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

Grant Award Summary

Children's Mercy Hospital received a $433,175 Project Grant from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855), effective July 1, 2025 through June 30, 2027. The award supports the development of a mosaic messenger ribonucleic acid (mRNA) vaccine designed to prevent hand, foot, and mouth disease (HFMD) caused by human enterovirus A viruses. The research deliverables include the design and testing of a hexavalent, computationally-optimized mosaic vaccine formulation that incorporates conserved B and T cell epitopes from multiple enterovirus A strains to achieve broad viral coverage. Additionally, the project encompasses isolation and characterization of broadly neutralizing enterovirus antibodies for potential therapeutic development.

The vaccine development approach leverages mosaic antigen technology to address the significant diversity of viral strains causing HFMD and overcome the current absence of antivirals or vaccines with broad protective coverage. Preliminary murine studies have demonstrated that the multivalent mosaic approach generates increased antibody titers against multiple viral proteins compared to single-strain vaccines. The ultimate objective is to develop and validate an mRNA-encoded virus-like particle vaccine formulation that will elicit broader and more cross-reactive immune responses than existing strain-specific vaccines, thereby providing protection against the diverse enterovirus serotypes responsible for HFMD-related complications, including central nervous system infections.

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.