A novel vaccine platform for Lassa Virus

Abstract

Lassa virus (LASV), the causative agent of Lassa fever (LF), exhibits significant genetic diversity as reflected by the several clades described in the literature. This poses a challenge for the development of a pan-Lassa vaccine. Current vaccine development efforts predominantly target the prototypic Josiah strain, while the LF burden in West Africa is largely driven by lineages II and III. We developed and characterized a novel vaccine platform based on recombinant Newcastle disease virus (rNDV). Reverse genetics allowed the introduction of the LASV glycoprotein precursor (GPC) and nucleoprotein (NP) from a clinically relevant but underrepresented lineage II Nigerian LASV strain within the NDV-LaSota/L289A genome. Six distinct live-attenuated vaccine candidates were generated, rescued and characterized in vitro. GPC constructs included wild-type, chimeric, and prefusion-stabilized versions, whereas NP included wild-type and type I interferon agonist transgenes. All rNDV-LASV candidates were genetically stable and robustly expressed LASV proteins. In vivo immunogenicity studies in C57Bl/6 mice revealed that vaccines expressing a prefusion-stabilized GPC elicited the most potent, polyfunctional CD8+ and CD4+ T-cell responses. However, LASV GPC-specific antibody responses were generally low. Conversely, the vaccine expressing wild-type NP induced strong humoral and CD4+ T- cell responses. Furthermore, we established a very low seroprevalence of pre-existing NDV immunity in a cohort of Nigerian LF survivors, supporting the suitability of this vaccination strategy in LF endemic regions. Collectively, these findings demonstrate the feasibility of the rNDV platform for developing LASV vaccines and provide a strong rationale for their advancement into preclinical challenge studies to evaluate protective efficacy against LASV.