Development of a Modified mRNA-Based Vaccine for Lassa Virus
Abstract
Lassa virus (LASV) has the highest impact of any hemorrhagic fever viruses (with the exception of dengue virus) causing 100,000 to 300,000 infections, which lead to approximately 5,000 deaths annually. LASV is a highly prevalent pathogen in West Africa, including Sierra Leone, Liberia, Guinea, and Nigeria. While 80% of LASV infections are asymptomatic, the remaining 20% generally result in severe disease, with the virus affecting several vital organs. The mortality rate among patients who contract severe disease exceeds a devastating 50%. In spring 2018, Nigeria was hit by unprecedented Lassa fever outbreak; more cases were recorded in the first 2 months than in any previous year. These alarming statistics demonstrate that LASV has a significant impact on the health and economy of West Africa. Owing to these ravaging consequences, Lassa fever has been included in the World Health Organization (WHO) list of top Priority Diseases in 2017. There is currently no approved vaccine for LASV. In summary, these significant effects have created a critical global unmet need for an effective LASV vaccine. This proposal addresses the requirements in “Vaccine Development for Infectious Diseases” section. More specifically, it addresses the need for the clause “Development and fielding of vaccines to prevent Service members from becoming ill from epidemic disease exposure during operational deployments. This includes, but is not limited to… Lassa fever…”. The proposed research is aimed at the development of an effective vaccine against LASV. The proposed vaccine will have two highly innovative components: (1) The modified mRNA-based vaccine platform. Vaccines based on a conventional mRNA platform do not possess sufficient immunogenicity as mRNA has the ability to stimulate innate immunity, which in turn prevents efficient production of the vaccine antigen. Recently, an innovative vaccine technology was developed based on chemically modified mRNA, which greatly enhances production of the vaccine antigen. (2) The modified stabilized form of the LASV envelope GPC protein. Recent studies demonstrated an alternative three-dimensional structure of the LASV envelope protein and demonstrated that highly protective antibodies isolated from LASV survivors effectively bind to this alternative structure. These new studies also identified ways to stabilize the LASV envelope protein in the recently discovered alternative form. LASV is a highly diverse virus and its strains are divided in four clades (lineages). A vaccine against a single clade is not expected to protect against the other LASV clades. Therefore, vaccine constructs against each of the four clades will be generated and tested followed by testing of a cocktail of vaccine constructs. The vaccine constructs for all four clades and their mixture will be tested for immunogenicity and protective efficacy in guinea pigs. The generated vaccine will have the following advantages: • Safety: The vaccine will be based on mRNA and not virus-based vaccine platform or DNA. Virus or DNA-based vaccine platforms can potentially become incorporated into the human genome and can hence make a vaccine unsafe. • Efficacy: The recent studies of the vaccine platform demonstrated protection against several pathogens. • Possibility of repeated administration: the proposed vaccine will result in the exclusive production of LASV envelope but not any other protein components. Generation of non-specific protein components can induce an immune response and prevent repeated immunization with the same type of vaccine. This is particularly important for the areas endemic for multiple emerging pathogens such as LASV. • Rapid manufacturing: Production of the proposed vaccine has the potential for rapid, inexpensive, and scalable manufacturing and is therefore ideal for highly divergent emerging viral infections such as LASV. We have recently demonstrated the ability to bring a program
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910019
Entities
People
- Alexander Bukreyev
Organizations
- United States Army
- University of Texas Medical Branch