Study demonstrates potential broad-spectrum anti-alphavirus therapeutics

A recent collaborative study has identified two promising single-domain antibodies (sdAbs) that may offer a therapeutic option against multiple subtypes of Venezuelan equine encephalitis virus (VEEV). The researchers, from the U.S. Army Medical Research Institute of Infectious Diseases, National Institutes of Health’s Vaccine Research Center, U.S. Naval Research Laboratory, and the Frederick National Laboratory for Cancer Research, have published their findings in the Journal of Virology.

A mosquito-borne alphavirus, VEEV can cause a spectrum of disease from mild febrile flu-like illness to neurological symptoms, including encephalitis, in 4%–14% of infected individuals. The last major outbreak of VEEV reported was in Colombia in 1995, with smaller epidemics occurring annually in Central and South America.

The study revealed two bivalent sdAbs capable of protecting mice from lethal challenges posed by both epizootic and enzootic subtypes of VEEV. Notably, the effectiveness of the bivalent sdAbs stems from their unique structural interactions, which enhance their protective capabilities.

“This research marks a pivotal advancement in our understanding of single-domain antibodies and their protective potential against encephalitic viruses,” said Crystal Burke, Ph.D., research microbiologist and branch chief, USAMRIID’s Viral Pathogenesis Branch.

The team genetically coupled two-lead bivalent sdAb constructs to an albumin-binding domain, assessed their serum half-life, and demonstrated efficacy against multiple subtypes of VEEV by different routes of exposure.

“What’s important about our work is we went beyond testing against a standard strain, like the Trinidad donkey strain, and tested multiple subtypes that covered strains affecting public health and biodefense concerns,” said Christina Gardner, Ph.D., lead author and a contract scientist with Chenega, Cherokee Nation Integrated Health, LLC working in USAMRIID’s Viral Pathogenesis Branch.

Next steps

The development of pan-alphavirus therapeutics is crucial for effective treatment and prevention strategies. The identified sdAbs could be utilized in combination with existing alphavirus IgG antibodies to create a comprehensive therapeutic approach.

“The identification of bispecific sdAbs that can protect against multiple lineages of VEEV is particularly exciting and warrants further in vivo testing,” said Gardner.

With no FDA-licensed vaccines or therapeutics currently available for VEEV, this research represents a significant step forward in addressing a potential biological threat agent, said Burke.

As USAMRIID runs the virus piece of the study, next steps could potentially be large pre-clinical model work against VEEV, outside collaboration efforts, and additional efficacy studies with other alphaviruses to look at a wider range of in vivo protection, said Burke.