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Principal Investigator: Bert L Semler
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $3,478,173
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract – Project 5: Multi-scale development and evaluation of broadly-effective
vaccines against picornaviruses with pandemic potential
Picornaviruses are the most common causes of viral illnesses worldwide. Within the picornavirus family of
positive-strand RNA viruses, enteroviruses such as poliovirus, coxsackievirus, enterovirus A71 (EV-A71), and
enterovirus D68 (EV-D68) have the potential to produce devastating disease sequelae in humans, including
paralytic poliomyelitis, cardiomyopathy, pancreatitis, encephalitis, meningitis, and acute flaccid myelitis (AFM).
Surprisingly, the only enterovirus vaccines with U.S. FDA approval are the highly successful inactivated and
attenuated vaccines against poliovirus. In addition, there are no approved antiviral drugs to successfully treat
enterovirus infections despite their considerable pandemic potential. The availability of phylogenetically-
conserved, structure-based design approaches across a large number of related enteroviruses provides a range
of new opportunities to generate a comprehensive panel of mRNA- and protein-based vaccine candidates to
combat infection by these important human pathogens. The experimental approach for this project involves the
testing of mRNA and protein/adjuvant vaccine candidates using in vitro virus culture and animal
challenge/pathogenesis models. The proposed project will also explore novel approaches to vaccine design and
construction that leverage the unique features of picornavirus biology to generate lead strategies that may prove
broadly effective. The proposal will also employ state-of-the-art murine models for evaluating vaccine efficacy
and protection from disease. This standardized series of in vivo models will provide a unique opportunity to
compare efficacy of vaccine responses across different enterovirus serotypes and species and identify the most
promising candidates for advancement to large animal models. Collectively, the breadth of experiments proposed
will create a validated workflow for developing and testing new vaccines that are designed to provide
broad protection against multiple different known pathogenic picornaviruses. Importantly, when
combined with the other cores and projects in this application, this approach is predicted to allow the
rapid development and preclinical evaluation of vaccines and nanobody therapeutics to any new
picornavirus that emerges and represents a significant public health concern.
Terms: <Acute Poliomyelitis><Adjuvant><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Agents><Antibodies><Assay><Attenuated Vaccines><Bioassay><Biological Assay><Biology><Blood Serum><Brain Inflammation><Cardiomyopathies><Cell Line><CellLine><Cessation of life><Coxsackie Viruses><Coxsackievirus><Death><Development><Disease><Disorder><EV-68><EV-71><EV-A71><EV-D68><Encephalitis><Enterovirus><Enterovirus 68><Enterovirus 71><Enterovirus A71><Enterovirus D68><Enterovirus Infections><Evaluation><Family><Family Picornaviridae><Goals><Human><Human poliovirus><Immune><Immune response><Immunes><Immunological response><In Vitro><Inactivated Vaccines><Inactivated Virus Vaccine><Infection><Killed Vaccines><Lead><Live-attenuated Vaccine><Meningitis><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Neonatal><Palsy><Pancreatitis><Paralysed><Pathogenesis><Pathogenicity><Pathology><Pattern><Pb element><Phylogenetic Analysis><Phylogenetics><Picornaviridae><Picornaviruses><Plegia><Polio><Polio Virus><Poliomyelitis><Poliovirus><Predisposition><Proteins><Public Health><RNA Viruses><RNA vaccine><RNA-based vaccine><Series><Serotyping><Serum><Severity of illness><Standardization><Strains Cell Lines><Structure><Susceptibility><Symptoms><Testing><Therapeutic><Transfusion><Vaccine Design><Vaccine Production><Vaccines><Viral><Virus><acute flaccid myelitis><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><block viral entry><combat><comparable efficacy><comparative efficacy><compare efficacy><cultured cell line><design><design and construct><design and construction><designing><developmental><disease severity><evaluate vaccines><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><host response><human pathogen><humanized mice><humanized mouse><immune system response><immunoresponse><in vivo Model><inhibit viral entry><live vaccine><live vaccines><mRNA><mRNA vaccine><mRNA-based vaccine><model of animal><mouse model><murine model><myocardium disease><myocardium disorder><nanobodies><nanobody><new approaches><new vaccines><next generation vaccines><novel><novel approaches><novel strategies><novel strategy><novel vaccines><pandemic concern><pandemic disease preparedness><pandemic planning><pandemic potential><pandemic preparedness><pandemic readiness><pandemic risk><pandemic threat><paralysis><paralytic><poliomyelitis virus><pre-clinical evaluation><preclinical evaluation><produce vaccines><sdAb><single domain antibodies><vaccine candidate><vaccine efficacy><vaccine evaluation><vaccine platform><vaccine response><vaccine responsiveness><vaccine screening><vaccine strategy><vaccine testing><vaccine-induced response><viral entry blocker><viral entry inhibitor><virus culture>