Investigators Discover a Soft Spot on Lassa Virus Surface

A recently discovered weak spot along the surface of Lassa virus has revealed a new target for a potential vaccine, say investigators from La Jolla Institute for Immunology in a new study.

Since early 2019, 22 states in Nigeria have been affected by a Lassa fever outbreak, which has led to 3303 suspected cases, 651 confirmed cases, and 145 deaths among confirmed cases. With support from the World Health Organization (WHO), the Nigeria Centre for Disease Control (NCDC) has contained the outbreak, although some states have reported more cases than in 2018, which saw Nigeria’s worst outbreak of Lassa fever yet. Amid the deadly outbreak, a study published recently in the journal Cell offers a potential path for the development of a Lassa virus vaccine, offering protection against every known lineage of Lassa virus.

In an interview with Contagion^®, study co-lead Kathryn Hastie, PhD, described the need for a vaccine for the virus, noting that treatment is often unavailable in the parts of West Africa where Lassa virus is endemic and that Lassa infections in pregnant women are nearly always fatal for both mother and child. “Currently, there is no approved Lassa fever vaccine and the only available treatment, off-label use of ribavirin, is effective only during early infection,” said Hastie. “Thus, development of a vaccine that can effectively prevent Lassa virus infection would provide a substantial reduction in the social and economic burden of this virus. Development of therapies that are effective throughout the disease course are also important as not everyone can be vaccinated.”

Hastie explained that investigators have had difficulty identifying a molecule that will promote production of neutralizing antibodies—those that stop the virus from infecting our cells—posing a significant challenge for the development of a Lassa virus vaccine. Neutralizing antibodies are rare, even in survivors of Lassa infection.

“The Lassa virus displays a single protein on its surface—called the glycoprotein, or GP, which is covered in sugars picked up from cells it infects. These sugar molecules act as a sort of cloaking device that hides the virus from our immune systems,” said Hastie, whose team made headway in 2017 when they finally visualized GP on a molecular level, as well as GP bound to an antibody from the largest class of neutralizing antibodies. “Our new paper extends these findings and describes Lassa GP bound by 2 other neutralizing antibodies. These antibodies bind to the same location on GP as the first antibody, which tells us that this binding site is a ‘hot spot’ for neutralizing antibodies and is one we should focus on for vaccines and therapeutics.”

In comparing the antibodies, investigators were able to pinpoint what parts of the antibodies result in very strong virus neutralization and then use this information to make one of the antibodies better against all types of Lassa virus. They were also able to identify a region of Lassa GP that seemed to interfere with the early steps of antibody development in our bodies.

“For Lassa, we found that 2 of the sugar molecules on GP blocked antibodies that hadn’t yet accumulated enough of these mutations,” Hastie explained. “This finding provides a possible answer to the question of why antibodies that block Lassa infection are rare—the sugars that cloak the GP not only hide it from the immune system, but also block access to the exposed parts of GP. By removing these sugars in the vaccine molecule, we could give the immune system a leg up that natural virus infection cannot.”

Next up, Hastie says the study team is beginning research to test whether an antibody that has superior activity in the lab also performs better in animal models, and eventually in humans as well. In addition, investigators plan to test new forms of the GP itself in vaccine trials to determine if the immune system can be trained to make these types of antibodies.