Hemorrhagic fever viruses, so named for their ability to induce massive, and at times fatal, internal bleeding, captured the world's attention during the Ebola outbreak of 2014-2016 in West Africa. But these pathogens' high lethality, fickle seasonal and geographic patterns, compounded by a lack of preventive therapies, have frustrated scientific and public health efforts to avert outbreaks for far longer than the recent epidemics.

The ultimate quest of those efforts is to develop a universal vaccine that works against multiple viruses and to design other broad-spectrum antibody therapies to rapidly treat those already infected. Now, in a small but illuminating study, Harvard Medical School scientists report that antibodies made in response to a vaccine against one hemorrhagic fever virus–Junin–can successfully disarm one of its cousins, Machupo, for which there's currently no vaccine. The experiments were conducted in vitro using antibodies obtained from a vaccine recipient.

Broad-spectrum therapies

Although limited to two viruses from one family, the results set the stage for the design of broad-spectrum therapies that can work against multiple or all members of a viral family, despite significant differences in molecular makeup, the researchers say. The findings, published in Nature Communications, build on isolated reports that people and primates vaccinated against Junin appear to be more resilient to Machupo. The new study, however, provides the first molecular proof of what thus far have been merely anecdotal observations. It also identifies a common, conserved site on both viruses that renders them defenseless to the same antibodies.

"Our findings raise the tantalizing possibility of designing universal therapies using antibodies made to one virus for which there is a vaccine as a way to prevent or treat other viruses for which there are none," said study senior author Jonathan Abraham. "We believe our results are a step in that direction." 

Traditionally, scientists have homed in on one promising commonality across related viruses: they tend to use the same gateway into their hosts–be they animals or people–a sort of "molecular key," called a protein receptor binding site (RBS), which fits into surface proteins on the host cell like a key in a lock. The RBS tends to be well-conserved across members of the same viral family because evolution discourages frequent mutations to a structure so critical for an organism's survival.

In the new study, however, researchers identified a tiny portion in the molecular keys used by Junin and Machupo that is identical and responds to the same antibodies, rendering both viruses sensitive to the same vaccine. It is from these very cells that the scientists isolated several Junin-specific antibodies developed as a result of past vaccination. Next, they tested in a lab dish these antibodies' affinity for binding to the RBS of the Machupo virus. Two of the handful of antibodies ended up binding to it.

The researchers used X-ray crystallography to pinpoint the exact location and other molecular details of the interaction between the viral RBS and the two antibodies. The visualization technique identified the precise location where virus and antibody latched onto one another–a genetically identical section shared by both Machupo and Junin. That, researchers said, is the very molecular chink that renders both viruses vulnerable to the same vaccine antibodies.

This conserved part of the viruses' molecular keys is a promising target for developing antibody therapies against multiple hemorrhagic fever viruses. Junin and Machupo are the most closely related viruses of the Arenavirus family. Even so, more than half of their RBS molecular makeup is different. The new findings, however, suggest that such common areas of vulnerability may exist among other members of the Arenavirus family.

"This approach can play an important role in controlling human infection and its most devastating consequences–a goal that's remained elusive," Abraham said. "As we get better in our ability to home in on progressively tinier parts shared across all viruses, we can start eyeing new precision-targeted therapies designed to work on conserved areas across multiple viral species."