Document text
Principal Investigator: Matthew R Vogt
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $5,421,688
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY - RP2
Picornaviruses are an ever-present threat to human health, causing myriad diseases ranging from mild
(common colds, hand, foot, and mouth disease) to more severe (meningitis, acute flaccid myelitis, myocarditis,
and neonatal sepsis). Fortunately, one of the most successful vaccine programs in history targeted
picornaviruses; the poliovirus vaccines completely eradicated two of three types and nearly eliminated the
third. Learning from this experience, neutralizing antibodies in the sera of vaccinees are a well-established
correlate of protection against paralytic poliomyelitis. Therefore, to prepare for a possible picornavirus
pandemic in the future, we must have tools in place to comprehensively analyze the antibody response to an
emerging pathogen to inform adaptable and streamlined picornavirus vaccine platforms. To accomplish those
goals, we have assembled a team of experts in picornaviruses and human antibodies with an established
record of collaboration. We will focus our studies on four prototype picornaviruses with antigenic diversity and
different sites of infection: respiratory (enterovirus D68 [EV-D68], rhinovirus C [RV-C]) and gastrointestinal
(enterovirus A71 [EV-A71], echovirus 11 [E11]). Studying these diverse viruses will best prepare us to respond
to an emergent picornavirus with unknown properties. Our first specific aim focuses on understanding the
polyclonal humoral immune response to picornavirus infections. We will leverage biobanked samples from a
previous study, new samples from a recently funded cohort, and our Virologic and Immunologic Sample
Acquisition Core (VISAC) samples to identify children with high neutralizing serum titers against the prototype
viruses. We will use cryo-electron microscopy to map the binding of polyclonal antibodies from these sera to
purified viruses to identify epitopes. We will supplement these data with tiled peptide arrays to
comprehensively analyze linear B cell epitopes of RV-C proteins. We will use these advanced techniques to
analyze sera before and after defined infections to define antibody binding patterns before and after children
develop high neutralization titers in their serum. Our second specific aim focuses on monoclonal antibody
(mAb) discovery. Starting with our established EV-D68 human mAb isolation methods, we will speed the time
of discovery from months to about two weeks, then use these methods to isolate EV-A71 and E11 mAbs. Our
prior screening methods (identifying mAbs that bind to native virions in ELISA) are suboptimal for RV-C, so we
will develop new screening methods for this virus that will better prepare us to respond to emergent pathogens.
As we identify new antiviral mAbs, we will select strongly neutralizing mAbs for study in our Structural Biology
Core and test them in models of infection developed in Project 1 of this program. We will use protective mAbs
as quality control reagents to ensure that new candidate vaccines maintain antigenicity at the cognate
epitopes. Finally, we will license protective mAbs to our industry partners to develop for therapeutic use in
humans.
Terms: <0-11 years old><Ab-mediated immunity><Ab-mediated protection><Acute Nasopharyngitis><Acute Poliomyelitis><Airway mucosa><Animals><Antibodies><Antibody Response><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigenic Determinants><Antigenic Diversity><Assay><Asthma><B blood cells><B cell><B cells><B-Cell Epitopes><B-Cells><B-Lymphocyte Epitopes><B-Lymphocytes><B-cell><BBC1><BCL2-Interacting Killer Gene><BIK><BIK gene><BIP1><BP4><Bik/Nbk Gene><Binding><Binding Determinants><Bioassay><Biological Assay><Blood Serum><Bronchial Asthma><Bunyavirus><C protein><Capsid Proteins><Cell Culture Techniques><Cell Line><CellLine><Child><Child Youth><Children (0-21)><Chronic lung disease><Clinical><Clinical Treatment Moab><Coat Proteins><Collaborations><Common Cold><Coxsackie Viruses><Coxsackievirus><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Development><Disease><Disorder><ELISA><EV-68><EV-71><EV-A71><EV-D68><Echo Viruses><Echovirus><Electron Cryomicroscopy><Enteral><Enteric><Enterovirus><Enterovirus 68><Enterovirus 71><Enterovirus A71><Enterovirus D68><Enzyme-Linked Immunosorbent Assay><Epidemic><Epitopes><Family Picornaviridae><Foot Diseases><Funding><Future><Goals><Hand's disease><Health><History><Hu-mABs><Human><Humoral Immunities><Hybridomas><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><In Vitro><Individual><Industry><Infection><Laboratories><Learning><Licensing><Life><Mammalian Cell><Maps><Mediating><Meningitis><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Mouth Diseases><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Myocarditis><NBK><NIAID><National Institute of Allergy and Infectious Disease><Oral Cavity Disease><Oral Cavity Disorder><Oral Disease><Oral Disorder><Orthobunyavirus><Palsy><Paralysed><Pathogenicity><Pattern><Peptides><Phylogenetic Analysis><Phylogenetics><Picornaviridae><Picornaviridae Infections><Picornavirus Infections><Picornaviruses><Plegia><Polio><Polio Vaccine><Poliomyelitis><Poliovirus Vaccines><Pre-Clinical Model><Preclinical Models><Preparedness><Production><Property><Prophylactic treatment><Prophylaxis><Protocol><Protocols documentation><Quality Control><Readiness><Reagent><Recording of previous events><Reporter><Research Proposals><Research Specimen><Respiratory Mucosa><Rhinovirus><Salk Vaccine><Sampling><Schedule><Sepsis><Serum><Services><Site><Specimen><Speed><Strains Cell Lines><Surface><System><Techniques><Technology><Testing><Therapeutic Uses><Time><Vaccinee><Vaccines><Viral><Viral Coat Proteins><Viral Outer Coat Protein><Virion><Virus><Virus Particle><Virus Replication><Wheezing><Work><academic preparation><academic readiness><acute flaccid myelitis><antibody-based immunity><antibody-mediated immunity><biobank><biorepository><blood infection><bloodstream infection><cardiac inflammation><cell culture><cell cultures><chronic pulmonary disease><citrate carrier><citrate periplasmic carrier protein><citrate transporter><citrate-binding transport protein><clinical development><cohort><cryo-EM><cryoEM><cryogenic electron microscopy><cultured cell line><develop a vaccine><develop vaccines><development of a vaccine><developmental><emerging pathogen><enzyme linked immunoassay><experience><future pandemic><gastrointestinal><histories><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immune system response><immunoresponse><in vivo><industrial partnership><industry partner><industry partnership><kids><mAbs><manufacture><member><monoclonal Abs><mouth disorder><neonatal sepsis><neonate><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><new pathogen><next pandemic><novel><novel pathogen><nucleic acid delivery><pandemic><pandemic disease><pandemic pathogen><paralysis><paralytic><pathogen><phase 1 trial><phase I trial><poliomyelitis vaccine><polyclonal antibody><pre-clinical><preclinical><preservation><programs><protective efficacy><prototype><respiratory><response><screening><screenings><seroconversion><structural biology><tool><tricarboxylate carrier><tricarboxylate transporter><tricarboxylate-binding C protein><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine candidate><vaccine development><vaccine platform><viral multiplication><viral replication><virus multiplication><wheeze><youngster>