Introduction and Background of the Project

Introduction
Lassa fever is a severe infectious disease caused by Lassa virus and is endemic in large parts of West Africa, where an estimated 2.7 million people are infected each year. Despite its significant public health impact, no approved vaccines or antiviral treatments are available. Because strong T‑cell immunity appears essential for protection, vaccine platforms that can safely induce robust cellular responses are urgently needed. Our recent studies showed that mRNA–lipid nanoparticle (LNP) vaccines encoding two key Lassa virus antigens—the glycoprotein precursor (LASgpc) and nucleoprotein (LASnp)—can protect animals in a surrogate BSL-2 mouse infection model, with combined administration suggesting the potential for enhanced protection. Building on these findings, this project aims to develop a single bicistronic mRNA vaccine that encodes both antigens to streamline manufacturing and reduce costs. We will also optimize LNP composition to improve thermostability for use in regions with limited cold‑chain capacity. This work seeks to advance a safe, scalable, and accessible mRNA vaccine for Lassa fever.

Project Objective
The objective of this project is to advance a safe, effective, and field deployable bivalent mRNA-LNP vaccine against Lassa virus (LASV) by encoding both LASV GPC and NPL within a single bicistronic mRNA construct. This approach aims to enhance antigenic breadth, improve protective immunity, and streamline manufacturing for future deployment in resource limited settings. During the project period, we will evaluate vaccine efficacy and immunogenicity in multiple animal models, including a bona fide LASV infection model, and optimize LNP formulations for improved thermal stability. These efforts will accelerate the transition toward clinical development of a thermostable, accessible LASV mRNA vaccine.

Project Design
We will develop and validate a bicistronic mRNA encoding LASV GPC and NP, supported by analytical assays to ensure its quality and manufacturability. Bicistronic mRNA-LNPs will be tested in the BSL-2 infection model to assess immunogenicity and protection, and promising candidates will be evaluated in a lethal guinea pig model of authentic LASV infection under BSL-4 conditions. Thermostable LNP formulations will be optimized through lyophilization and compositional adjustments, and their stability will be assessed at elevated temperatures. A scalable manufacturing process will be established to produce preclinical-grade vaccine lots using a controlled mixing method suitable for future clinical production. Finally, protective efficacy will be evaluated in a lethal BSL-4 guinea pig model to support the progression toward clinical development.

How can your partnership (project) address global health challenges?

Lassa virus infects an estimated 2.7 million people annually in West Africa. Despite this burden, no licensed vaccines or antivirals are available, making vaccine development an urgent global health priority. Our project addresses this gap by developing a bivalent mRNA‑LNP vaccine encoding LASgpc and LASnp to elicit broad cellular immunity. This dual‑antigen strategy builds on evidence from live‑attenuated vaccine studies suggesting that inclusion of both antigens may enhance protection. Importantly, unlike viral‑vectored vaccines mRNA vaccines are not limited by anti‑vector immunity, which provides flexibility for repeated vaccination or antigen updates as needed. Because mRNA vaccines are non‑replicating, they are also suitable for vulnerable groups, including children and pregnant women. Rapid prototyping and the BSL‑2 surrogate challenge model enable accelerated evaluation, while long‑term efforts focus on developing a thermostable, scalable platform suitable for resource‑limited settings.

What sort of innovation are you bringing in your project?

Our project introduces several key innovations to address long-standing challenges in Lassa fever vaccine development. First, we employ a bicistronic mRNA design that enables the coordinated expression of LASgpc and LASnp from a single transcript. This approach is highly efficient for enhancing antigenic breadth while simplifying manufacturing. This dual-antigen approach builds on the evidence that co-expression supports cross-lineage protection, thereby addressing the genetic diversity of Lassa virus. Second, we integrate thermostability-focused formulation innovations, including optimized LNP compositions and lyophilization, to reduce dependence on ultra-cold storage and improve suitability for use in resource-limited endemic regions. Third, unlike viral-vectored vaccines, our mRNA platform is not constrained by anti-vector immunity, allowing repeated boosting and broader applicability. Finally, the platform’s non-replicating nature may offer particular advantages for vulnerable populations, including children and pregnant women. Together, these innovations advance a scalable, field-ready vaccine approach tailored to global health needs.

Role and Responsibility of Each Partner

CAMaD (The University of Osaka): Oversees project management and milestone decisions, leads the design and external production of the bicistronic mRNA, and provides high‑quality research‑grade materials. 

RIMD (The University of Osaka): Conducts BSL‑2 mouse studies to evaluate immunogenicity and protective efficacy in rapid in vivo models.

UOsaka Med (The University of Osaka): Responsible for LNP formulation, thermostability optimization, and establishing a scalable manufacturing process suitable for future clinical production.

UTMB: Performs BSL‑4 efficacy studies using the guinea pig model of authentic Lassa virus infection and generates critical data for advancing toward clinical development.