Rethinking rabies vaccine

Newswise — LA JOLLA — Rabies virus shockingly kills 59,000 people every year, Many of them are children. Some victims, especially children, are unaware that they have been exposed until it is too late. For others, a fierce rabies treatment regimen is out of the question. Treatment is not widely available, and the average cost of $ 3,800 poses an unthinkable financial burden for most people around the world.

Rabies vaccine is much more affordable and easier to administer than treatment. However, these vaccines also have major drawbacks.

“The rabies vaccine doesn’t provide lifelong protection. You have to boost your pet to three years each year,” he says. Professor LJI Dr. Erica Olman Safia “Currently, rabies vaccines for humans and livestock are made from killed viruses, but this inactivating process can cause the molecule to lose shape, so these vaccines are correct for the immune system. It doesn’t show shape. A more structured vaccine, will immunity last longer? ”

Saphire and her team Herve Bourhy, A PhD at the Pasteur Institute may have found a way to better vaccine design. In a new study Science AdvancesResearchers share one of the first high-resolution studies of vulnerable “trimeric” rabies virus glycoproteins.

“Rabies glycoproteins mean that rabies is the only protein expressed on its surface and is a major target for neutralizing antibodies during infection,” said Dr. Heather Callaway, head of research at LJI Postok. I am saying. First author.

“Rabies is the most deadly virus we know. Rabies is a big part of our history. We have lived with the ghost for hundreds of years.” Saphire, who is also President and CEO of LJI, adds. “Scientists have not yet observed the organization of its surface molecules. Understanding its structure for more effective vaccines and treatments, and how rabies and other viruses can invade cells. It is important to do. “

Transformed rabies

Scientists don’t know exactly why rabies vaccines don’t provide long-term prophylaxis, but they do know that the shape-changing protein is the problem.

Like the Swiss Army knife, rabies glycoproteins have sequences that expand and invert upwards as needed. Glycoproteins can move back and forth between pre-fusion (pre-fusion with host cells) and post-fusion morphology. It can also change from a trimer structure (a bundle of three copies) to a monomer (one copy itself) and fall apart.

Changing this shape gives rabies a kind of invisible cloak. Human antibodies are designed to recognize a single site on a protein. They cannot follow when proteins change to hide or move these sites.

New research provides scientists with important images of the correct glycoprotein morphology targeted for antibody protection.

Finally capture glycoprotein

Callaway has been working for three years to stabilize and freeze rabies glycoproteins in the form of trimers. This “pre-fusion” form is the form that glycoproteins take before they infect human cells.

Callaway combined glycoproteins with human antibodies to help identify one site where the viral structure is vulnerable to antibody attack. Next, researchers used LJI’s state-of-the-art cryo-electron microscopy equipment to capture 3D images of glycoproteins.

The new 3D structure highlights some important features that researchers have never seen before. Importantly, this structure shows two important parts of the viral structure, called fusion peptides, and what they look like in real life. These two sequences link the lower part of the glycoprotein to the viral membrane, but project it onto the target cells during infection. Obtaining a stable image of these sequences is very difficult. In fact, other rabies researchers had to cut them to get images of glycoproteins.

Callaway solved this problem by incorporating rabies glycoprotein into the detergent molecule. “This allows us to see how the fusion sequence is attached before it snaps upwards during infection,” says Saphire.

Scientists have a clear understanding of the structure of the virus, so they can better design vaccines that tell the body how to make antibodies that target the virus.

“Instead of being exposed to four or more different protein forms, we really need to see one immune system, the right one,” says Callaway. “This could lead to a better vaccine.”

Virus family prevention

Saphire’s stronger and broader immunity helps people who are in regular contact with animals, such as veterinarians and wildlife workers, and billions of people who can accidentally come into contact with ferocious animals. I hope you can do it. Rabies is endemic on all continents except Antarctica and infects many species such as dogs, raccoons, bats and skunks.

This new study may also open the door to vaccines to protect against the entire Lyssavirus genus, including rabies and similar viruses that may spread with other mammals.

The next step in this task is to capture more images of the rabies virus and its relatives along with neutralizing antibodies. Callaway says scientists are working on solving some of these structures. This may reveal antibody targets that lyssaviruses have in common.

“Previously, it was difficult to design a broad-spectrum vaccine because of the lack of these structures of such a conforming rabies virus,” says Callaway.

Additional authors of the study, “Structure of Rabies Viral Glycoprotein Trimer Binding to Pre-Fusion Specific Neutralizing Antibodies,” 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 the Swiss National Science Foundation’s Early Postdoctoral Mobility Fellowship (P2EZP3_195680). Part of this study was supported by the NIH grant U24GM129547, conducted at OHSU’s 742 PNCC, and accessed from EMSL (grid.436923.9), a DOE Science Department user facility sponsored by the Department of Bioenvironmental Studies. The Zeiss LSM 880 confocal microscope was supported by the instrument grant NIH745S10OD021831.

About La Jolla Institute for Immunology

Lahora Immunology Institute Dedicated to understanding the complexity and power of the immune system, that knowledge can be applied to promote human health and prevent a variety of illnesses. Since its establishment in 1988 as an independent, non-profit research organization, the Institute has made many advances towards its goal of a disease-free life.

About Pasteur Institute

The Pasteur Institute, a non-profit organization founded by Louis Pasteur in 1887 as a charity, is today the center of internationally renowned biomedical research. The Pasteur Institute operates in four key areas: research, public health, training, and the development of research applications to pursue its mission to tackle diseases in France and around the world. The Pasteur Institute is a globally recognized leader in infectious diseases, microbiology and immunology, with a focus on the biology of life systems. Areas of research include emerging infectious diseases, antibiotic resistance, certain cancers, neurodegenerative diseases, and impaired brain connectivity. The Pasteur Institute’s outstanding research is driven by the development of a state-of-the-art technical environment with core equipment for nanoimaging, computational biology and artificial intelligence. Since its inception, 10 Pasteur Institute scientists have won the Nobel Prize in Medicine. Two of them were awarded in 2008 for the 1983 discovery of the human immunodeficiency virus (HIV) that causes AIDS.

Since July 1, 2021, the Pasteur Institute has been a research partner organization at the University of Parisite.

The Pasteur Institute is part of the Pasteur Network, a global network of 33 members on five continents connected by Pasteur values ​​and contributes to global health.