Molecular test confirms antimalarial antibody’s efficacy

A highly sensitive molecular lab test recently confirmed that an experimental monoclonal antibody targeting malaria can prevent malaria parasite infection.  The lab test was developed at the University of Washington School of Medicine

The researchers hope the results from the study will lead to wider adoption of the test in global malaria-control efforts.

“Our molecular test for malaria parasites is like a crystal ball for clinical trials and field studies. It allows us to detect infections even when there are very few parasites in a person, which is impossible with older, more conventional tests,’ said study co-author Dr. Sean Murphy, professor of laboratory medicine and pathology and director of the Malaria Molecular Diagnostic Laboratory at the University of Washington School of Medicine. 

The research results are reported this month in Nature Medicine. Jeff Skinner of the NIH’s National Institute of Allergy and Infectious Diseases is the first author.

The study evaluated an experimental antibody that targets Plasmodium falciparum, the parasite that causes the deadliest form of malaria. Plasmodium is spread by mosquitoes that pick up the parasite when they bite an infected person and then transmit it when they bite someone else. 

Each year, P. falciparum causes 200 million malaria cases and 600,000 deaths, mostly among young children in Africa. 

The antibody, called CIS43LS, was created at the National Institutes of Health (NIH). It binds to a protein found on the surface of the parasite. This neutralizes the parasite when it enters the body, before it can establish an infection. 

The molecular diagnostic test was used to confirm the results of a randomized, double-blind trial conducted in 2021 in Mali, West Africa. In the study, 330 adult participants were first given antimalarial medication to ensure they were free of malaria. They then received either the antibody or a placebo. The antibody was given in one of two doses, 40 mg per kilogram or 10 mg per kilogram. 

The participants were then checked during Mali’s six-month malaria season with a series of tests to look for infection. The initial test the researchers used, called the thick blood smear, has been available for more than a century. Today it is still used routinely in clinics and in research.

Thick blood smears consist of spreading a blood sample on a glass slide, staining it and looking for malaria parasites under a microscope. Using this method, researchers determined that the higher-dose vaccine reduced a person’s risk of infection by 88.2% and the lower-dose vaccine reduced their risk by 75% over the study span.

Although these results were promising, the thick blood smear is not very sensitive, said Weston Staubus, a research scientist who worked on the project in Murphy’s Malaria Molecular Diagnostic Laboratory. 

“Typically, a sample of blood needs to have about 40,000 parasites per milliliter for an infection to be seen in a blood smear. As a result, low-level infections in some participants may not have been detected by the smears,” Staubus said.

People with such infections may not feel ill but can still contribute to the spread of the parasite if they are bitten by a mosquito that can transmit it to others.

 “This is a big problem because you may have infected people walking around without any signs or symptoms and who have tested negative with the thick blood smear test who can still spread the infection in the community,” Staubus said. “These infections need to be accounted for in malaria-control efforts”.

The researchers wanted to see if the study’s results held up when participants’ blood samples were tested with a more sensitive molecular test that can detect minuscule amounts of parasite RNA in the blood. The molecular lab test, which is about 2,000 times more sensitive than the thick blood smear, makes it possible to detect parasites when there are as few as 20 per milliliter.

The test looks for the 18S subunit of the plasmodium ribosome, hence it is named the Plasmodium 18S rRNA qRT PCR assay. 

“This test is so sensitive (that) it captures almost everyone who is infected,” Murphy said. 

With this approach, the researchers were able to confirm that infusions of the CIS43LS antibody were 87.4% effective with the larger dose and 77% effective with the lower dose.

The findings indicate that a single dose of CIS43LS might not only protect people from symptoms of malaria, but also completely prevent infection as well as transmission from person to person.

With Gates Foundation funding, Murphy and his colleagues are working on a Malaria Molecular Diagnostic Network to make the test more readily available in clinics located in high malaria regions like Africa. 

The study was a collaboration between NIH and UW Medicine researchers and researchers at the University of Sciences, Techniques and Technology of Bamako, Bamako, Mali.

The work was supported by the Division of Intramural Research and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health and by the Gates Foundation (INV-052365, INV-061041).

The same molecular test is being used in local Seattle-based malaria human challenge studies. One such local study that is just starting will test the PfSPZ-LARC2 malaria vaccine. LARC2 is a vaccine candidate developed by Drs. Stefan Kappe, Ashley Vaughan and their teams of scientists at Seattle Children’s Research Institute. This clinical trial is currently recruiting healthy volunteers to participate at the Vaccine Research Center at Harborview Medical Center in Seattle. 

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