New High-Resolution Look at Rabies Virus May Lead to Better Vaccines

Researchers from La Jolla Institute for Immunology (LJI) may have discovered targets that could make for more effective vaccines for rabies when focused on.

Rabies Virus

Rabies Virus. Image Credit: Scientific Animations

Vaccination is preferable to treatment when looking to keep rabies issues at bay. Vaccines are better, less costly, and more accessible.

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However, people do not get permanent protection from taking rabies vaccines.

“You have to get your pets boosted every year to three years,” said Dr. Erica Ollmann Saphire, senior study author, and a professor at La Jolla Institute for Immunology. “Right now, rabies vaccines for humans and domestic animals are made from killed virus. But this inactivation process can cause the molecules to become misshapen – so these vaccines aren’t showing the right form to the immune system. If we made a better shaped, better-structured vaccine, would immunity last longer?”

Saphire’s team produced one of the first high-resolution views of rabies glycoprotein in its most susceptible form.

The study was done in collaboration with researchers from the Institut Pasteur. It appeared in the journal Science Advances.

Rabies and shapeshifting

The rabies virus causes one of the most lethal viral infections that are known. It kills almost everyone it infects if not promptly treated. The virus kills nearly 60,000 people every year, with most of the victims being children.

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Those infected with this virus are often not aware of the infection until when it has reached an advanced state. Also, treatment is not very accessible and costs are rather prohibitive for most people, especially in low-income countries.

Scientists have found it quite difficult to unravel why vaccines do not offer lasting protection against the rabies virus.

The shapeshifting nature of the rabies glycoprotein has been suspected to play a part in reduced vaccine protection. This protein that is present on the surface of the virus changes its pre-fusion and post-fusion shapes. It can also alter its structure from trimeric (three copies in one bundle) to monomeric (a copy by itself).

Before infecting a host cell, the rabies glycoprotein changes into the pre-fusion form.

This shapeshifting provides protection for the rabies virus because human antibodies cannot keep up with the transformations. The antibodies can make out only a spot on a protein.

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Solving the problem

In this new research, scientists set out to have a better look at the glycoprotein in its more vulnerable trimeric form.

Heather Callaway, a postdoctoral fellow at LJI, stabilized and froze the glycoprotein in its trimeric shape over three years. She then paired the protein with a human antibody, thus enabling her to identify a single site where the viral structure can be damaged by antibodies.

The research team took a 3D image of the rabies glycoprotein using advanced cryogenic electron microscopy (cryo-EM). This revealed several vital features that were previously unknown.

Most notably, the 3D image shows two sequences (also called the fusion peptides) as they actually appear. It had proved quite difficult to capture a steady image of the sequences until now.

The two sequences serve as a link between the bottom of the glycoprotein and the membrane of the virus. The protein launches into a host cell during infection, according to researchers.

This high-resolution view of the rabies glycoprotein is a breakthrough. To overcome the instability challenge, previous researchers have had to sever the fusion peptides to capture images of the glycoprotein.

This discovery could greatly aid in the development of better rabies vaccines. It can improve the ability of new vaccines to help antibodies aim for the virus.

“Instead of being exposed to four-plus different protein shapes, your immune system should really just see one – the right one,” said Callaway, who is the first study author. “This could lead to a better vaccine.”

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The researchers noted that their work may aid the design of a vaccine against a whole family of viruses. Specifically, it could help guard against the entire lyssavirus genus, of which the rabies virus is just a member. These viruses can spread between mammals, including humans.

The team plans to get more images of the rabies virus and its cousins along with counteracting antibodies. These scientists hope to discover antibody targets that are common to all lyssaviruses in their research.

References

Structure of the rabies virus glycoprotein trimer bound to a prefusion-specific neutralizing antibody

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