Researchers at La Jolla Institute for Immunology (LJI) Centre for Vaccine Innovation are exploring ways to prevent the fusion of measles “machinery” with host cell membranes. Using an imaging technique called cryo-electron microscopy, they have shown “in unprecedented detail” how an antibody can neutralise the measles virus before it completes fusion. Their work in Science (not open access) seeks to explain the mechanism of action of monoclonal antibody (mAb) 77, and could have implications beyond measles, such as for other members of the paramyxovirus family.
Measles concerns
Despite “extensive” vaccine efforts, measles remains a “major health threat”, particularly to children. Dr Erica Ollmann Saphire, LJI professor, states that the virus “causes more childhood deaths than any other vaccine-preventable disease” and is “one of the most infectious viruses known”. The study first author and LJI postdoctoral researcher Dr Dawid Zyla highlights that the risk is not just for young children.
“The current vaccine works well, but it cannot be taken by pregnant people or people with compromised immune systems.”
Furthermore, there is currently no specific treatment for measles.
mAb 77
An antibody called mAb 77 targets the measles fusion glycoprotein, which is the “piece of viral machinery” that enables the virus to enter human cells by fusion. Working with a team at Columbia University, the LJI team sought to engineer a version of the measles fusion glycoprotein that was stable enough for cryo-electron imaging. Dr Matteo Porotto, Professor of Viral Molecular Pathogenesis (in Paediatrics), had been exploring “strange mutations” in a measles variant that had targeted the central nervous system. This variant had weak points in the fusion glycoprotein structure that “forced” the virus to evolve.
“The virus has to mutate to go into the brain, but then it needs these stabilising mutations to compensate.”
Using this research, Dr Zyla could engineer a fusion glycoprotein with the same mutations; it could be mass produced and was “sturdy” enough for structural investigations. With the LJI Cryoelectron Microscopy Core, the researchers started to capture images that showed the fusion glycoprotein “in complex” with mAb 77. This revealed that mAb 77 “arrests the virus in the middle of the fusion process”, interrupting the “folding” towards fusion.
“It was striking to see what this intermediate step in the fusion process actually looks like.”
Dr Saphire agrees that it was “exciting” to capture “snapshots of the fusion process in action”.
“The series of images is like a flip book where we see snapshots along the way of the fusion protein unfolding, but then we see the antibody locking it together before it can complete the last stage in the fusion process. We think other antibodies against other viruses will do the same thing but have not been imaged like this before.”
Translating the research into treatment
With this newfound understanding of mAb 77, the researchers hope it could be used in a “treatment cocktail” for prevention or treatment of active measles infection. They found that mAb 77 offered “significant” protection against measles in cotton rat models, which were pretreated before virus exposure. The rats showed either no infection or “reduced signs of infection” in lung tissue.
However, the investigations will continue into different antibodies against measles. Dr Zyla states that “we’d like to stop fusion at different points in the process and investigate other therapeutic opportunities”. This can be done in collaboration with the team at Columbia University.
“The combination of structural biology expertise from LJI and cell biology and virology expertise from Columbia was key to pushing this project forward.”
Furthermore, this work could have implications for other viruses, such as Nipah, parainfluenza viruses, and Hendra viruses.
“These are all viruses with pandemic potential.”
We will explore the returning threat of measles at the Congress in Barcelona this October, so do get your tickets to join us there and don’t forget to subscribe to our weekly newsletters for more research updates.
