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

Project Summary/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.

Grant Number: 1R21AI185859-01A1
NIH Institute/Center: NIH
Principal Investigator: Todd Bradley