Monoclonal antibodies are among our greatest strengths in the treatment and prevention of diseases caused by viruses. While the spotlight has focused squarely on Covid-19 monoclonal antibodies throughout the pandemic, candidate antibodies for other serious pathogens have also made strides forward. Here we describe a novel antibody cocktail that neutralizes a lesser-known but nonetheless dangerous virus circulating in West Africa: Lassa virus.
What is Lassa virus?
Lassa virus is a pathogen responsible for Lassa hemorrhagic fever, which affects between 300,000 and 500,000 people annually, usually in West African countries such as Nigeria, Liberia, Sierra Leone, Guinea and Ghana. Lassa fever has a fatality rate of about 1 percent. Pregnant women are at the greatest risk of death, with a mortality rate of up to 90%. Symptomatic cases present with issues such as fever, headaches, vomiting and muscle aches.
Spread usually occurs through contact with infected mouse feces or urine, although direct contact person-to-person transmission is also common. Unfortunately, a vaccine is not yet available for the virus and antivirals are weak at best. Lassa virus, like SARS-CoV-2, is an RNA virus that is constantly mutating. Treatment or prophylactic is required to fill the Lassa virus drug gap.
Lassa virus monoclonal antibody therapy
Fortunately, a new contender may be just around the corner. A team of researchers from the La Jolla Institute of Immunology in California led by Dr. Erica Ollmann Saphire identified a cocktail of three antibodies that bind and neutralize the Lassa virus. This same group discovered a widely accepted cocktail of monoclonal antibodies to the Ebola virus, which we described previously. This cocktail arrived just in time as the current treatment for the current outbreak caused by the Sudanese strain of Ebola in Nigeria.
The new Lassa virus treatment, called Arevirumab-3, consists of three different antibodies, each of which binds to distinct regions of the Lassa virus glycoprotein.
The Lassa virus spike protein comes in a set of three identical membrane-embedded subunits. The virus is synthesized as a single long polypeptide and is cleaved into three parts, a leader sequence, GP1 encoding the receptor binding function, and membrane-embedded GP2 (Figure 1).
8.9F inhibits virus-cell attachment by blocking the GPC/α-DG interaction
The first antibody, 8.9F, binds to the apex of the trimeric spike, spanning all three parts of the glycoprotein. 8.9F is an unusual antibody in that the single antibody binds all three faces of the trimer. The antibody also binds the three cleavage sites of GP1 subunits. It binds to the part of the glycoprotein that attaches to the host cell, directly inhibiting virus-cell attachment by mimicking the alpha-dystroglycan cell receptor.
Antibody 8.9F also binds a glycan, N119, which is required for neutralization activity. This glycan is required for binding to the alpha-dystroglycan receptor, so the recognition of 8.9F is surprising.
A native N89 glycan plays a central role in GPC 12.1F/LASV recognition
The second antibody, 12.1 F, binds to a distinct site on GP1, directly interacting with the N-glycans for neutralization activity. The antibody binds more to the membrane and has a direct interaction with six critical amino acid residues and the critical glycans N89 and N109.
To infect a cell, Lassa virus must bind to the cell membrane and be engulfed by a cell endosome. The protein then undergoes a structural change to bind the LAMP-1 protein inside the endosome. Binding to LAMP-1 is essential for fusion of viral and cell membranes and entry into the cytoplasm where replication occurs.
37.2D neutralizes LASV by locking the GPC trimer into an inactive conformation.
The third antibody, 37.2D, binds two adjacent subunits of GP2. The antibody spans subunits, locking the trimer in place by binding conserved peptides and conserved glycans N390 and N395. 37.2D is specific in that it attacks GP2 at a unique angle, stabilizing the trimer prior to fusion, preventing fusion activation and thus contamination.
These three mechanisms work together to yield a highly effective antibody cocktail.
A critical question for monoclonal antibody therapy is, can the virus escape by mutating the binding sites? The team of Dr. Ollmann Saphire shows that this is true for treatment with a single 8.9 F antibody. However, no resistance mutations emerged when using the cocktail of all three antibodies, nor was the virus able to escape.
The antibody Arevirumab-3 may provide a long-awaited answer to the lack of treatment and prevention of Lassa infections. This is especially important for cases involving pregnant women and their fetuses.
It will be important to reduce the cost of this antibody cocktail as much as possible so that it is available when needed in West Africa. Current technologies allow production of monoclonal antibodies at $200 and $250 per gram.
The next step in the development of Lassa fever control is the development of a vaccine effective against all variants of the Lassa virus. This work may serve as a guide to creating such a vaccine.