Rethinking the rabies vaccine - News of Fauna and Flora

Rethinking the rabies vaccine – News of Fauna and Flora

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The rabies virus kills 59,000 people each 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 cost of $3,800 represents an unimaginable financial 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 big disadvantage:

“Rabies vaccines do not provide lifelong protection. You should vaccinate your pets every year or three years,” says LJI professor Erica Ollmann Saphire, Ph.D. “Currently, human and pet rabies vaccines are made from killed viruses. But this inactivation process can distort the molecules, so these vaccines don’t show the immune system the correct shape. If we made a better, better trained and better structured vaccine, would immunity last longer? »

Saphire and her team, in collaboration with a team led by Hervé Bourhy, Ph.D., at the Pasteur Institute, may have discovered the path to better vaccine design. In a new study published in scientists make 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 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 investigator. First author.

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

rage the shapeshifter

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

Like a Swiss army knife, the rabies glycoprotein has sequences that unfold and flip up when needed. The glycoprotein can alternate 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 package) to a monomer (one copy on its own).

This shapeshifting gives rage a kind of invisibility cloak. Human antibodies are built to recognize a single 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 correct form of glycoprotein for antibody protection.

Finally capturing the glycoprotein

For three years, Callaway worked to stabilize and freeze the rabies glycoprotein in its trimeric form. This “prefusion” form is the form the glycoprotein takes before it infects human cells.

Callaway combined the glycoprotein with a human antibody, which helped her identify a site where the viral structure is vulnerable to attack by the antibodies. 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 that 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 lower part of the glycoprotein to the viral membrane, but project towards the target cell after infection. It is very difficult to obtain a stable image of these sequences. In fact, other rabies researchers have had to slice them open 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 bind before they are lifted 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 fight the virus.

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

Prevent a family of viruses

Saphire hopes that stronger, broader immunity could help people who come into regular contact with animals, such as 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 to resolve 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 Rabies Virus Glycoprotein Trimer Bound to Specific Neutralizing Antibody Prior to Fusion,” 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 Fund Early Postdoctoral Mobility Grant (P2EZP3_195680). Part of this research was supported by NIH grant U24GM129547 and was conducted at OHSU PNCC 742 and accessed through EMSL (grid.436923.9), a DOE Office of Science user facility sponsored by the Office of Science. Biological and environmental research. Confocal microscopy on the Zeiss LSM 880 was supported by NIH Equipment Grant 745 S10OD021831.

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