By analyzing the antibody response of a survivor of Marburg virus infection, researchers at the University of Texas Medical Branch and Vanderbilt University Medical Center have gained new insights into the function of non-neutralizing antibodies in fighting infections.
The team showed that non-neutralizing antibodies, though they were not able to directly neutralize the virus, protected mice against otherwise lethal infections with Marburg virus via two indirect mechanisms.
“Antibodies developed by the immune system work in concert,” Alex Bukreyev told BioWorld. “The antiviral effect of each antibody is affected by the presence of other antibodies.” Bukreyev is a professor of virology at the University of Texas Medical Branch, and a co-corresponding author of the study reporting the findings, which was published in the April 21, 2020, online issue of Cell Host & Microbe.
When neutralizing antibodies bind to viral particles, they directly neutralize the virus’ ability to infect its target cells, without the need for any further intervention by immune cells.
Non-neutralizing antibodies, on the other hand, either bind weakly or bind to sites on the virus that are not critical to its ability to infect cells.
In the work now published in Cell Host & Microbe, Bukreyev, James Crowe and their teams characterized a panel of antibodies that were isolated from a survivor in 2015.
They identified an antibody, MR228, that protected mice from an otherwise lethal dose of virus, despite being unable to neutralize the virus.
“We didn’t expect to see that an antibody that completely lacked neutralizing capacity would be protective in vivo,” Bukreyev said.
The team showed that the non-neutralizing antibodies were protective via two separate mechanisms.
Through binding of the Fc receptors, those antibodies engaged with immune cells, which are capable of killing infected cells. In addition, those antibodies also changed conformation of the targeted Marburg envelope protein, resulting in strengthened binding of neutralizing antibodies.
Together, those effects were able to reduce the mortality rate from 100% to 40% in guinea pigs when the non-neutralizing antibodies were administered 24 hours after exposure to Marburg virus. Mice were fully protected by the antibody.
In some instances, non-neutralizing binding can be worse than no binding at all. In a phenomenon called antibody-dependent enhancement (ADE), antibodies against one virus can help related viruses enter cells, making infections worse than they otherwise would have been.
Dengue virus, which has four widely circulating strains, is the clearest example of problematic ADE. Because it protects only poorly against one such strain, the only licensed vaccine increased the risk of hospitalization for children in one study.
ADE can also facilitate Zika virus infection with individuals that have previously been infected with dengue.
And Bukreyev’s team has previously shown that ADE can occur with Ebola, a close relative of Marburg’s.
“At this point, we don’t know the relative contributions of ADE and protective effects” on the overall clinical course of an infection, Bukreyev said.
However, if there are both protective and harmful effects, it could explain a longstanding mystery about Ebola, namely why both passive vaccination with antibodies themselves and active vaccination that aims to elicit an immune response are only effective at very high doses.
Bukreyev noted that ADE was likely to be less of a problem with Marburg virus than with dengue, both because the strains are more similar and because infection is overall a much rarer event. Dengue accounts for hundreds of millions of infections a year.
However, though those infections are still rare in an absolute sense, their case fatality rate of up to 90% have earned filoviruses a spot on the WHO blueprint list of “emerging infectious diseases requiring urgent research and development efforts.”
As humans continue to encroach on wild habitats, outbreaks are increasing in both frequency in magnitude. Zoonotic spillovers happen, on average, every four months.
And although most of those spillovers are no SARS-CoV-2, increased mobility is making outbreaks bigger as well as more frequent.
In their paper, the authors wrote that “it was thought that filoviruses only cause local sporadic outbreaks in sub-Saharan Africa, but the unprecedented 2013–2016 EBOV epidemic in West Africa has changed this view.”
“We need to be ready,” Bukreyev said, “to respond to such outbreaks in the future.”