Lassa Virus (LASV) is a highly prevalent pathogen in West Africa, including Sierra Leone, Liberia, Guinea and Nigeria. The virus causes 100,000 to 300,000 infections per year, which lead to approximately 5,000 deaths annually. There is no approved vaccine against LASV. Recently, an innovative vaccine technology was developed based on mRNA modified by incorporation of pseudouridin, which dramatically minimizes the indiscriminate activation of innate immune sensing and increases translation by an order of magnitude. We propose to use the lipid nanoparticle (LNP)-formulated modified mRNA vaccine platform for development of a vaccine against LASV. LASV expresses just one glycoprotein precursor, termed GPC, which is the target of protective antibody response. GPC is a trimer of heterodimers, each containing the receptor-binding subunit GP1 and the transmembrane fusion-mediating subunit GP2. This protein has two different conformations: an unstable prefusion and a stable postfusion conformation. Most of LASV-neutralizing antibodies, including protective antibodies, effectively bind to prefusion, but not postfusion form of GPC. Two types of vaccine constructs will be generated: based on wild type and stabilized prefusion forms of GPC. Inclusion of the unique stabilized GPCs should allow improvement of the type and quality of neutralizing antibody response. Initially, vaccines expressing wild type and prefusion stabilized forms of the clade IV LASV GPC will be generated and compared for immunogenicity and protective efficacy in guinea pigs. This will be followed by generation of clades I, II and III vaccine constructs, for which the more immunogenic and protective form of GPC (wild type or stabilized prefusion) will be selected. The vaccine constructs for all four clades and their mixture will be tested for immunogenicity and protective efficacy in guinea pigs. As such, the following Specific Aims are proposed: 1) To generate LNP-formulated modified mRNA-based vaccine constructs expressing wild type or stabilized prefusion LASV GPC proteins; 2) To test immunogenicity and protective efficacy of vaccine constructs in guinea pigs. The proposed vaccine will have the following advantages: (A) Safety: as mRNA is non-infectious, non- integrating platform, there is no risk of infection or insertional mutagenesis. (B) Efficacy: various nucleoside modifications make mRNA more translatable and more stable, and co-administration with certain carriers can further increase efficiently of delivery in vivo. (C) Possibility of repeated administration: mRNA is the minimal genetic vector; therefore, anti-vector immunity is avoided and mRNA vaccines can be administered repeatedly. This is particularly important for the areas endemic for multiple emerging pathogens. (D) Rapid manufacturing. Production of mRNA vaccines has the potential for rapid manufacturing by in vitro transcription and is therefore ideal for highly divergent emerging viruses such as LASV. (E) A possibility of room temperature formulations, which is highly advantageous for a vaccine against LASV, which is endemic for some remote parts of Africa.
There is an urgent need in development of a vaccine against Lassa Virus (LASV), which is a highly prevalent pathogen causing 100,000 to 300,000 infections per year, including approximately 5,000 deaths in West Africa. The proposal includes development of a LASV vaccine using an innovative vaccine technology based on mRNA modified by incorporation of pseudouridin, which dramatically minimizes the indiscriminate activation of innate immune sensing and increases translation by an order of magnitude. This proposal is relevant to the NIH mission because it will result in the development of a safe LASV vaccine based on a non-infectious non- replicating platform, with a possibility of repeating administration due to the lack of a vector, and which can be quickly and easily manufactured and formulated to store at room temperature.