Rethinking the Rabies Vaccine

The rabies virus kills a shocking 59,000 people every year, many of them children. Some victims, especially children, don’t realize they’ve been exposed until it’s too late. For others, the intensive treatment regimen for rabies is out of the question: Treatment is not widely available and the average cost 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 those vaccines also have a huge disadvantage:

“Rabies vaccines don’t provide lifelong protection. You need to boost your pets every year for up to three years,” says LJI professor Erica Ollmann Saphire, Ph.D. “Right now, rabies vaccines for humans and pets are made from killed viruses. But this inactivation process can cause the molecules to become misshapen — so these vaccines don’t show the right shape for the immune system. If we had a better-formed, better-structured vaccine, the immunity last longer?”

Saphire and her team, in collaboration with a team led by Hervé Bourhy, Ph.D., at the Institut Pasteur, may have discovered the way to better vaccine design. In a new study, published in scientific progressthe researchers 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 surface expresses rabies, meaning it will be the primary target of neutralizing antibodies during infection,” said LJI Postdoctoral Fellow Heather Callaway, Ph.D., who serves as the study. first author.

“Rabies is the deadliest virus we know. It’s so much a part of our history — we’ve lived with its specter for hundreds of years,” added Saphire, who also serves as LJI’s president and CEO. “Yet scientists have never observed the organization of its surface molecule. It’s important to understand that structure to make more effective vaccines and treatments — and to understand how rabies and other viruses like it enter cells.”

Rabies the Shapeshifter

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

Like a Swiss army knife, the rabies glycoprotein has sequences that unfold and flip upwards when needed. The glycoprotein can slide back and forth between pre-fusion (before fusion with a host cell) and form post-fusion. It can also break apart and change from a trimeric structure (where three copies come together in a bundle) to a monomer (one copy on its own).

This metamorphosis gives rabies a kind of invisibility cloak. Human antibodies are built to recognize a single site on a protein. They can’t track when a protein transforms to hide or move those sites.

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

Finally capturing the glycoprotein

Over the course of 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 it infects human cells.

Callaway combined the glycoprotein with a human antibody, which helped her locate a site where the viral structure is vulnerable to antibody attack. The researchers then created a 3D image of the glycoprotein using advanced cryo-electron microscope equipment at LJI.

The new 3D structure highlights several key features that researchers hadn’t seen before. Importantly, the structure shows two important parts of the virus structure, the fusion peptides, as they appear in real life. These two sequences connect the bottom of the glycoprotein to the viral membrane, but protrude into the target cell during infection. It is very difficult to get a stable picture of these sequences. Other rabies researchers have even had to cut them off to get images of the glycoprotein.

Callaway solved this problem by trapping the rabies glycoprotein in detergent molecules. “That shows us how the fusion sequences are attached before they skyrocket during infection,” Saphire says.

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

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

Preventing a family of viruses

Saphire hopes stronger, broader immunity could help those who come into regular contact with animals, such as veterinarians and conservationists, as well as the billions of people who could accidentally come into contact with a rabid animal. Rabies is endemic to every continent except Antarctica and infects numerous 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, including 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, along with neutralizing antibodies. Callaway says scientists are working to resolve several of these structures, which could reveal antibody targets common to lyssaviruses.

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

Other authors of the study, “Structure of the rabies virus glycoprotein trimer bound to a pre-fusion-specific 4 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 a Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2EZP3_195680). Part of this research was supported by NIH grant U24GM129547 and conducted in the 742 PNCC at OHSU and accessible through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. Confocal microscopy on the Zeiss LSM 880 was supported by equipment grant NIH 745 S10OD021831.

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