Lassa virus (LASV), a member of the Arenaviridae family, poses a significant global health threat, particularly in West Africa, where outbreaks continue to occur, including as recently as October 2025¹. Despite its impact, there are currently no approved medical countermeasures for LASV, and the genetic diversity of circulating clades further complicates therapeutic development. Addressing this challenge, we employed a human monoclonal antibody (mAb) discovery platform developed by USAMRIID and collaborators to identify cross-clade neutralizing mAbs using plasma, serum, and peripheral blood mononuclear cells (PBMCs) from LASV survivors in Sierra Leone.

Through a systematic in vitro down-selection process, including MAGPIX multiplex assays, qualitative and quantitative ELISAs, and microneutralization assays, we identified promising convalescent LASV samples for further interrogation. LASV-GPC antigen specific B cells were sorted, and the resulting cloned IgG antibodies were evaluated for affinity and kinetics by biolayer interferometry, epitope specificity, and neutralization activity against six diverse clades (I, II, III, IV, and VII) prevalent in West Africa. Notably, candidate mAb0074 demonstrated cross-neutralizing and binding activity against clades II, IV, and VII. Additionally, antibody-dependent cellular phagocytosis (ADCP) and binding assays revealed that non-neutralizing antibodies mAb0090 and mAb0095 exhibited potential as components of a cross-protective antibody cocktail.

This study highlights the potential of monoclonal antibody platforms to address the genetic diversity of LASV and provides a foundation for the development of cross-clade therapeutics. We will discuss the implications of these findings and outline future directions for advancing lead mAb candidates toward clinical evaluation.