Lassa fever: Three rare antibodies, combined in a ‘cocktail’, are effective in blocking infection


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A new study from scientists in La Jolla Immunology Institute (LJI) Researchers give evidence of Lassa virus neutralization using a trio of rare antibodies isolated from survivors of Lassa virus infection.

Scanning electron micrograph of budding Lassa virus from a Vero cell.
Image / NIAID

Lassa virus is a deadly virus that is endemic to West Africa, where it is mainly spread by rodents. The virus causes Lassa fever, a disease that affects up to 300,000 people each year and usually begins with flu-like symptoms, but can lead to severe illness, death, and long-term symptoms, such as deafness. The Lassa virus is especially dangerous for pregnant women: approximately 90% of infections during pregnancy are fatal.

LJI scientists can now show exactly how a combination of three human antibodies can prevent viral infection. These antibodies may prove valuable in upcoming clinical trials of Lassa treatments, and the LJI team plans to use their new map of Lassa virus surface glycoprotein to design a much-needed vaccine.

“We now know where these three therapeutic antibodies work and How says Kathryn Hastie, PhD, an LJI trainer and director of the LJI Antibody Discovery Center.

The results have been published in Translational Medicine Sciences As a cover story on October 26, 2022. The research was led by the Saphire Laboratory at LJI, including instructor Haoyang Li, Ph.D., Hastie and Professor Erica Ollmann Saphire, Ph.D., in collaboration with Luis Branco, Ph.D.D. , from Zalgen Labs LLC.

Neutralizing power of antibodies

In 2017, Hastie and colleagues at the Saphire Laboratory (and then at Scripps Research) published the first-ever structural images of a Lassa virus glycoprotein. Lassa uses glycoproteins to enter host cells and initiate infection. The structure of Hastie’s glycoprotein gave the researchers an idea of ​​what they were facing.

Hastie’s breakthrough came as researchers search for rare human antibodies that can penetrate Lassa’s defenses. The hope was that researchers would use these neutralizing antibodies to develop treatments or vaccines for Lassa fever.

That hope became a reality when research partners at Tulane University and Zalgen Labs LLC isolated a promising set of Lassa-resistant antibodies from the blood of Lassa fever survivors. Collaborators from the University of Texas Medical Branch went on to test a mixture of three neutralizing antibodies in non-human primates. This antibody treatment, called Arevirumab-3, has been shown to be 100% effective in treating Lassa fever, even in animals with advanced disease.

“This was a groundbreaking discovery,” Safire says. “The dogma was that the antibodies would not be protective against the Lassa virus.”

When it came time to test the cocktail in human clinical trials, the researchers ran into a problem. The FDA wasn’t ready to start clinical trials until researchers could uncover the mechanism that made the treatment so effective. Exactly how did these neutralizing antibodies target the Lassa virus glycoprotein and prevent infection?

To answer this question, the researchers needed a more detailed map of the Lassa glycoprotein. The original Hastie structure of the glycoprotein required complex molecular engineering to provide sufficient stability for imaging. Its structure has given scientists a critical glimpse into Lassa glycoprotein, but not the whole picture. In addition, some promising therapeutic antibodies were unable to recognize this or any version of the Lassa glycoprotein. The researchers need to isolate a natural glycoprotein target for further investigation.

Fortunately, Sapphire’s lab had the tools and expertise to reveal these molecular details. Lee led efforts to produce an “original” Lassa glycoprotein. Thanks to advances in protein production and three years of persistence, the Li version of the glycoprotein was a copy of the real thing and was identifiable by all three antibodies used in Arevirumab-3. Lee then used a technique called cryo-electron microscopy single-particle analysis to image the original glycoprotein with the three antibodies.

“Haoyang’s ingenuity and hard work enabled us to see structures that we couldn’t see before.” Hastie says.

New map of Lassa virus targets

Based on the high-resolution structures and several functional tests, the team revealed exactly how the three antibodies used in Arevirumab-3 neutralize the Lassa virus.

Learn about neutralizing antibodies: 8.9F, 12.1F and 37.2D.

Hastie was surprised to see how the 8.9F antibody binds to the top of the glycoprotein structure. This region of the glycoprotein is where three molecules (called protomers) come together to form a “terminal,” a type of twisted trilobite, as Hastie describes it. Lassa normally uses this region of the glycoprotein to bind to receptors in host cells, but the Li structure shows how a single 8.9F jumps and binds to all three protomers simultaneously to prevent infection.

“The structure is really a pretty illuminating of how this antibody mimics the host receptor to block the glycoprotein receptor from binding,” Hastie says. “It’s a very cool structure to see.”

Meanwhile, the neutralizing antibody labeled 12.1F binds to only one protomer in the three-pronged trimmer. Fortunately, any remedy contains many copies of 12.1F. Going as a team of three, each 12.1F antibody can bind to a protomer to help neutralize the virus.

At the same time, 37.2D antibody transcripts target the Lassa virus by binding in a way that binds adjacent protomers together. This antibody activity is a major problem for Lassa, as the virus needs to open its trimmer (where protomers clump together) to infect host cells. With the 37.2D on the scene, its entry mechanism is closed, and unable to function.

“Lhasa has another trick. It protects itself by using a thick layer of human carbohydrate molecules—like a wolf in sheep’s clothing,” says Saphire, “the structures of Haoyang clearly show how these powerful, protective antibodies penetrate or even use the carbohydrates to target and neutralize the virus.”

“The results fill a critical gap in Lassa virus research and may pave the way for arivirumab-3 to move into clinical trials.” says Branko, who will lead the Zalgen team for future clinical trials.

Navigating the weak points of Lhasa

With this new study, researchers have evidence for better targeting of three Lhasa vulnerabilities (called loops). Two of these critical episodes have not been mapped before.

In fact, just this year, the Saphire Lab published three articles on anti-Lassa antibodies (including this paper). The other two investigations were published in cell reports (Enriquez et al Cell Reports 2022; PMID: 3561358) And the mbi (Buck et al mBio 2022; PMID: 35730904).

“This working group now presents the first-ever complete epitope map, revealing every weak target of the Lassa glycoprotein.” Sapphire says.

“We now have a very clear idea of ​​what the neutralizing adhesive surface is and the requirements for a glycoprotein in order to bond and identify a person,” Hastie adds.

Li and Hastie use a new glycoprotein epitope map to guide vaccine design. They hope a future vaccine will prompt those at risk to make neutralizing antibodies themselves.

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