Ebola Virus Mutations Block Antibody Cocktail from Working

The most recent Ebola virus outbreak that began in March 2014 caused a significant amount of damage, spurring renewed efforts to develop a vaccine. While an inhalable vaccine recently showed promising results and another potential vaccine showed 100% efficacy, there have been setbacks along the way. New research may be able to explain why some strategies resulted in failures.

Investigators from the US Army Medical Research Institute of Infectious Diseases (USAMRIID) identified genetic mutations, called “escape variants,” in Ebola that seem to help the virus dodge immune system response. One treatment method provides an antibody-based “cocktail” of sorts in order to help the cell’s host produce an immune response.

MB-003 and ZMab were early cocktails that helped with the development of the more a more advanced cocktail, ZMapp, which may soon be used in West Africa. However, when nonhuman primates were treated with just MB-003, the animals succumbed to the disease in a day or two. The team aimed to find the drive behind the improved vaccine, as reported in Cell Reports.

“The molecular analysis allowed us to see where the cocktails were inducing changes in the genome, and to link those changes to the treatment failure,” co-first author CPT Jeffrey Kugelman, PhD, of USAMRIID, said in a news release.

In one of the animals that died from Ebola, the researchers found two clusters of viral genome changes — multiple of which were the viral targets of the cocktail treatment.

“When this rescued virus was sequenced, we observed that the clusters of changes had progressed from affecting a small portion of the viral population to becoming mutations — permanent changes in the genome – without disrupting any major viral functions, including the ability to cause infection,” Kugelman continued.

The antibody cocktail was tested against the rescued virus and failed to control the infection. This demonstrates the significance of the mutations, but also gives information for moving forward towards an effective vaccine.

“At this point, we knew that the mutations were, in fact, ‘escape variants’ that were cumulatively responsible for reduced efficacy of the MB-003 therapeutic. However, we were unsure of the frequency of this type of event,” explained senior author Gustavo Palacios, PhD, director of USAMRIID.

Furthermore, the researchers were able to confirm these findings with a second animal who displayed similar changes, including four common sites with the first. They suspect that the antibody cocktail binds and attacks the original virus while the escape variants promote the infection. However, they already found that making a few changes to amino acids could destroy the process.

Future research should concentrate on the specific changes that impact the binding process. In addition, Palacio says that they need to find how each mutation influences the three antibodies.