The National Institutes of Health’s National Institute of Allergy and Infectious Disease awarded more than $12 million for research into Lassa fever.Virologist Robert F. Garry Jr., PhD, received two, five-year grants for the preclinical research: $5.72 million to evaluate a potent Lassa fever antibody drug cocktail and $6.32 million to design a vaccine based on a recently discovered key antibody target on the surface of the virus.
Lassa fever is a severe and often fatal hemorrhagic illness caused by, which infects more than 300,000 annually. There is no vaccine against the virus.
“These two projects complement each other. In West Africa, we need a drug to treat acutely infected patients as well as a preventative measure to stop it,” said Dr. Garry, a professor of microbiology and immunology at Tulane University School of Medicine, in New Orleans. “Vaccine initiatives in rural Africa are difficult, so you are never going to be able to vaccinate everyone. You need to be able to treat people when they get sick.”
The vaccine will test antibodies that target a recently identified viral surface structure, called the surface glycoprotein, which can block it from infecting a host cell (Science
2017;356:923-928). A team of scientists, including virologists from Tulane University, identified this key antibody target that they hope will serve as the blueprint for developing the vaccine or antibody drug.
The researchers collected blood samples from survivors in Sierra Leone and sent them back to New Orleans, where the lab of James Robinson, PhD, worked to identify and clone more than 100 different antibodies used in the research.
“The antibodies were a very important tool for trying to understand the structure of the glycoprotein,” said Dr. Robinson, a professor of pediatrics. “It was key to understanding where the antibodies were binding and the mechanisms for neutralization of the virus.”
Scientists had not been able to successfully solve the structure of Lassa virus because the glycoprotein falls apart under conditions normally used to create a crystal model. Scripps researchers were able to engineer a more stable version of the glycoprotein. This was used to identify a key binding site for antibodies from survivors’ blood samples.
Researchers detailed how subunits of the glycoprotein work together to infect a cell. They also discovered how three pairs of proteins, called a trimer, come together to form a tripod-like structure. Roughly 90% of the effective antibodies target that trimer nexus, locking the subunits together to prevent them from enabling Lassa virus to enter a host cell.
“The trimer structure of the Lassa virus glycoprotein will have a lasting impact on the field of viral hemorrhagic fever research,” Dr. Garry said.
The vaccine also will incorporate similar glycoproteins against Ebola that are already being tested in clinical trials.
“Ebola is likely to come back, and Lassa isn’t going away so you have to protect against both,” Dr. Garry said. “We think we can do it with one shot.”
The other project will test the three most potent Lassa antibodies to see which formulation will work best in a drug therapy. Together, the three have been highly protective in early animal studies, Dr. Garry said. Collaborators on the grants include Tulane virologist Dr. Robinson and scientists at Zalgen Labs, the Scripps Research Institute, the University of Texas Medical Branch at Galveston and the Sanford Burnham Prebys Medical Discovery Institute.