Alphavirus vector-based replicon particles expressing multivalent cross-protective Lassa virus glycoproteins.

Area of Science:

• Virology and Immunology
• Vaccine Development
• Public Health

Background:

• Lassa virus (LASV) is a significant public health threat in West Africa, causing thousands of deaths annually.
• The high genetic diversity of LASV presents a major challenge for developing effective vaccines.
• Existing vaccine research and development (R&D) strategies require innovative approaches to address LASV.

Purpose of the Study:

• To develop novel, multivalent virus-like particle vectors (VLPVs) for Lassa fever vaccine development.
• To assess the immunogenicity and protective efficacy of VLPV-based vaccines against LASV.
• To investigate the mechanism of antigen presentation and T cell response induction by VLPVs.

Main Methods:

• Engineered VLPVs using Venezuelan equine encephalitis virus (VEEV) replicon particles.
• Incorporated Lassa virus glycoproteins (GPC) from diverse clades (I and IV) into VLPVs.
• Evaluated VLPV immunogenicity, protective effects in mice, and immune cell responses.

Main Results:

• VLPVs induced simultaneous expression of LASV wild-type and modified glycoproteins (ΔGPfib).
• LASV ΔGPfib promoted antigen cross-priming by inducing ER stress and apoptosis in transduced cells.
• VLPV vaccination demonstrated immunogenicity and protection in mice, upregulating key dendritic cells for cross-presentation and inducing cross-reactive T cell responses.

Conclusions:

• Multivalent RNA replicon-based VLPVs are a promising next-generation vaccine platform for Lassa fever.
• The developed VLPVs elicit robust, cross-reactive immune responses against diverse LASV clades.
• These VLPV vaccines could be crucial for protecting at-risk populations, including first responders and travelers.