Antibodies targeting internal viral protein protect mice from lethal tick-borne disease

Scientists at the University of California, Riverside have identified multiple antibody targets on the nucleocapsid protein (NP) of Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne pathogen with a fatality rate up to 40% and no widely approved treatments or vaccines. The study, published in Nature Communications, focused on NP, an internal viral protein previously used mainly for diagnostics rather than considered a therapeutic target.

The researchers mapped four distinct antigenic sites on the NP, which consists of a head and a stalk region. Antibodies binding to either region were able to protect against infection in mouse models. The most potent antibody, designated 9D5, bound to the head region and protected mice from lethal challenge, also showing cross-strain reactivity.

X-ray crystallography revealed that the 9D5 binding site on the NP head is nearly identical across different CCHFV strains, suggesting a structural basis for broad-spectrum protection. The virus is transmitted primarily by Hyalomma ticks, which are expanding into new regions due to changing environmental conditions, increasing the risk to densely populated areas across Europe, Asia, Africa, and the Middle East.

Unlike typical neutralizing antibodies that block viral entry by targeting surface proteins, these NP-targeting antibodies are non-neutralizing. They appear to work by binding NP on the surface of infected cells or free-floating NP, then engaging the intracellular protein TRIM21 to trigger immune presentation and clearance of infected cells. This mechanism mobilizes the immune system rather than directly inactivating the virus.

The team found additional protective antibodies targeting other sites on NP, raising the possibility of antibody cocktails that hit multiple epitopes. The current 9D5 antibody is of mouse origin and not a candidate for human use, but the structural and mechanistic insights provide a blueprint for designing human or humanized antibodies with broad protective activity.

Lead researcher Scott Pegan estimates that an antibody treatment derived from this work could reach patients in approximately five years, contingent on successful preclinical and clinical development. The findings may also extend beyond CCHFV, as similar NP-targeting strategies have emerged in research on other viruses such as Lassa virus, suggesting nucleocapsid proteins represent a broader class of therapeutic targets previously overlooked.