Measles is a highly contagious, airborne disease that tends to strike children the hardest. Despite extensive vaccine efforts, the virus remains a major health threat. Scientists at the La Jolla Institute for Immunology (LJI) Center for Vaccine Innovation and Columbia University have discovered how a neutralizing antibody blocks measles virus infection. Using cryo-electron microscopy to observe how the antibody can neutralize the virus before it completes the fusion process.

The findings are published in Science in an article titled, “A neutralizing antibody prevents post-fusion transition of measles virus fusion protein.”

To better understand how the measles virus fuses with cells, the LJI team turned to an antibody called mAb 77. They found that mAb 77 targets the measles fusion glycoprotein, the piece of viral machinery measles uses to enter human cells via a specialized process called fusion.

“What’s exciting about this study is that we’ve captured snapshots of the fusion process in action,” explained LJI professor, president, and CEO Erica Ollmann Saphire, PhD, who co-led the study with Matteo Porotto, PhD, professor of viral molecular pathogenesis (in pediatrics) at Columbia University. “The series of images is like a flip book where we see snapshots along the way of the fusion protein unfolding, but then we see the antibody locking it together before it can complete the last stage in the fusion process. We think other antibodies against other viruses will do the same thing but have not been imaged like this before.”

The measles virus is just one member of the larger paramyxovirus family, which also includes the deadly Nipah virus.

“What we learn about the fusion process can be medically relevant for Nipah, parainfluenza viruses, and Hendra virus,” said study first author and LJI postdoctoral researcher Dawid Zyla, PhD. “These are all viruses with pandemic potential.”

“Measles causes more childhood deaths than any other vaccine-preventable disease, and it’s also one of the most infectious viruses known,” added Saphire.

It’s not just young children at risk, explained Zyla. “The current vaccine works well, but it cannot be taken by pregnant people or people with compromised immune systems,” Zyla said.

The LJI team needed to engineer a version of the measles fusion glycoprotein—a harmless fragment of the virus—stable enough to image with a cryo-electron microscope. To do this, Zyla worked closely with scientists in Porotto’s laboratory at Columbia University.

Porotto’s group had uncovered some strange mutations in a measles variant that attacked peoples’ central nervous systems. This mutated variant had some weak points in its fusion glycoprotein structure. To compensate, the virus had evolved special stabilizing mutations. “The virus has to mutate to go into the brain, but then it needs these stabilizing mutations to compensate,” said Porotto.

Thanks to these discoveries at Columbia, Zyla had a strategy for engineering a fusion glycoprotein with these same stabilizing mutations. This new fusion glycoprotein could be mass produced in cell culture, and it was sturdy enough for structural investigations.

“We got extremely good yields for the glycoprotein, which also enabled us to do structural biology and biochemical and biophysical studies,” said Zyla.

The scientists then captured images with the help of the LJI Cryoelectron Microscopy Core. The new images showed the fusion glycoprotein together “in complex” with mAb 77.

The scientists observed how mAb 77 arrests the virus in the middle of the fusion process—when fusion glycoprotein is already part way done “folding” into the right conformation to complete membrane fusion.

“It was striking to see what this intermediate step in the fusion process actually looks like,” said Zyla.

Looking toward the future, the scientists hope the antibody could be used as part of a treatment cocktail to protect people against measles or to treat people with active measles infection.

In a follow-up experiment, the scientists showed that mAb 77 provided significant protection against measles in cotton rat models of measles virus infection. Cotton rats pretreated with mAb 77 prior to measles virus exposure showed either no infection or reduced signs of infection in their lung tissue.

Going forward, Saphire and Zyla are interested in studying different antibodies against measles. “We’d like to stop fusion at different points in the process and investigate other therapeutic opportunities,” Zyla said.

Zyla also plans to continue working closely with measles researchers at Columbia University. “The combination of structural biology expertise from LJI and cell biology and virology expertise from Columbia was key to pushing this project forward,” said Zyla.

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