Rethinking the rabies vaccine

The rabies virus kills 59,000 people every year, many of them children. Some victims, especially children, do not realize they have been exposed until it is too late. For others, intensive rabies treatment is out of the question: treatment is not widely available, and the average expense of $3,800 represents an unimaginable economic burden for most people around the world.

Rabies vaccines, rather than treatments, are much more affordable and easier to administer. But these vaccines also have a huge downside:

“Rabies vaccines don’t provide lifelong protection. You should have your pets vaccinated every year to three years,” says LJI professor Erica Ollmann Saphire, Ph.D. “Currently, rabies vaccines for humans and pets are made from killed viruses. But this process of inactivation can distort the molecules – so these vaccines don’t show the correct shape in the first place. immune system. If we made a better vaccine that was better trained and better structured, would immunity last longer?”

Saphire and his team, in collaboration with a team led by Hervé Bourhy, Ph.D., at the Institut Pasteur, may have discovered the path to better vaccine design. In a new study published in Scientists progressresearchers share one of the first high-resolution looks at the rabies virus glycoprotein in its vulnerable “trimeric” form.

“The rabies glycoprotein is the only protein that rabies expresses on its surface, which means it will be the primary target for neutralizing antibodies during an infection,” says Heather Callaway, Ph.D., LJI Postdoctoral Fellow. , who serves as the study’s researcher. first author.

“Rabies is the deadliest virus we know of. It’s such a part of our history – we’ve lived with its specter for hundreds of years,” adds Saphire, who is also president and CEO of LJI. “Yet scientists have never observed the organization of its surface molecule. Understanding this structure is important for making more effective vaccines and treatments – and for understanding how rabies and other similar viruses enter cells.”

Rage the shapeshifter

Scientists aren’t exactly sure why rabies vaccines don’t provide long-term protection, but they do know that its shape-changing proteins are a problem.

Like a Swiss army knife, the rabies glycoprotein has sequences that unfold and flip upwards when needed. The glycoprotein can cycle back and forth between pre-fusion (before fusing with a host cell) and post-fusion forms. It can also collapse from a trimeric structure (where three copies come together in a bundle) to a monomer (one copy by itself).

This shapeshifting gives rage a sort of cloak of invisibility. Human antibodies are built to recognize a unique site on a protein. They cannot track when a protein transforms to mask or displace these sites.

The new study gives scientists a critical picture of the right form of glycoprotein to target for antibody protection.

Finally capturing the glycoprotein

For three years, Callaway worked to stabilize and freeze the rabies glycoprotein in its trimeric form. This “pre-fusion” form is the form the glycoprotein takes before infecting human cells.

Callaway paired the glycoprotein with a human antibody, which helped her identify a site where the viral structure is vulnerable to antibody attack. The researchers then captured a 3D image of the glycoprotein using state-of-the-art cryo-electron microscope equipment at LJI.

The new 3D structure highlights several key features the researchers hadn’t seen before. Importantly, the structure shows two key structural elements of the virus, called fusion peptides, as they appear in real life. These two sequences connect the bottom of the glycoprotein to the viral membrane, but project into the target cell upon infection. It is very difficult to obtain a stable image of these sequences. In fact, other rabies researchers have had to cut them to try to image the glycoprotein.

Callaway solved this problem by capturing the rabies glycoprotein in detergent molecules. “This allowed us to see how the fusion sequences are attached before they lift during infection,” says Saphire.

Now that scientists have a clear view of this viral structure, they can better design vaccines that tell the body how to make antibodies to target the virus.

“Instead of being exposed to more than four different protein forms, your immune system should really only see one — the good one,” Callaway says. “It could lead to a better vaccine.”

Prevent a family of viruses

Saphire hopes stronger and broader immunity could help people who come into regular contact with animals, like veterinarians and wildlife workers, as well as the billions of people who might accidentally come into contact with a rabid animal. Rabies is endemic on every continent except Antarctica and infects many species including dogs, raccoons, bats and skunks.

This new work could also open the door to a vaccine to protect against the entire lyssavirus genus, which includes rabies and similar viruses that can spread between humans and other mammals.

The next step in this work is to capture more images of the rabies virus and its relatives with neutralizing antibodies. Callaway says scientists are working on resolving several of these structures, which could reveal antibody targets that lyssaviruses have in common.

“Because we didn’t have these rabies virus structures in this conformational state before, it was difficult to design a broad-spectrum vaccine,” says Callaway.

Other authors of the study, “Structure of the Rabies Virus Glycoprotein Trimer Bound to a Pre-Fusion Specific Neutralizing Antibody”, include Dawid Zyla, Florence Larrous, Guilherme Dias de Melo, Kathryn M. Hastie, Ruben Diaz Avalos, Alyssa Agarwal and David Corti.

This study was supported by the National Institutes of Health (grants 5T32AI07244-36 and 5F32AI147531-03) and an Early Postdoctoral Mobility Fellowship from the Swiss National Fund (P2EZP3_195680). Some of this research was supported by NIH grant U24GM129547 and performed at OHSU’s PNCC 742 and accessed through EMSL (grid.436923.9), a DOE Office of Science user facility sponsored by the Office of Biological Research and environmental. Confocal microscopy on the Zeiss LSM 880 was supported by NIH Equipment Grant 745 S10OD021831.

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