Highly Potent Neutralizing Nanobodies Acting Against Chikungunya Virus Infection via Inhibiting Multiple Stages of the Viral Life Cycle

The Chikungunya virus (CHIKV) is a priority endemic pathogen identified by the World Health Organization and its infection induces an acute febrile illness in humans that is often associated with arthritis and musculoskeletal pain. Therefore, specific vaccines and treatments are urgently needed to prevent or treat Chikungunya disease. Here, we identify a series of CHIKV-specific neutralizing nanobodies (Nbs) from an alpaca which exhibit distinct binding modes compared to those previously reported. Two representative anti-CHIKV Nbs, N033-Fc and N053-Fc, demonstrated significant antiviral activity in Ifnar−/− mice against lethal challenge. Further studies elucidated the functional mechanisms of N033-Fc and N053-Fc in blocking CHIKV infection at multiple stages of the viral life cycle. This study identifies multiple candidate Nbs that may be suitable for next-generation antibody therapies to combat CHIKV infection.