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Principal Investigator: Matthew R Vogt
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2022
Award: $653,847
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Manifestations of enterovirus infections are variable, with several severe illnesses such as meningitis, acute
flaccid myelitis (AFM), myocarditis, and neonatal sepsis. Poliovirus vaccines are near perfect at preventing
severe illness by generating strong, circulating antibody responses. However, the polioviruses represent only
three of the more than 100 enteroviruses capable of causing human disease. Recently approved vaccines for
enterovirus A71 are demonstrating that other enterovirus diseases, in this case hand, foot, and mouth disease,
can be prevented by vaccination as well. Our previous work shows that monoclonal antibodies that cross-react
to all clades of enterovirus D68 can protect infected mice from AFM-like disease, and even treat disease after
onset. Rather than try to make 100 vaccines to cover each enterovirus, we propose to understand the qualities
of the human antibody response that could provide cross-reactive immunity across many enteroviruses. With
this knowledge, immunogens can be designed that preserve the B cell epitopes that stimulate cross-reactive
antibodies. We first aim to determine the degree of cross-reactivity of enterovirus antibody responses at a B cell
level. We will complement seroepidemiology studies of hundreds of healthy adults, looking to see what proportion
of them have naturally made antibody responses to the four species of enterovirus, with studies of stimulated
memory B cells from the peripheral blood mononuclear cell compartment. The latter will allow us to see how
many individual B cells in healthy adults produce antibodies that cross-react between enterovirus species, a
knowledge gap with no existing data. Second, we aim to determine the molecular details of enterovirus species
cross-reactivity using human mAbs. We will create human hybridomas that produce monoclonal antibodies
(mAbs), screening and selecting for mAbs that bind to multiple enteroviruses. Antigen-binding fragments of the
mAbs, in complex with virions from all immune-reactive enteroviruses, will be used for cryo-electron microscopy
studies to obtain atomic resolution maps of antibody epitopes, detailing at a molecular level the determinants of
cross-reactivity. Third, we aim to determine mechanisms of antibody action utilizing human primary cell infection
models. As we investigate which stage of the viral life cycle different mAbs disrupt to exert function, using ex
vivo differentiated human epithelial cell cultures will preserve the natural cell surface receptors used by viruses
during in vivo human infection. The knowledge gained from these studies will allow detailed understanding of
how cross-reactive antibodies bind to enteroviruses and how they function. In turn, the mAbs can be used to
functionally validate that candidate immunogens preserve these cross-reactive B cell epitopes. Finally, some
mAbs could later have potential for direct use in humans, either as prophylactic or therapeutic agents. This is an
especially important consideration for populations such as the immunocompromised, who may not be able to
generate strong antibody responses upon vaccination.
Terms: <0-11 years old><21+ years old><Acute Poliomyelitis><Adult><Adult Human><Airway infections><Animals><Antibodies><Antibody Response><Antibody Therapy><Antigen Binding Fragment><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cell Epitopes><B-Cells><B-Lymphocyte Epitopes><B-Lymphocytes><B-cell><Binding><Binding Determinants><Blocking Antibodies><Blood Serum><Cell Body><Cell Compartmentation><Cell Compartmentations><Cell Culture Techniques><Cell Surface Receptors><Cells><Child><Child Youth><Children (0-21)><China><Clinical><Clinical Treatment Moab><Complement><Complement Proteins><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Disease><Disease Outbreaks><Disorder><ELISA><Electron Cryomicroscopy><Ensure><Enterovirus><Enterovirus 68><Enterovirus D68><Enterovirus Infections><Enzyme-Linked Immunosorbent Assay><Epidemic><Epidemiology><Epithelial Cells><Epitopes><Fab Fragments><Fab Immunoglobulins><Future><Hand, Foot and Mouth Disease><Hemagglutination><High Throughput Assay><Hu-mABs><Human><Human poliovirus><Humoral Immunities><Hybridomas><Immune><Immunes><Immunity><Immunize><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunoglobulin, F(ab) Fragment><Immunosuppressed Host><Individual><Infection><Knowledge><Life Cycle><Life Cycle Stages><Mainland China><Maps><Memory B Cell><Memory B-Lymphocyte><Meningitis><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Movement><Murine><Mus><Myocarditis><Outbreaks><PBMC><Palsy><Paralysed><Peripheral Blood Mononuclear Cell><Plegia><Polio><Polio Vaccine><Polio Virus><Poliomyelitis><Poliovirus><Poliovirus Vaccines><Population><Position><Positioning Attribute><Prevention><Quality Control><Receptor Protein><Resolution><Respiratory Infections><Respiratory Tract Infections><Salk Vaccine><Serum><Structure><Surface><Symptoms><Therapeutic Agents><Vaccination><Vaccine Design><Vaccines><Viral><Viral Receptor><Virion><Virus><Virus Particle><Virus Receptors><Virus-like particle><Work><acute flaccid myelitis><adulthood><antibody based therapies><antibody treatment><antibody-based immunity><antibody-based therapeutics><antibody-based treatment><body movement><cardiac inflammation><cell culture><cell cultures><cross reactivity><cryo-EM><cryoEM><design><designing><develop a vaccine><develop therapy><develop vaccines><development of a vaccine><enzyme linked immunoassay><epidemiologic><epidemiological><experience><genomic RNA><high throughput screening><humAbs><human disease><human mAbs><human monoclonal antibodies><human monoclonals><immunogen><immunosuppressed patient><in vivo><in vivo Model><intervention development><life course><mAbs><neonatal sepsis><neutralizing antibody><paralysis><paralytic><poliomyelitis vaccine><poliomyelitis virus><polyclonal antibody><pre-clinical development><preclinical development><preservation><prevent><preventing><prophylactic><receptor><receptor binding><receptor bound><recombinant virus><response><screening><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy development><treatment development><vaccine development><virus-like nanoparticles><viruslike particle><youngster>