We still do not have a life-long protection giving rabies virus – a virus known to kills as many as 59,000 people each year. However, things could change soon as a new discovery has led to determination of vulnerable state of the protein on the rabies virus thereby paving way for development of better vaccines that would last for a while lifetime.
Currently available rabies vaccines are made from killed virus and because of this inactivation process, the molecules of the virus become misshapen and in the process not revealing the right form to the immune system. This leads to development of antibodies that are weak and the effect of which wears off in 1-3 years.
Researchers at Institut Pasteur may have discovered the path to better vaccine design. In a new study, published in Science Advances, the researchers share one of the first high-resolution looks at the rabies virus glycoprotein in its vulnerable “trimeric” form. The glycoprotein is the only protein that rabies expresses on its surface, which means it is going to be the major target of neutralizing antibodies during an infection.
Scientists don’t know exactly why rabies vaccines don’t provide long-term protection, but they do know that its shape-shifting proteins are a problem. Like a Swiss Army knife, the rabies glycoprotein has sequences that unfold and flip upward when needed. The glycoprotein can shift back and forth between pre-fusion (before fusing with a host cell) and post-fusion forms. It can also fall apart, changing from a trimer structure (where three copies come together in a bundle) to a monomer (one copy by itself).
This shapeshifting gives rabies a kind of invisibility cloak. Human antibodies are built to recognize a single site on a protein. They can’t follow along when a protein transforms to hide or move those sites.
The new study gives scientists a critical picture of the correct glycoprotein form to target for antibody protection.