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Principal Investigator: Rachael Wolters
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $122,850
Funding agency: NIH Office of the Director
Project Summary/Abstract
Influenza causes an estimated 1 billion cases yearly, with severe cases leading to fatal
bronchopneumonia, particularly in vulnerable populations. Influenza virions express two major surface
glycoproteins, hemagglutinin (HA) and neuraminidase (NA), the latter of which is of interest due to its role in
viral egress and cleavage from mucus. Currently, the only FDA-approved antivirals used to treat influenza are
neuraminidase inhibitors, which are ineffective against some strains. Monoclonal antibodies (mAbs) directed at
NA provide an alternative therapeutic candidate. Delivering NA mAbs to the respiratory mucosal surface,
where the virus replicates, is a novel delivery method that could improve drug efficacy and patient compliance.
This five-year research career development award will provide training and development of the skills necessary
for the candidate to establish an independent research laboratory focused on understanding how human
antibodies against influenza can be harnessed to treat and prevent disease and transmission in animal
models. Currently, the candidate is a veterinarian and a graduate trainee at the Vanderbilt Vaccine Center who
will transition to an assistant professor position on the physician-scientist track in July 2024. Her training to
date has focused on the isolation and characterization of human monoclonal antibodies (mAbs) from subjects
with prior influenza history and mouse models of therapy. She will supplement this experience with further
training in developing in vivo ferret and ex vivo human tissue models of influenza infection with which to study
the natural pathogenesis of this virus and how human mAbs bind influenza to reduce pathogenesis. The short-
term goals of the proposed studies are to test the central hypothesis that neuraminidase-directed antibodies
play a significant role in the protective immune response and can be harnessed with antibody therapeutics.
This training will be supported by mentoring from national experts in the study of human antibodies (James
Crowe, Jr., Ivelin Georgiev), human airway epithelial cultures (Timothy Blackwell), influenza vaccinology
(Spyros Kalams), and small animal models of virus infection and pathology (Katherine Gibson-Corley). The
applicant aims to 1) elucidate the mechanisms of influenza type B (IBV) inhibition by mAbs specific to the
neuraminidase (NA) glycoprotein to test the hypotheses that NA antibodies exert distinct mechanisms of
protection, 2) use a human airway model of IBV infection to determine how NA mAbs in the presence of mucus
behave, 3) and test these mAbs in a ferret model of intranasal delivery to test the hypothesis that NA mAbs
delivered topically can reduce viral load and shedding. Overall, these studies will help define the role of IBV NA
antibodies and the mechanism of delivering mAbs to the respiratory mucosal surface. Industry groups are
developing protective mAbs made by the candidate as human therapeutic agents. Thus, these studies directly
translate the importance of human health and contribute to a more fundamental understanding of the disease.
Terms: <7S Gamma Globulin><Active Follow-up><Acylneuraminyl hydrolase><Air><Airway mucosa><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Agents><Antibodies><Antibody Therapy><Assay><Binding><Bioassay><Biologic Models><Biological><Biological Agent><Biological Assay><Biological Models><Biological Products><Biophysics><Bronchopneumonia><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Culture Techniques><Cell Line><Cell Surface Glycoproteins><CellLine><Cells><Cessation of life><Childhood><Clinical Treatment Moab><Clinical Trials><Complex><Death><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drugs><ELISA><Elderly><Environment><Enzyme-Linked Immunosorbent Assay><FDA approved><Family><Ferrets><Glycoproteins><Goals><Grippe><Health><Health Care Professional><Health Professional><Healthcare professional><Hemagglutinin><History><Hu-mABs><Human><IV Infusion><IgA><IgG><Immune response><Immunoglobulin A><Immunoglobulin G><Immunological response><In Vitro><Industry><Infection><Influenza><Influenza A><Influenza A virus><Influenza B><Influenza B Virus><Influenza Vaccines><Influenza Virus><Influenza Viruses Type A><Influenza Viruses Type B><Influenzavirus A><Intramuscular><Intramuscular Injections><Intravenous><Intravenous infusion procedures><K-Awards><K-Series Research Career Programs><Knowledge><Laboratory Research><Length of Life><Liquid substance><Longevity><Lung><Lung Respiratory System><MAb Therapeutics><Medication><Membrane Glycoproteins><Mentors><Methods><Modality><Model System><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Mucous body substance><Mucus><N-Acetylneuraminic Acids><N-Acylneuraminate Glycohydrolases><Nebulizer><Neuraminidase><Neuraminidase inhibitor><Nucleoproteins><Occluding Junctions><Oligosaccharide Sialidase><Orthomyxoviridae><Orthomyxovirus Type A><Orthomyxoviruses><Orthomyxoviruses Type B><Pathogenesis><Pathology><Patient Compliance><Pharmaceutical Preparations><Phylogenetic Analysis><Phylogenetics><Physicians><Physiologic><Physiological><Play><Population><Position><Positioning Attribute><Preclinical Testing><Program Development><Proteins><Public Health><Receptor Protein><Recombinants><Recording of previous events><Research><Research Career Program><Respiratory Disease><Respiratory Epithelium><Respiratory Mucosa><Respiratory System Disease><Respiratory System Disorder><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Scientist><Seasons><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sialic Acids><Sialidase><Site><Staining method><Stains><Strains Cell Lines><Structure of respiratory epithelium><Study models><Surface><Surface Glycoproteins><System><Techniques><Testing><Therapeutic><Therapeutic Agents><Therapeutic Monoclonal Antibodies><Therapeutic antibodies><Tight Junctions><Tissue Model><Topical Drug Administration><Topical application><Training><Translating><Transmission><Transmission Electron Microscopy><Type A Influenza><Vaccination><Vaccine Design><Vaccinee><Vaccines><Veterinarians><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Viral Pathogenesis><Viral Shedding><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Virus Shedding><Visualization><Vulnerable Populations><Work><Zonula Occludens><active followup><administer topically><advanced age><aerosolized><airway epithelium><animal model development><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><apply topically><biologic><biologics><biopharmaceutical><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><biotherapeutic agent><career><career development><cell culture><cell cultures><cell immortalization><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cultured cell line><deliver topically><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><drug candidate><drug detection><drug discovery><drug efficacy><drug testing><drug/agent><druggable target><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><enzyme linked immunoassay><evaluate efficacy><examine efficacy><exo alpha sialidase><experience><flu infection><flu vaccine><flu virus infection><flu virus vaccine><fluid><follow up><follow-up><followed up><followup><geriatric><histories><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><human tissue><immune system response><immunoresponse><improved><in vitro Assay><in vitro testing><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenza virus vaccine><influenzavirus><insight><interest><intramuscular drug administration><intraperitoneal><intravenous infusion><liquid><mAbs><member><model of animal><monoclonal Abs><monoclonal antibody drugs><mouse model><mucous><murine model><nebulization><nebulize><new approaches><novel><novel approaches><novel strategies><novel strategy><pandemic><pandemic concern><pandemic disease><pandemic potential><pandemic risk><pandemic threat><patient adherence><patient cooperation><pediatric><pre-clinical><pre-clinical testing><preclinical><prevent><preventing><professor><prophylactic><pulmonary><receptor><respiratory tract epithelium><respiratory virus><response><seasonal flu><seasonal influenza><senior citizen><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><skill acquisition><skill development><social role><structural biology><therapeutic candidate><therapeutic mAbs><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><translational applications><transmission process><treat topically><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine against flu><vaccine against influenza><vaccine development><vaccinology><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people>