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Principal Investigator: YUYING LIANG
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2023
Award: $232,500
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
The COVID-19 pandemic has had a profound, global impact on public health. Of the 120,000,000 cases
documented world-wide, over 30 million cases have occurred in the Unites States, with >530,000 COVID
deaths to date. Considerable progress in control of the pandemic has been realized in the USA by licensure of
three effective vaccines, and many additional immunization strategies are now in preclinical study and clinical
trials. An emerging consensus is that an effective vaccine will require responses to the viral-encoded spike (S)
protein, in particular, its receptor-binding domain (RBD). However, uncertainties remain about the optimal
expression platform(s), as well as concerns for untoward effects conferred by vaccination, including the
concern of potential antibody-dependent enhancement of infection. Another major issue is the need for
vaccine-mediated protection of the pregnant patient and the fetus/neonate. Although congenital and
perinatal transmission of SARS-CoV-2 infection has been documented, and serious COVID-19 disease in
children is increasingly described, no strategy for immunization during pregnancy has been forthcoming.
To help inform and direct future vaccine strategies for COVID-19 disease, we will address these areas of
knowledge deficiency using a guinea pig model of SARS-CoV-2 vaccination. Our plan is to test hypotheses
about optimized COVID-19 vaccine strategies using a Pichinde virus (PICV) vector. PICV is an enveloped RNA
virus within the Arenavirus family and is not known to cause disease in humans or most animals. We have
developed a PICV-based viral vector rP18tri and demonstrated it as a safe, effective, and versatile vaccine
vector that elicits a balanced antibody and T cell response. We have preliminary data showing that a novel
rP18tri-based SARS-CoV-2 S RBD domain vaccine can induce specific antibodies, including neutralizing
antibodies, in mice. In Aim 1, we will test the hypothesis that this PICV-vectored vaccine (and other vaccines
with improved antigen design) will demonstrate immunogenicity in guinea pigs, with enhanced immune
responses compared to an MPL-adjuvanted RBD protein vaccine. We will compare mucosal, subcutaneous
and intramuscular routes of immunization, comparing ELISA and neutralization titers. We will also include
mucosal read-outs, including IgA responses, and will test the hypothesis that the PICV vector is associated
with enhanced IFN-γ ELISPOT responses (compared to adjuvanted RBD vaccine). In Aim 2, we will examine
vaccine safety and transplacental antibody transfer in neonatal guinea pigs following immunization in early
pregnancy, comparing PICV vectored and subunit RBD vaccines in a dam-to-newborn antibody transfer model.
We will examine serum from newborn pups to test the hypothesis that virus-neutralizing antibodies cross the
placenta. These experiments have high relevance to human health, and will lay the groundwork for future
SARS-CoV-2 challenge studies in the guinea pig pregnancy model that, in turn, can help clarify the optimal
vaccine strategies to control congenital and perinatally-acquired COVID-19 disease in women and infants.
Terms: <(TNF)-α><0-11 years old><0-4 weeks old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><21+ years old><Address><Adjuvant><Adult><Adult Human><Angiitis><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody-Dependent Enhancement><Antigens><Area><Arenaviridae><Arenavirus><Arenavirus group><Assay><Attention><Award><B pertussis infection><B. pertussis infection><Bioassay><Biologic Assays><Biological Assay><Blood Serum><Bordetella pertussis infection><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID><COVID complications><COVID crisis><COVID epidemic><COVID pandemic><COVID related complications><COVID-19><COVID-19 S protein><COVID-19 complications><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 related complications><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 transmission><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID-19 virus infection><COVID-19 virus transmission><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cachectin><Cavia><Cells Placenta-Tissue><Cessation of life><Child><Child Youth><Children (0-21)><Clinical><Clinical Trials><CoV disease><CoV-2><CoV2><Consensus><Data><Death><Disease><Disorder><ELISA><ELISPOT><Enzyme-Linked Immunosorbent Assay><Evaluation><Family><Fetus><Future><Generations><Gestation><Goals><Grippe><Guinea Pigs><Guinea Pigs Mammals><Health><Histopathology><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IgA><Immune><Immune Interferon><Immune response><Immunes><Immunity><Immunization><Immunoglobulin A><Immunological response><Infant><Infection><Inflammatory><Influenza><Interferon Gamma><Interferon Type II><Intramuscular><Knowledge><LCM Viruses><LCMV><Licensing><Licensure><Light><Lymphocytic choriomeningitis virus><Macrophage-Derived TNF><Mediating><Medical><Methods><Mice><Mice Mammals><Modeling><Modern Man><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Neonatal><Newborn Infant><Newborns><Normal Placentoma><Patients><Perinatal><Perinatal Infection><Perinatal transmission><Peripartum><Pertussis><Photoradiation><Pichinde><Pichinde virus><Placenta><Placenta Embryonic Tissue><Placentome><Pregnancy><Pregnancy Complications><Pregnancy Outcome><Pregnant Women><Protein Binding Domain><Protein Binding Motif><Protein-Protein Interaction Domain><Proteins><Public Health><RNA Viruses><Reporting><Reproductive Biology><Reproductive Health><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 transmission><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Serum><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 CoV 2 vaccine><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 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Syndrome><System><T cell response><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Transmission><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Uncertainty><United States><Vaccinated><Vaccination><Vaccines><Variant><Variation><Vasculitis><Viral><Viral Vector><Virus><Whooping Cough><Woman><Work><Writing><Wuhan coronavirus><adulthood><antibody transfer><clinical practice><communicable disease transmission><complications due to COVID-19><complications during pregnancy><congenital infection><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 S protein><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 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 transmission><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><disease transmission><doubt><early pregnancy><enzyme linked immunoassay><enzyme linked immunospot assay><expectant mother><expecting mother><experiment><experimental research><experimental study><experiments><fetal><guinea pig model><hCoV19><host response><immune system response><immunization strategy><immunogen><immunogenicity><immunoresponse><improved><infected with B pertussis><infected with B. pertussis><infected with Burkholderia pertussis><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infectious disease transmission><kids><lFN-Gamma><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><maternal immunization><maternal vaccination><model of animal><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neonate><neutralizing antibody><newborn child><newborn children><novel><pandemic containment><pandemic control><pandemic mitigation><pandemic response><plasmid vaccine><pre-clinical development><pre-clinical study><preclinical development><preclinical study><pregnancy-related complications><pregnant><pregnant mothers><public health priorities><public health relevance><pup><receptor binding><receptor bound><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 transmission><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><subcutaneous><subdermal><success><transmission process><transmitted COVID-19><transmitted SARS-CoV-2><transmitted coronavirus disease 2019><transmitted severe acute respiratory syndrome coronavirus 2><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccination strategy><vaccination study><vaccination trial><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine antibodies><vaccine candidate><vaccine development><vaccine for novel coronavirus><vaccine induced antibodies><vaccine safety><vaccine strategy><vaccine 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