A recent study from the La Jolla Institute for Immunology (LJI) provides researchers with guidance to neutralizing the Lassa virus utilizing a trio of unusual antibodies obtained from Lassa virus survivors.Lassa virus is a lethal virus that is indigenous to West Africa and is mostly transmitted by rodents.
The virus is responsible for Lassa fever, a disease that affects up to 300,000 people each year and normally begins with flu-like symptoms but can progress to severe sickness, death, and long-term problems such as deafness. Lassa virus is especially deadly for pregnant women: over 90% of infections during pregnancy are fatal.
LJI researchers can now demonstrate how a mixture of three human antibodies can prevent viral infection. These antibodies may be useful in planned clinical trials for Lassa therapies, and the LJI team intends to use their newly discovered map of the Lassa virus surface glycoprotein to develop a much-needed vaccine.
“We now know where these three therapeutic antibodies act and how exactly they act,” says Kathryn Hastie, Ph.D., an LJI Instructor and the Director of the Antibody Discovery Center at LJI.
The findings were published in Science Translational Medicine as a cover story on October 26, 2022. The research was led by the Saphire Lab at LJI, including Instructor Haoyang Li, Ph.D., Hastie, and Professor Erica Ollmann Saphire, Ph.D., in collaboration with Luis Branco, Ph.D., of Zalgen Labs LLC.
The power of neutralizing antibodies
In 2017, Hastie and her colleagues at Scripps Research’s Saphire Lab published the first structural photos of the Lassa virus glycoprotein. Lassa enters host cells via glycoproteins and initiates infection. The structure of Hastie’s glycoprotein gave researchers a sense of what they were up against.
Hastie’s discovery emerged while researchers searched for the rare human antibodies that could overcome Lassa’s defenses. Researchers hoped to use these neutralizing antibodies to produce Lassa fever treatments or vaccinations.
This hope was realized when Tulane University and Zalgen Labs LLC researchers discovered a promising group of Lassa-fighting antibodies from the blood of Lassa disease survivors. The University of Texas Medical Branch then tested a combination of three neutralizing antibodies in nonhuman primates. This antibody therapy, known as Arevirumab-3, was completely efficient in curing Lassa fever in animals with advanced disease.
“This was a groundbreaking finding,” says Saphire. “The dogma had been that antibodies would not be protective against Lassa virus.”
When it came time to put the combination through human clinical trials, the researchers ran into a snag. The US Food and Drug Administration refused to allow clinical trials to begin unless researchers identified the mechanism that made the therapy so effective. How did these neutralizing antibodies specifically target the Lassa virus glycoprotein and prevent infection?
Researchers needed a more detailed map of Lassa glycoprotein to address the question. Hastie’s original glycoprotein structure required complex molecular engineering to offer enough stability for imaging. Her structure provided scientists with a key peek of the Lassa glycoprotein, but not the complete picture. Furthermore, certain prospective therapeutic antibodies were unable to identify this or any other type of modified Lassa glycoprotein.
For additional research, the researchers were required to extract a natural glycoprotein target.Fortunately, the Saphire Lab had the tools and expertise to reveal these molecular details. Li led the effort to produce a “native” Lassa glycoprotein. Thanks to advances in protein production and three years of perseverance, Li’s version of the glycoprotein was a copy of the real thing and could be recognized by all three antibodies used in Arevirumab-3. Li then used a technique called cryo-electron microscopy single-particle analysis to image the native glycoprotein together with the three antibodies.
“Haoyang’s ingenuity and hard work enabled us to see the structures we couldn’t see before,” says Hastie.
A new map of the Lassa virus targets
The scientists discovered how the three antibodies utilized in Arevirumab-3 neutralize the Lassa virus using high-resolution structures and various functional experiments.
Hastie was taken aback when he saw how antibody 8.9F binds to the very top of the glycoprotein molecule.
This region of the glycoprotein is where three molecules (called protomers) combine to form a “trimer,” which Hastie characterizes as a “twisted trefoil.” Lassa would typically use this section of the glycoprotein to attach to host cell receptors, but Li’s structure shows how a single 8.9F leaps in and binds to all three protomers at the same time to prevent infection.
“The structure is really a beautiful illumination of how this antibody essentially mimics the host receptor to block the glycoprotein receptor from binding,” says Hastie. “It’s an absolutely gorgeous structure to see.”
Meanwhile, the neutralizing antibody 12.1F attaches to only one of the three-sided trimer’s protomers. Fortunately, any treatment would have a large number of copies of 12.1F. Each 12.1F antibody can bind to a protomer to aid in virus neutralization when moving as a team of three.
Simultaneously, copies of antibody 37.2D target the Lassa virus by binding in a way that binds adjacent protomers together. This antibody activity is a major issue for Lassa, as the virus has to open up its trimer (where the protomers come together) in order to infect host cells. With 37.2D on the scene, its entry mechanism is rendered inoperable.
“Lassa has another trick. It shields itself using a thick coat of human carbohydrate molecules — like a wolf in sheep’s clothing,” says Saphire, “Haoyang’s structures clearly show how these potent, protective antibodies breach or even utilize the carbohydrates to target and neutralize the virus.”
“The findings fill a critical gap in Lassa virus research and may pave the way for Arevirumab-3 to move into clinical trials,” says Branco, who will lead the Zalgen team to perform future clinical trials.
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