Multimeric single-domain antibody complexes protect against bunyavirus infections.

Area of Science:

• Virology
• Immunology
• Biotechnology

Background:

• Bunyaviruses are a significant global health concern, with several listed by the WHO as potential epidemic threats lacking adequate countermeasures.
• Rift Valley fever virus (RVFV) and Schmallenberg virus (SBV) represent zoonotic and emerging ruminant pathogens within the Bunyaviridae family.

Purpose of the Study:

• To develop a broadly applicable strategy for creating bunyavirus biotherapeutics using llama-derived single-domain antibodies (VHHs).
• To validate this VHH-based approach against model bunyaviruses, RVFV and SBV.

Main Methods:

• Development of VHH building blocks derived from llamas.
• Assembly of VHHs into multimeric neutralizing complexes using bacterial superglue technology.
• Engineering of bispecific molecules by fusing VHHs to an Fc domain.

Main Results:

• VHH-based multimeric complexes demonstrated potent virus neutralization.
• Prophylactic administration of these complexes significantly reduced and prevented morbidity and mortality in mice infected with RVFV and SBV.
• Bispecific VHH-Fc molecules showed efficacy upon therapeutic administration in mouse models.

Conclusions:

• The VHH-based technology provides a versatile platform for developing novel antiviral therapies against bunyaviruses.
• This approach holds significant promise for combating bunyavirus threats, including those posing major epidemic risks.