Development of mosaic enterovirus mRNA vaccine to prevent hand, foot and mouth disease

/Abstract Hand Foot Mouth Disease (HFMD) is primarily caused by human enterovirus serotype A viruses (HEV-A), and predominantly affects young children. Most cases result in mild flu-like symptoms and painful sores and rash, but severe complications can occur that involve the central nervous system (CNS), such as viral meningitis and encephalitis, that can lead to serious illness and death. Moreover, emergent viral strains could evolve to have enhanced infectivity and severe disease in future viral outbreaks. Currently, there are no antivirals or vaccines that target the broad diversity of viral strains that cause HFMD. Thus, there is an urgent need to develop broadly protective vaccines and effective antivirals to the broad range of viral strains that cause HFMD. In this project, we propose to develop broad mosaic multivalent HFMD mRNA vaccines for optimal vaccine efficacy and longevity, and to isolate broadly neutralizing enterovirus antibodies for therapeutic development. An effective and broad vaccine against HFMD will need to accommodate the diverse viral sequence diversity within HEV-A. We have computationally designed a hexavalent mosaic HEV-A vaccine by taking conserved B and T cell epitopes from multiple HEV-A viruses and creating mosaic vaccine antigens for broad viral sequence coverage of HEV-A viruses. We showed that mice immunized with our hexavalent HEV-A vaccine had increased antibody titers against multiple HEV-A viral proteins compared to a single-strain vaccine. Our overall hypothesis is that computationally-designed mosaic HEV-A vaccines will elicit broader and more cross-reactive B and T cell immune responses to the viruses that cause HFMD compared to single EV-A71 strain-specific vaccines. Our overall objective of this proposal is to develop and test an mRNA-encoded virus- like particle (VLP) vaccine that consists of multivalent HEV-A capsid antigens that were designed for optimized sequence coverage of HEV-A serotype viruses. Moreover, we will isolate HEV-A broadly neutralizing antibodies to identify cross-reactive B cell epitopes that could be further developed as therapeutic monoclonal antibodies. This work is significant because it will lead to the development of a broad HEV-A vaccine that could be utilized as an effective vaccine for HFMD and utilizes an innovative vaccine development platform integrating computational antigen design and mRNA-encoded VLP technology that could also be applied to other pathogens. In aim 1, we will engineer a multivalent mosaic HEV-A mRNA-encoded VLP vaccine and determine B and T cell immune responses compared to a strain specific vaccines. In aim 2, we will isolate and characterize cross-reactive broadly neutralizing HEV-A antibodies. This project will develop a novel mRNA HEV-A vaccine that generates cross-reactive immunity against the diverse viruses that cause HFMD and utilized to prevent infection and disease. Moreover, we will isolate broadly neutralizing antibodies that will identify conserved neutralizing epitopes within HEV-A viruses, for further development as immunotherapies for HFMD and related HEV-A infections. Project Number: 1R21AI185859-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Todd Bradley | Institution: CHILDREN'S MERCY HOSP (KANSAS CITY, MO), KANSAS CITY, MO | Award Amount: $433,175 | Activity Code: R21 | Study Section: Vaccines Against Infectious Diseases Study Section[VID] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18585901A1