Marburg virus, a member of the filovirus family—which also contains the five species of Ebola virus—typically causes a serious disease of hemorrhagic fever, with a fatality ratio of up to 88%. There is no treatment for Marberg infection and although experimental treatments have been validated in nonhuman primates models, they have never been tried in humans.
A detailed study of the monoclonal antibodies from a person who survived a Marburg infection led researchers to identify novel mechanisms that contribute protection against the disease, according to the latest findings of a collaborative team led by the University of Texas Medical Branch (UTMB) at Galveston and Vanderbilt University Medical Center.
The findings are now available in a paper titled, “Non-neutralizing Antibodies from a Marburg Infection Survivor Mediate Protection by Fc-Effector Functions and by Enhancing Efficacy of Other Antibodies” in Cell Host & Microbe.
In an earlier study, the research team had isolated a large panel of monoclonal antibodies (mAbs) from B cells of a human survivor with previous naturally acquired Marburg virus infection. In this new study, they characterized functional properties of these mAbs and identified non-neutralizing mAbs targeting the glycoprotein (GP) of the virus.
“Antibodies are currently the most promising platform for developing post-exposure treatments for Marburg virus infection and are critical tools for the design of improved vaccines,” said Alex Bukreyev, a UTMB virologist in the departments of pathology and microbiology & immunology and senior author on the study. “Understanding the mechanisms of antibody-mediated protection during Marburg virus infection is also useful for understanding antibody protection against other viral pathogens, including SARS-CoV-2, which causes COVID-19.”
The researchers found that a non-neutralizing monoclonal antibody, MR228, protects animals from lethal infection with Marburg virus. More specifically, it showed therapeutic protection in mice and guinea pigs infected with Marburg virus. The monoclonal antibody binds to the envelope protein of Marburg virus called glycoprotein. It binds to an epitope in the wing region of Marburg virus glycoprotein, targeting the GP2 wing. The protection was mediated by the Fc fragment functions of MR228, inducing strong Fc domain-mediated effector functions. Here, they recruit immune cells that contribute by killing infected cells. In addition, one of these antibodies rearranges the glycoprotein in a way that facilitates access for other antibodies that are able to kill the virus, thus strengthening the protective effect.
Binding of another GP2 wing-specific non-neutralizing mAb, MR235, to the Marburg virus GP increased accessibility of epitopes in the receptor-binding site (RBS) for neutralizing mAbs, resulting in enhanced virus neutralization by these mAbs. These findings highlight an important role for non-neutralizing mAbs during natural human MARV infection.
To study the protective effect of the monoclonal antibodies, mice were infected with Marburg virus and then given a single antibody dose 24 hours later. All of the mice who received the antibodies survived the Marburg infection, which would have otherwise been uniformly lethal.
Infections are typically found in Africa—normally from prolonged exposure to mines or caves inhabited by the African fruit bat (Rousettus aegyptiacus) as they are the reservoir host of Marburg virus. The largest known outbreak of Marburg virus occurred in 2004–2005 in Angola, which had a 90% case fatality rate, according to the CDC.