Document text
Principal Investigator: Surojit Sarkar
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2022
Award: $166,916
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT (COVID-19 SUPPLEMENTAL RESEARCH)
During fast-spreading disease outbreaks (such as the present COVID-19 pandemic), quick induction of
herd immunity through vaccination is critical. Currently there are many SARS-CoV2 candidate vaccines in
various stages of clinical development, aimed at inducing robust multimodal protective immunity comprising
both long-lived antibody and memory T cells. However, we have little control over how quickly protective
immunity may be established following immunization. At the very minimum, vaccine-induced T cells require a
period of ~20-30 days of antigenic rest after initial immunization to effectively downregulate their effector
program and convert into quiescent, functionally potent, long-lived memory cells poised at portals of pathogen
entry. If vaccine-induced T cells are re-exposed to antigen during this mandatory rest period – as might occur
in case of exposure to virulent pathogen during an outbreak – the quantity, quality and overall protective
efficacy of immune memory are significantly jeopardized. Hence, shortening the window of immune memory
development is a key goal during vaccination, and is of high significance during pandemics to establish
accelerated protection in frontline healthcare and essential service providers, and speed up herd immunity in
the general population for expedited return to normalcy and economic growth.
In this administrative supplement, we will evaluate candidate immunomodulatory strategies to accelerate and
enhance vaccine-induced protective T cell memory to SARS-CoV2 by facilitating Treg-aided effector-to-
memory conversion. This work is based on our studies establishing a critical role of Tregs in promoting
effector-to-memory conversion through CTLA4, an inhibitory molecule most highly expressed on Tregs
(amongst all immune cells) (Immunity, 2015). Importantly, soluble CTLA4 administered in trans, is alone able
to fully supplement the function of Tregs in memory differentiation, and accelerates the formation of protective
anti-viral immunity by promoting the metabolic switch necessary for effector-to-memory conversion. These
proof-of-concept studies in models of viral immunity (conducted under the aegis of past R21, and parent R01
awards) lay a strong foundation for enhancing SARS-CoV2-specific immune memory following immunization
with candidate SARS-CoV2 vaccine in preclinical murine model. These studies represent a natural
translational extension of the parent R01 focused on mechanistic and molecular details of Treg-dependent
memory enhancement through CTLA4 in model viral infections. Importantly, CTLA4-Ig is FDA-approved Phase
III drug – ready for clinical translation. Therefore, immediate impact on our ability to quickly establish herd
immunity against SARS-CoV2 is expected. In addition to addressing the current COVID-19 exigency, these
studies are also relevant to other pandemics and situations of urgent vaccination of our defense troops for
quick deployment to disease endemic areas.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><ACE2><AIDS><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunologic Deficiency Syndrome><Address><Administrative Supplement><Antibodies><Antigens><Area><Atrophic Arthritis><Award><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bacterial Infections><CD152><CD152 Antigen><CD152 Gene><CD28><CD28 gene><CDC><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 immunity><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 immunity><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CTL A4-Ig B7 Inhibitor><CTLA 4><CTLA-4 Gene><CTLA-4-Ig><CTLA4><CTLA4 gene><CTLA4-Fc><CTLA4-Ig><CTLA4-Ig immunoconjugate><CTLA4-TM><CV-19><CV19><Causality><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Childhood><Clinical><Clinical Trials><CoV-2><CoV2><Communicable Diseases><Consensus><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Development><Disease Outbreaks><Drug usage><Drugs><Economic Burden><Economics><Endemic Diseases><Engineering><Epidemic><Etiology><Evaluation><Exploratory/Developmental Grant for Diagnostic Cancer Imaging><Exposure to><FDA approved><Foundations><Future><General Population><General Public><Generalized Growth><Goals><Growth><HCV><Healthcare><Hepatitis C virus><Herd Immunity><Human><Humoral Immunities><Immune><Immune memory><Immune response><Immunes><Immunity><Immunization><Immunologic Memory><Immunologic Sensitization><Immunologic Stimulation><Immunological Memory><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intracellular Communication and Signaling><Lead><Length of Life><Location><Longevity><Lung><Lung Respiratory System><Lymphatic Tissue><Lymphoid Tissue><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Malaria><Mediating><Medication><Memory><Metabolic><Modeling><Modern Man><Molecular><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIH><National Institutes of Health><Normalcy><Normalities><Nucleoproteins><Outbreaks><Outcome><Paludism><Parents><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Plasmodium Infections><Play><Poxvirus officinale><Property><Proteins><Public Health><R21 Award><Recovery><Regulatory T-Lymphocyte><Research><Rest><Rheumatoid Arthritis><Role><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><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 immunity><SARS-CoV-2 pandemic><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><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><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><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 CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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 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 immunity><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><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Structural Protein><T memory cell><T-Cells><T-Lymphocyte><T44><TB infection><Time><Tissue Growth><Transgenic Mice><Travel><Treg><Tuberculosis><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><United States National Institutes of Health><Vaccination><Vaccine Design><Vaccines><Vaccinia virus><Viral><Viral Diseases><Virulent><Virus Diseases><Work><Wuhan coronavirus><anamnestic reaction><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral immunity><antibody-based immunity><antigen-specific T cells><antiviral immunity><bacteria infection><bacterial disease><base><biological signal transduction><causation><clinical development><clinical translation><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><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 immunity><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><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><cytotoxic T lymphocyte-associated antigen 4-immunoglobulin><cytotoxic T-lymphocyte antigen 4><depository><developmental><disease causation><disseminated TB><disseminated tuberculosis><drug detection><drug repurposing><drug testing><drug use><drug/agent><expression vector><fight against><hCoV19><health care><heavy metal Pb><heavy metal lead><host response><immune modulating strategy><immune modulatory strategy><immune system response><immunity against COVID-19><immunity against COVID19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunogen><immunomodulatory strategy><immunoresponse><infection due to Mycobacterium tuberculosis><inhibitor><life span><lifespan><memory T lymphocyte><mouse model><multi-modality><multimodality><murine model><nCoV2><neutralizing antibody><ontogeny><pandemic><pandemic disease><pathogen><pediatric><pre-clinical><preclinical><programs><protective efficacy><protein expression><pulmonary><recombinant vaccinia virus><regulatory T-cells><repository><repurposing agent><repurposing medication><response><rheumatic arthritis><secondary immune response><service providers><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><thymus derived lymphocyte><tool><tuberculosis infection><tuberculous spondyloarthropathy><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><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 candidate><vaccine for novel coronavirus><vaccine platform><vaccine-induced immunity><vaccine-induced protection><vector><viral infection><virus infection><virus-induced disease>