New antibody and unique binding site offer possible paths to malaria prevention

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New antibody and unique binding site offer possible paths to malaria prevention

Led by NIH, Fred Hutch researchers, early study holds promise for direct infusion or vaccine design

March 19, 2018
A graphic representation of 3-D protein structures showing the surface circumsporozoite protein of the malaria parasite being recognized very differently by two different antibodies.

The specific portion (the junctional epitope) of the surface circumsporozoite protein of the malaria parasite is shown in pink in this illustration. It is being recognized very differently by two different antibodies: The green (heavy chain) and tan (light chain) antibody is not protective while the blue (heavy chain) and tan (light chain) one is CIS43, a protective antibody. Researchers study these structures to better understand why one antibody is more protective than others.

Illustration courtesy of Connor Weidle and Dr. Marie Pancera.

Scientists have discovered a human antibody that, when tested in mice, prevented malaria infection by binding a specific portion of a surface protein found in almost all strains of the malaria parasite worldwide.

The paired findings — of both the antibody and the site it targets on the surface protein — could open new pathways to malaria prevention. The research, published today in the journal Nature Medicine, was led by scientists at the National Institutes of Health and the Vaccine and Infectious Disease Division of Fred Hutchinson Cancer Research Center.

The study shows that the antibody, called CIS43, protects against malaria better than any antibody that has been described before, said Dr. Marie Pancera, a Fred Hutch structural biologist and co-senior author of the study with the NIH’s Dr. Robert A. Seder. If shown to be effective in humans, the antibody could be given to people directly — similar to another antibody now being tested against HIV in clinical trials — and potentially protect them from malaria for up to six months. Preventive malaria drugs available now must be taken daily.

What especially interests Pancera is whether researchers could use the unique binding site the study identified on the surface protein known as circumsporozoite protein, or CSP, to design a vaccine that could tickle the immune system to produce such antibodies.

Malaria kills about 445,000 people a year, mostly young children in sub-Saharan Africa, and sickens more than 200 million. It is caused by the Plasmodium parasite and spread to humans through the bite of an infected Anopheles mosquito. About half the world’s population lives in areas that put them at risk of infection and the huge social and economic burdens that infection entails.

The parasite’s complex life cycle and rapid mutations have long challenged vaccine developers. Only one experimental vaccine, known as RTS,S, has made it as far as a Phase 3 clinical trial, which found it to protect only about one-third of young children who received it. Pilot introduction with continued evaluation is scheduled to begin this year in selected areas of Ghana, Kenya and Malawi.

RTS,S uses a fragment of CSP, the protein exposed at the surface of the malaria parasite, to elicit an immune response. Notably, however, it does not include this new site of vulnerability identified in Seder and Pancera’s study. That gives scientists reason to believe that a vaccine that did so would provide broader protection.

The search for malaria antibodies

Seder and his team began looking for antibodies in the blood of volunteers who had been immunized with yet another experimental vaccine known as PfSPZ, developed by Sanaria Inc. This vaccine protected them against infection.

If that experimental vaccine worked, why not use it? The problem is mass production. Rather than just protein fragments, PfSPZ is made from whole, weakened malaria parasites. This approach has been shown to be highly effective. But so far, such vaccines have also been difficult to produce and administer in scales larger than needed for small studies.

So scientists have been trying to figure out what made it protective, and then use their findings to design a more practical approach. That is how Seder’s team came to be fishing around for antibodies in the blood of those PfSPZ-protected volunteers. One antibody, CIS43, was found to be more protective than any other tested.

Dr. Marie Pancera

Fred Hutch's Dr. Marie Pancera

Photo by Robert Hood / Fred Hutch News Service

Pancera at the time was working upstairs from Seder’s lab at the Vaccine Research Center, part of the NIH’s National Institute of Allergy and Infectious Diseases. She was (and still is) studying another challenging pathogen for which there is not yet a vaccine: HIV. Seder studies HIV as well, and work done in that field informed his pursuit of malaria antibodies.

“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.

A virologist by training, Pancera had shifted toward structural biology — essentially, figuring out what can be learned from how a protein is shaped. Here, too, HIV research “is really pushing the field forward,” she said, with discoveries about how antibodies bind a site on proteins exposed on the surface of the virus. Pancera had begun to think about applying this approach to the malaria parasite when she learned of Seder’s search for antibodies.

A hotbed of malaria research

After moving to Seattle and joining the Hutch’s Vaccine and Infectious Disease Division, or VIDD, in 2016, Pancera received funding from a VIDD Initiative Grant to pursue work on malaria and support from VIDD to apply for a J.B. Pendleton Charitable Trust grant for equipment. Because of her initial work on malaria, she received a subaward grant from the Bill & Melinda Gates Foundation.

She had landed in a hotbed of malaria research. The Seattle-based Gates Foundation had in 1999 almost single-handedly revitalized efforts to combat and even eradicate malaria.

Pancera’s contribution to the Nature Medicine study was to describe the molecular structure of the CIS43 antibody — found in those protected volunteers — and of the sites where it bound to portions of the parasite surface.

“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,” said Dr. Sean Murphy of the Seattle-based Center for Infectious Disease Research, who designed the diagnostic tool used in the study. He added that further study of the target of the antibody could reveal ways to get a vaccine to trigger the exact antibody response.

“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 said.

Next steps

NIH researchers are planning to test the CIS43 antibody in human clinical trials next year.

Pancera will continue studying CIS43 — as well as another antibody that was able to bind the same site but was not protective — to see what can be learned from their differences that might influence the design of a vaccine.

“They bind in a different way, from a different angle. Maybe that matters and maybe it doesn’t,” she said. “What excites me about structural biology is that you see things and then use what you see to try to understand the biology and possibly apply this to make vaccines. “

By puzzling out what she sees, she hopes to develop a vaccine with a group of collaborators from the NIH and the University of Washington that is more protective than RTS,S, and then test it by November 2020.

Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.

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