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Principal Investigator: Vaughn Vasil Smider
Organization: APPLIED BIOMEDICAL SCIENCE INSTITUTE
Fiscal Year: 2019
Award: $359,955
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Vaccines are the primary means by which to prevent, control, or eradicate infectious
diseases. While many vaccines have been successfully developed and have resulted in
enormous medical and veterinary benefit, there are certain viruses that have eluded
effective vaccine development. Generally, viruses with multiple strains or that have high
mutation rates can evade neutralizing antibodies, as their surface determinants are
variable and result in the inability of neutralizing antibodies raised against one strain to
bind and neutralize alternative strains. Certain rare epitopes, however, are required for
viral infection and are conserved across strains. Interestingly, neutralizing antibodies
against these rare epitopes tend to have long CDR H3 regions. In the case of HIV, long
CDR H3s can pierce the viral glycan shield and reach into the conserved epitope on the
gp120 spike protein. While long CDR H3 regions in human antibodies are infrequent in
the repertoire, cattle routinely produce long (20-40 amino acids) and ultralong (40-70
amino acids) CDR H3 regions that have unique “stalk” and “knob” structural features that
protrude far from the antibody surface. Therefore, cattle may be an excellent model
organism to identify and define new and conserved neutralizing epitopes in these
challenging viruses. Indeed, in preliminary experiments we have found that cattle make
a robust and broadly neutralizing antibody response to the HIV gp120 antigen. Here we
propose to use the unique cow antibody repertoire to define new conserved neutralizing
epitopes on two viruses of great importance to human and animal health, HIV and
BVDV. Effective vaccines against both of these viruses have been a major challenge to
develop. We will immunize animals against these viruses, generate monoclonal
antibodies that neutralize the virus as well as related strains, and molecularly map the
antigen-antibody interaction using mutagenesis and structural biology techniques.
Definition of new conserved epitopes could lead to engineered epitope-specific vaccines.
Thus, the outcomes of this proposal could enable generation of next-generation
vaccines for these two viruses, but could also have broad utility in vaccine development
against other challenging viruses in the future.
Terms: <AIDS Virus><ATGN><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Amino Acids><Animal Model><Animal Models and Related Studies><Animals><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Antibodies><Antibody Repertoire><Antibody Response><Antigenic Determinants><Antigens><Binding><Binding Determinants><Biochemical><Bovine Species><Cattle><Clinical Treatment Moab><Common Epitope><Communicable Diseases><Cysteine><Data><Development><Electron Microscopy><Engineering><Epitopes><Flavivirus><Future><General Viruses><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genetics-Mutagenesis><Glycans><Group B Arbovirus><HER2 Monoclonal Antibody><HIV><HIV Antibodies><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-Associated Antibodies><HTLV-III Antibodies><HTLV-III gp120><HTLV-III-LAV Antibodies><Half-Cystine><Health><Herceptin><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Immune Globulins><Immune response><Immunization><Immunize><Immunoglobulins><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunology><Immunostimulation><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><L-Cysteine><LAV Antibodies><LAV-HTLV-III><Lead><Length><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><Maps><Medical><Mice><Mice Mammals><MoAb HER2><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Mutation><Outcome><Outcome Study><Pb element><Polysaccharides><Position><Positioning Attribute><Property><Protein Engineering><Proteins><Recombinant DNA Technology><Retroviridae><Retroviruses><Single Crystal Diffraction><Structure><Structure-Activity Relationship><Surface><System><Techniques><Texas><Trastuzumab><Vaccination><Vaccine Design><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Virus-Retrovirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><aminoacid><antigen antibody binding><antigen binding><antigen bound><bovid><bovine><c-erb-2 Monoclonal Antibody><chemical structure function><clinical relevance><clinically relevant><cow><deep sequencing><develop a vaccine><development of a vaccine><developmental><disulfide bond><experiment><experimental research><experimental study><genetic protein engineering><genetically engineered><genome mutation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><heavy metal Pb><heavy metal lead><host response><humanized antibody><immunogen><immunoresponse><insight><knob protein><mAbs><model of animal><model organism><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><new vaccines><next generation><next generation vaccines><novel><novel vaccines><prevent><preventing><protein design><rhuMAb HER2><structural biology><structure function relationship><success><tool><vaccine development><vaccine formulation><viral infection><virology><virus infection><virus-induced disease><ward>