Study reveals weak point of Lassa virus

While the Lassa fever epidemic in Nigeria finally dropped this year, the total number of people affected was more than 600, of which a quarter died. Thousands more die each year, not to mention in rural villages all over West Africa. With an annual wave of infections and the emergence of new viral strains, it has never been more important to understand the characteristics of a globally protective immune response in order to develop effective treatments or, better still, a vaccine. .

A new study, published on August 8, 2019, in Cell by a team of researchers led by Professor Kathryn Hastie, Ph.D., and Professor Erica Ollmann Saphire, Ph.D., from the La Jolla Institute of Immunology (LJI), identified and then modified the molecular properties common to antibodies particularly effective to inactivate or "neutralize" the virus. The team's findings also revealed that most neutralizing antibodies bind to the same spot on the surface of the Lassa virus, providing a map for rational vaccine design.

The beauty of structural biology lies in the fact that it allows you to dissect high resolution molecular details to accurately explain how something works. Once you do, you have a plan to develop powerful immunotherapeutic products or a vaccine that induces the desired immune response. "

Ollmann Saphire, structural immunologist, La Jolla Institute of Immunology

Identified 50 years ago and named after the city of Nigeria where the first known cases were identified, the Lassa virus is endemic in West Africa where it infects hundreds of thousands of people each year. For the majority of people infected, the symptoms are mild and the infection is usually not diagnosed. But in 20% of patients, the disease causes a more serious disease including neurological symptoms and hemorrhage, which can lead to multiple organ failure and death.

A deceptively simple virus, Lassa carries only four genes and displays a single protein, called a glycoprotein, on its surface. The surface glycoprotein is crucial for the attachment and entry of Lassa virus into cells. "Because it's the only thing the immune system sees, it's the primary target of antibodies that prevent viral infection," says Hastie, who solved the structure of Lassa's glycoprotein when 39, an innovative effort only two years ago. Since then, the pair-developed version of the glycoprotein has become the international standard for testing candidate vaccines.

In the present study, Hastie compared the structure of three neutralizing antibodies of different activities: high, moderate and low, related to the glycoprotein. The side-by-side comparison revealed specific amino acid residues that generate great power and allowed researchers to accurately manufacture mediocre antibodies to transform them into highly effective antibodies.

"Not only have we been able to increase the potency of the antibody, which means that you can produce a lot less antibodies, but we have also managed to transform it into pan-Lassa. It can affect all lineages. of Lassa viruses characterized up to now, "Hastie said.

However, few naturally infected individuals generate neutralizing antibodies and current immunization efforts focus on obtaining T cell immunity "Historically, researchers have discovered Antibody is not a good correlate of protection against natural infections in Lassa, "Hastie said. "It is actually very difficult to induce neutralizing antibodies."

The second part of the study explains why.

Before B cells could trigger a complete antibody response against invading pathogens, their progenitors were subjected to a tightly orchestrated, multi-step maturation process. Often compared to a miniaturized Darwinian struggle for survival, this process selectively promotes the proliferation of cells that produce high affinity antibodies and eliminates those that produce less potent antibodies. Survivors undergo successive series of hypermutation and somatic selection, which allows to obtain better antibodies during the immune response.

Hastie and his colleagues discovered that in the absence of somatic hypermutation, the first antibodies recognizing the Lassa surface glycoprotein did not have sufficient affinity to repel two sugar chains that were blocking access to the antibody binding site. When they removed the sugar chains, the low affinity antibodies could bind and only required a few hypermutations to go further in the neutralization.

"Using these structures, we were able to identify the parts of the glycoprotein that prevent the early development of antibodies," says Hastie. "This allowed us to give the immune system a boost by developing a glycoprotein that could perhaps better induce these earlier antibodies to trigger the process of hypermutation." When they discovered the native virus, they developed enough mutations to bind closely enough for glycans. "

This type of information is of crucial importance to the ongoing international immunization efforts of CEPI (the Coalition for the Prevention of Epidemics), which has made Lassa fever a priority disease, and many more.