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Principal Investigator: Jarrod Mousa
Organization: FLORIDA STATE UNIVERSITY
Fiscal Year: 2024
Award: $682,008
Funding agency: National Institute of Allergy and Infectious Diseases
While vaccines are available for SARS-CoV-2, influenza virus, and RSV, and our laboratory has advanced mAbs
and vaccines for hMPV, there has been a lack of research on parainfluenza virus (PIV) disease prevention and
treatment, despite being the second highest cause of acute lower respiratory infection (ALRI) in young children.
Globally, PIVs cause 18 million ALRI cases, 700,000 hospital admissions, and 34,000 deaths in children younger
than five years of age each year. As a comparison, RSV causes nearly 60,000 deaths in children under 5 years
of age each year, while hMPV causes approximately 12,000 deaths in the same age range. Among adults,
severe disease can occur in those with immuncompromising conditions, especially those with hematopoietic
stem cell and solid organ transplants, as well as those with hematologic malignancy, with high resulting mortality
rates. PIVs are members of the Paramyxoviridae family, which consists of both endemic viruses as well as
zoonotic viruses with pandemic potential. This R01 proposal seeks to advance the development of monoclonal
antibodies (mAbs) for the treatment of infectious diseases, which is a major priority of NIAID and our research
laboratory. Our major objective is to define the structural and mechanistic determinants mediating the
neutralization and protection against paramyxoviruses. For this proposal, we will specifically focus on the PIV
fusion (F) and hemagglutinin-neuraminidase (HN) surface proteins. In Aim 1, we will define the human B cell
repertoire to PIV HN and F in adults and children. We will leverage recent advances in single B cell sequencing
for the generation of human mAbs, which will then be assessed for neutralization potency, epitope specificity,
and interfering with the viral life cycle. In Aim 2, we will determine the optimal therapeutic strategy for anti-PIV
mAbs. We will utilize two rodent models, including Syrian golden hamsters for mAb screening, followed by cotton
rats for verification of therapeutic value. In Aim 3, we will determine the structural epitopes mediating antibody
functionality and protective efficacy. We will define these protective mAb epitopes at the molecular level using
cryo-electron microscopy, which will be essential to advancing the mAb candidates and future vaccine
candidates by identifying the optimal epitopes for mAb efficacy. With the recent approval of the first RSV vaccine,
and the critical use of antibody guided structure-based vaccine design to stabilize the RSV F protein in the pre-
fusion conformation, this proposal is conceptually innovative as we will incorporate recently described PIV pre-
fusion F proteins in our strategies, conduct the first in-depth B cell repertoire studies for PIV infection, and by the
exciting collaborations. Furthermore, this proposal is technically innovative as we will leverage state of the art
tools, including high-throughput single B cell sequencing and cryo-electron microscopy for determination of
protective and non-protective epitopes on the PIV surface proteins. Our research will advance the field by
developing new human mAb therapeutics for the treatment of PIV infection, and by defining protective epitopes
important for vaccine development for PIVs, which will translate to additional paramyxoviruses.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><5 year old><5 years of age><Acute><Acylneuraminyl hydrolase><Adult><Adult Human><Advanced Development><Age><Antibodies><Antigenic Determinants><B blood cells><B cell><B cell repertoire><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Blood Precursor Cell><COVID-19 virus><COVID19 virus><Cessation of life><Child><Child Youth><Children (0-21)><Chimera Protein><Chimeric Proteins><Clinical Treatment Moab><CoV-2><CoV2><Collaborations><Cotton Rats><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Death><Death Rate><Disease><Disorder><Electron Cryomicroscopy><Epitopes><Family><Fusion Protein><Future><Generations><Glycoproteins><Golden Hamsters><Golden Syrian Hamsters><Grafting Procedure><Grant><Hemagglutinin><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hematopoietic Progenitor Cells><Hematopoietic stem cells><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Hospital Admission><Hospitalization><Hu-mABs><Human><Human Metapneumovirus><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Influenza Virus><Laboratories><Laboratory Research><Life Cycle><Life Cycle Stages><Lower Respiratory Tract Infection><Lower respiratory infection><MAb Therapeutics><Malignant Hematologic Neoplasm><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mesocricetus auratus><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><N-Acylneuraminate Glycohydrolases><NIAID><National Institute of Allergy and Infectious Disease><Neuraminidase><Oligosaccharide Sialidase><Organ Transplantation><Organ Transplants><Parainfluenza Virus Infections><Paramyxoviridae><Paramyxovirus><Prevention><Proteins><RSV Vaccines><Receptor Inhibition><Research><Respiratory Syncytial Virus Vaccines><Respiratory syncytial virus><Rodent Model><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Sialidase><Solid><Specificity><Structure><Surface Proteins><Syrian Hamsters><Therapeutic><Therapeutic Monoclonal Antibodies><Translating><Vaccine Design><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><access to vaccination><access to vaccines><adulthood><age 5 years><ages><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><candidate identification><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 virus><coronavirus disease-19 virus><cross reactivity><cryo-EM><cryoEM><cryogenic electron microscopy><develop a vaccine><develop vaccines><development of a vaccine><disease prevention><disorder prevention><exo alpha sialidase><five year old><five years of age><hCoV19><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><infectious disease treatment><influenzavirus><innovate><innovation><innovative><kids><life course><mAbs><member><monoclonal Abs><monoclonal antibody drugs><mortality><mortality rate><mortality ratio><nCoV2><neutralizing mAb><neutralizing monoclonal antibodies><organ allograft><organ graft><organ xenograft><pandemic concern><pandemic potential><pandemic risk><pandemic threat><parainfluenza virus><protective efficacy><receptor binding><receptor bound><respiratory virus><response><screening><screenings><success><therapeutic mAbs><tool><vaccination access><vaccination availability><vaccine access><vaccine availability><vaccine candidate><vaccine development><viral infection><virus infection><virus-induced disease><youngster>