HRP-2 and confirmed that the gene was present in P. falciparum samples from around the world. The researchers then proposed a diagnostic test based on the Pf HRP-2 protein.
"Skepticism about the costs and practicality of RDTs was widespread," says Dr. Wellems, who leads the NIAID Laboratory of Malaria and Vector Research, "but to us it didn't seem far-fetched to think that new detection technologies could support tests that were cheap, gave immediate results, and provided sensitivities as good as standard microscopy."
In 1986, Drs. Howard and Wellems filed a U.S. patent claiming uses of cloned DNA from P. falciparum that encodes an antigenic, or immune-stimulating, portion of the Pf HRP-2 protein; the patent was approved in 1992. Joseph Perrone, Sc.D., of medical technology firm Becton, Dickinson and Company (BD) initiated discussions with Dr. Wellems in 1989 about collaborating on the development of a rapid malaria test. BD ultimately licensed NIAID's invention, and a team of BD scientists, including S. Melissa Maret, Ph.D., and Hans Feindt, Ph.D., used Pf HRP-2 to create ParaSight F, the world's first malaria RDT.
The test hit the market in 1995 after successful clinical testing in several malaria-endemic countries. It was conducted by placing a strip of paper containing Pf HRP-2 antibody in a drop of blood, then applying to the reaction site a detection reagent containing red dye, followed by a wash reagent to remove any unbound reagents from the paper. The dye left a visible red band if the sample was positive for P. falciparum infection.
Right Product, Wrong Time
ParaSight F proved that it was possible to make a simple and accurate malaria diagnostic that didn't require a microscope, electricity, or lengthy training to perform. It seemed like the ideal tool for rural, malaria-endemic settings, where a lack of infrastructure forced health workers to treat patients based on presumptive malaria diagnoses.
However, the high cost of ParaSight F compared with the low cost of first-line malaria drugs like chloroquine hampered widespread adoption of the test. For cash-strapped malaria control programs, it was cheaper to treat suspected malaria cases than to obtain an accurate diagnosis. ParaSight F was not a commercial success, and BD took it off the market in 2000.
Its Time Is Now
Today, more than a decade after ParaSight F provided the prototype, malaria treatment requires new and more expensive drugs because P. falciparum has become chloroquine-resistant. Because these new drugs must be used only when needed, it is more important than ever to make accurate field diagnoses of the illness. WHO estimates that less than one-third of fevers in malaria-endemic areas are actually caused by malaria.
"Artemisin-based combination therapies are now used against chloroquine-resistant malaria, but they are much more expensive than chloroquine, so subsidies to support their availability and diagnostic tests to assure their appropriate use are vital," adds Dr. Wellems.
Today, companies from around the world use Pf HRP-2 detection to make malaria diagnostics similar to ParaSight F. Competition among these manufacturers has led to tests with longer shelf lives, better temperature tolerance, and lower costs. One RDT, called BinaxNOW Malaria, was developed in collaboration with the U.S. military. It received Food and Drug Administration approval in 2007, and today is used in the United States to diagnose malaria in travelers and military personnel returning from areas where the disease is widespread.
WHO estimates that 45 million malaria RDTs will be purchased worldwide this year. While ParaSight F was just a few years ahead of its time, the discoveries of NIAID researchers live on in many of today's malaria RDTs, helping to accurately diagnose a global disease that afflicts millions of people each year.