LJI structural biologist Erica Ollmann Saphire, Ph.D., is a world leader in studies of viral proteins that could be targeted to block spread of Lassa fever or Ebola. In 2017, she was the first to report the crystal structure of a Lassa virus glycoprotein in direct contact with an antibody found in the blood of a Lassa survivor. That image was the first snapshot of how an antibody capable of blocking infection directly interferes with an essential viral protein, and it provided a template for vaccine design.
This work has challenged the assumptions about Lassa. Prior to Saphire’s discoveries, vaccinologists had been skeptical that antibody-mediated immunity could effectively combat Lassa. Researchers had found that vaccine candidates did not seem to stimulate the immune system to potent neutralizing antibodies. Studies had also shown that few Lassa survivors had high titers of anti-Lassa antibodies in their bloodstream. Further complicating vaccine development efforts, Lassa is caused by four similar but molecularly-distinct variants or strains, and their prevalence differs from country to country.
To address these issues, in 2019 Saphire expanded structural analysis of Lassa’s outer protein spikes, called glycoproteins, this time scrutinizing how human antibodies target the glycoprotein with low, moderate and high affinity. This research compared molecular components of the target glycoprotein that either hindered or promoted high affinity interactions against all four strains.
These findings have fueled a global effort to engineer proteins that could make up an effective “pan-Lassa” vaccine. This ongoing research is a focus of international efforts underway by the Coalition for Epidemic Preparedness Innovations (CEPI), which has made Lassa fever a priority disease.
Thanks to a collaboration with Scripps Research, the Saphire Lab has also uncovered a potential drug target for Lassa virus. In 2022, the researchers showed how a critical Lassa virus protein, called polymerase, drives infection by harnessing a cellular protein in human hosts. Their work suggests future therapies could target this interaction to treat patients. The next step is to start testing this theory in animal models.