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Principal Investigator: Jarrod Mousa
Organization: UNIVERSITY OF GEORGIA
Fiscal Year: 2023
Award: $134,666
Funding agency: National Institute of Allergy and Infectious Diseases
The goal of this research project is to further the development of a pan-Pneumovirus vaccine and to test our
hypothesis that a chimeric Pneumovirus fusion (F) protein vaccine displaying immunodominant epitopes of
respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) will induce broad protection against both
viruses. RSV and hMPV are widely prevalent agents of childhood viral respiratory infection, causing thousands
of deaths and hundreds of thousands of hospitalizations each year. There are currently no approved vaccines
to elicit protective antibodies against either virus, and no specific treatment options are available. The F
glycoproteins of RSV and hMPV have been well-studied as targets of neutralizing antibodies, and several
vaccine candidates for RSV are in clinical trials. We have developed a novel vaccine candidate (RHMS-1)
encompassing immunodominant epitopes of both RSV and hMPV F proteins and verified its protective
efficacy in mouse and cotton rat models. The rationale for pursuing a chimeric vaccine candidate is based
on several factors, including focusing the immune response to only those epitopes that elicit potent neutralizing
antibodies rather than less potent or non-neutralizing epitopes to improve protection, reducing vaccine escape
compared to previous chimeric vaccines incorporating a single epitope, and the assessment of the first chimeric
vaccine candidate beyond the mouse model. Additionally, we will determine immune correlates of protection for
hMPV infection in a nonhuman primate model. These critical studies will provide a wealth of immunologic
information in highly relevant, pre-clinical models that will guide an evidence-based path toward the optimization
of a safe and effective pan-Pneumovirus vaccine. Our research will substantially advance the field by
developing a vaccine for protection against the two leading causes of acute lower respiratory tract infection in
children. As the pre-fusion RSV F protein has already demonstrated safety and the ability to elicit an effective
immune response, we will build upon this success to extend this vaccine for protection against hMPV. In Aim 1,
we will computationally stabilize and redesign our vaccine candidate, RHMS-1, using Rosetta to enhance protein
stability and immunogenicity, and the best candidates will be rapidly screened in mice as both protein subunit
and mRNA-lipid nanoparticle vaccines. In Aim 2, we will conduct structural and epitope analysis of our top
vaccine candidate to verify the epitopes on RHMS are similar to RSV F and hMPV F proteins. In Aim 3, we will
determine the protective efficacy of the top candidate RHMS vaccine in cotton rat and African Green Monkey
models of RSV and hMPV infection. Our proposal is both conceptually and practically innovative as we are
designing and testing novel vaccine candidates for protection against two important respiratory pathogens, and
we are challenging current paradigms in the field by providing a single antigen for dual-virus protection.
Furthermore, the innovation of the team is very high, as this proposal brings together diverse investigators and
several state of the art technologies.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Advanced Development><African Green Monkey><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigenic Determinants><Antigens><Binding Determinants><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><Cell surface><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Chimera Protein><Chimeric Proteins><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical Treatment Moab><Clinical Trials><CoV-2><CoV2><Complex><Cotton Rats><Death><Development><Dose><ELISA><Ensure><Enzyme-Linked Immunosorbent Assay><Epitope Mapping><Epitopes><Fusion Protein><Glycoproteins><Goals><Green Monkey><Hospital Admission><Hospitalization><Human Metapneumovirus><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infection><Interferometry><Investigators><Lower Respiratory Tract Infection><Lower respiratory infection><Messenger RNA><Mice><Mice Mammals><Modeling><Monkeys><Monoclonal Antibodies><Murine><Mus><Pneumoviridae><Pneumovirinae><Pneumovirus><Pre-Clinical Model><Preclinical Models><Protein Subunits><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><Rapid screening><Recombinant Proteins><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Respiratory syncytial virus><Respiratory syncytial virus RSV proteins><Respiratory syncytial virus proteins><Rodent><Rodentia><Rodents Mammals><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Serology><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Structure><Technology><Testing><Vaccinated><Vaccination><Vaccines><Viral><Viral Respiratory Tract Infection><Virus><Wuhan coronavirus><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><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 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><enzyme linked immunoassay><evidence base><hCoV19><host response><immune system response><immunogen><immunogenicity><immunoresponse><improved><in vivo><innovate><innovation><innovative><kids><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><mRNA Stability><manufacture><model of animal><monoclonal Abs><mouse model><murine model><nCoV2><neutralizing antibody><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel vaccines><pediatric><permissiveness><pre-clinical><preclinical><protective efficacy><protein structure><protein structures><proteins structure><respiratory pathogen><screening><screenings><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><success><synergism><vaccine candidate><vaccine development><viral respiratory infection><youngster>