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Principal Investigator: Anne Moscona
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $5,035,895
Funding agency: National Institute of Allergy and Infectious Diseases
Human parainfluenza virus type 3 (HPIV3) is the P1-Respiroviruses prototype for advancement of vaccines
and therapeutic antibodies against respiroviruses due to the advanced state of knowledge of structure and
function of the viral surface proteins: HN (receptor-binding protein; hemagglutinin-neuraminidase) and F (fusion
protein). Respirovirus HN and F form a functional complex on the virus surface and mediate entry by fusing the
viral envelope directly with the cell membrane. Structural transitions in the HN/F complex during sequential
steps of entry will be characterized using cryo-electron microscopy (cryo-EM) and tomography (cryo-ET) to
identify optimal antigenic targets for respirovirus vaccines and antibodies. HPIV3 and human parainfluenza
virus type 1 (HPIV1) bracket the diversity of known respiroviruses making HPIV1 ideal for testing strategies
established with HPIV3. We will determine the utility of each surface glycoprotein as a target for immunity and
how best to present the antigen(s) by evaluating three vaccine platforms (subunit, mRNA, rVSV).
Aim 1: Define structure-function relationships of HN and F and extend the findings from prototype
HPIV3 to HPIV1. Structures of HN, F, and HN/F complexes and their intermediates for the prototype
respirovirus HPIV3 will be obtained to address gaps in basic understanding of the functions of the envelope
proteins in viral entry and assembly, reveal essential functional interactions between the proteins, and inform
immunogen design for vaccines and antibodies. Immunogenicity of proteins will be assessed in mice and
iterated back to antigen design. Results will be extended to HPIV1 to assess generalizability.
Aim 2: Identify monoclonal antibodies to prototype respirovirus HPIV3 HN and F with a high genetic
barrier to resistance and assess the generalizability of strategies using HPIV1. We will produce HPIV3-
binding mAbs from human B cells, compare their binding affinity, epitopes, and neutralization potencies;
identify neutralization mechanisms, leveraging mAbs that bind one or both proteins, different domains, and
different intermediate states of HN/F during entry; and evaluate mechanisms of escape. Abs that block critical
entry functions of HN/F, are protective, and have a high genetic barrier to resistance will be assessed for in
vivo protective/therapeutic capacity. Antigens that elicit such desirable antibodies will iteratively aid vaccine
antigen design. HPIV3-based approaches will be generalized and tested against HPIV1.
Aim 3: Comparison of vaccine platforms expressing HPIV3 HN, F, or HN/F complex. Immunogenicity of
mRNA- and VSV-expressed vaccine candidates will be evaluated in mice and compared to subunit antigens.
All three vaccine platforms (subunit, mRNA, rVSV) will be assessed for efficacy in cotton rats (HPIV3 model),
with iteration back to Aims 1 and 2. Generalizability of each platform design will be determined with HPIV1.
The results will define optimal immunogens and vaccine platforms for respiroviruses and inform the
development of vaccines against other paramyxovirus family members.
Terms: <Acylneuraminyl hydrolase><Address><Affinity><Antibodies><Antigen Presentation><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Back><Binding><Binding Determinants><Binding Proteins><Blocking Antibodies><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Surface Glycoproteins><Cell fusion><Cell membrane><Chimera Protein><Chimeric Proteins><Clinical Treatment Moab><Complex><Cotton Rats><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasmic Membrane><Dorsum><Electron Cryomicroscopy><Envelope Protein><Epitopes><Family member><Fusion Protein><Genetic><Glycoproteins><HANA Glycoprotein><HN Protein><HPIV1><HPIV3><Hemadsorption Type 2 Virus><Hemadsorption Virus 1><Hemadsorption Virus 2><Hemagglutinin><Hemagglutinin-Neuraminidase Glycoprotein><Hu-mABs><Human><Human Parainfluenza Virus 1><Human Parainfluenza Virus 3><Ideal 1><Immune system><Immunity><In Vitro><Knowledge><Learning><Ligand Binding Protein><Ligand Binding Protein Gene><Mediating><Membrane Fusion><Membrane Glycoproteins><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><N-Acylneuraminate Glycohydrolases><Neuraminidase><Oligosaccharide Sialidase><Para-Influenza Virus Type 1><Para-Influenza Virus Type 3><Paramyxoviridae><Paramyxovirus><Pathway interactions><Plasma Membrane><Process><Protein Binding><Protein Subunits><Proteins><Receptor Protein><Resistance><Resolution><Respirovirus><Sialidase><Structure><Structure-Activity Relationship><Surface><Surface Glycoproteins><Surface Proteins><Testing><Therapeutic><Therapeutic antibodies><VSV><Vaccine Antigen><Vaccine Design><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><bound protein><cell sorting><chemical structure function><cryo-EM><cryoEM><cryogenic electron microscopy><design><designing><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><electron tomography><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate efficacy><examine efficacy><exo alpha sialidase><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immunogen><immunogenicity><in vivo><mAbs><mRNA><member><monoclonal Abs><parainfluenza virus type 1><parainfluenza virus type 3><pathway><plasmalemma><pre-clinical development><preclinical development><programs><prototype><receptor><receptor binding><receptor bound><resistant><resolutions><structure function relationship><vaccine antibodies><vaccine candidate><vaccine development><vaccine induced antibodies><vaccine platform><vaccine-induced antibodies>