SBIR-STTR Award

This grant will establish immunologic proof-of-concept for a second-generation SARS-CoV-2 vaccine providing extraordinarily durable T-cell and antibody responses, which together protect the respiratory mucosa and minimize the risk of antibody-dependent enhancement (ADE). The vaccine platform combines the immunostimulatory power and proven safety of adenovirus-vectored vaccines with novel in- vector adjuvants and a robust humoral component. In particular, our preliminary data show that this vaccine candidate stimulates T-cell responses in macaques that are virtually undiminished ten months after vaccination. We hypothesize that a memory-promoting adenovirus (MPAd) drives robust CD4+ T-cell responses to SARS- CoV-2 that provide both airway-resident protection and superior B-cell helper function. Aim 1: Demonstrate robust, durable CD4+ T-cell responses to MPAd/N vaccination, localized to airways and exceeding responses seen with conventional Ad vectors. Here we test if key differentiating features of Tendel’s memory-promoting Ad vaccine, previously demonstrated for immunization against SIV Gag, are also seen when immunizing against SARS-CoV-2 nucleocapsid. Our hypothesis predicts balanced CD4 and CD8 responses with effector-memory character and localization to airways, which are maintained with minimal dimunition throughout the experiment. Milestone 1: Demonstrate superiority of MPAd vaccine for eliciting SARS-CoV-2-specific T cells in airways. Aim 2: Evaluate SARS-CoV-2 neutralizing antibodies and subtypes in rhesus macaques receiving Ad/RBD vs. MPAd/RBD. Tendel aims to provide a second-generation SARS-CoV-2 vaccine that evades any tendency to enhancement by combining appropriate T-cell and B-cell responses. Some previous reports have demonstrated enhanced extrinsic ADE for Th2-associated antibodies of the IgG1 class, as well as intrinsic ADE that is linked to Th2-associated effector mechanisms, especially IL-10. In this aim we test the antibody subclasses and capacity for enhancement of antibodies elicited by Ad/RBD vs. MPAd/RBD, to determine the best component for inclusion in a second-generation vaccine. Milestone 2: Choose an optimal B cell-targeted vaccine component, which does not mediate ADE, for combination with an MPAd-based T-cell component. These innovative Phase I experiments will be sufficient to establish both the technical merit and—in light of the proven commercial and government interest in Ad-vectored vaccination against SARS-CoV-2—the commercial potential of Tendel’s approach. Public Health Relevance Statement The goal of this work is to urgently provide a SARS-CoV-2 vaccine candidate that engages all arms of the adaptive immune system to protect against COVID-19. We will find an optimal B-cell component to drive antibody production when administered with a memory-promoting T-cell component that creates extraordinarily long-lived T-cell responses in the lung.

Project Terms:
Adenoviruses ; Adenoviridae ; Antibodies ; Antibody Formation ; Ab response ; Antibody Production ; antibody biosynthesis ; immunoglobulin biosynthesis ; B-Lymphocytes ; B blood cells ; B cell ; B cells ; B-Cells ; B-cell ; California ; Cell Culture Techniques ; cell culture ; Cells ; Cell Body ; Goals ; Government ; Grant ; Hand ; Helper-Inducer T-Lymphocyte ; Helper Cells ; Helper T-Cells ; Helper T-Lymphocytes ; Helper-Inducer T-Cells ; Inducer Cells ; Inducer T-Lymphocytes ; Human ; Modern Man ; IgG1 ; Immune Sera ; Antisera ; immune serum ; Immunity ; Immunization ; Immunologic Sensitization ; Immunologic Stimulation ; Immunological Sensitization ; Immunological Stimulation ; Immunostimulation ; Infection ; Light ; Photoradiation ; Lung ; Lung Respiratory System ; pulmonary ; Macaca ; Macaque ; Macaca mulatta ; M mulatta ; M. mulatta ; Rhesus Macaque ; Rhesus Monkey ; Maintenance ; Memory ; Mucous Membrane ; Mucosa ; Mucosal Tissue ; Persons ; Paint ; Primates ; Primates Mammals ; Proteins ; Research ; Safety ; SIV ; Simian Immunodeficiency Viruses ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; CD4 Positive T Lymphocytes ; CD4 Cells ; CD4 T cells ; CD4 helper T cell ; CD4 lymphocyte ; CD4+ T-Lymphocyte ; CD4-Positive Lymphocytes ; T4 Cells ; T4 Lymphocytes ; Testing ; Tryptophan 2,3 Dioxygenase ; IDOase ; Indoleamine 2,3-Dioxygenase ; tryptamine 2,3 dioxygenase ; Vaccination ; Vaccines ; Virus ; Work ; Generations ; Interleukin-10 ; CSIF ; CSIF-10 ; Cytokine Synthesis Inhibitory Factor ; IL-10 ; IL10 ; IL10A ; Interleukin 10 Precursor ; Mediating ; base ; Nucleocapsid ; Left ; Surface ; Phase ; Link ; Ensure ; Evaluation ; Promonocyte ; CD8-Positive T-Lymphocytes ; CD8 Cell ; CD8 T cells ; CD8 lymphocyte ; CD8+ T cell ; CD8+ T-Lymphocyte ; CD8-Positive Lymphocytes ; T8 Cells ; T8 Lymphocytes ; Cellular Structures ; Cell Components ; Cell Structure ; Antibody-Dependent Enhancement ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; neutralizing antibody ; interest ; develop a vaccine ; development of a vaccine ; vaccine formulation ; vaccine development ; plasmid vaccine ; vector vaccine ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Dioxygenases ; Immunomodulation ; immune modulation ; immune regulation ; immunologic reactivity control ; immunomodulatory ; immunoregulatory ; immunoregulation ; novel ; memory T lymphocyte ; T memory cell ; Reporting ; Respiratory Mucosa ; Modeling ; Property ; response ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Herd Immunity ; SARS Virus ; SARS corona virus ; SARS-Associated Coronavirus ; SARS-CoV ; SARS-Related Coronavirus ; Severe Acute Respiratory Syndrome Virus ; Severe Acute Respiratory Syndrome corona virus ; Severe Acute Respiratory Syndrome coronavirus ; severe acute respiratory syndrome-CoV ; SARS coronavirus ; CD8 ; CD8B ; CD8B1 ; LYT3 ; CD8B1 gene ; Ad vector ; Adenoviral Vector ; adeno vector ; adenovector ; Adenovirus Vector ; Data ; IRES ; Internal Ribosome Entry Segment ; Ribosome Entry Site ; Internal Ribosome Entry Site ; Vaccine Antigen ; Immunologics ; Immunochemical Immunologic ; Immunologic ; Immunological ; Immunologically ; Adjuvant ; Development ; developmental ; vector ; virtual ; vaccine efficacy ; design ; designing ; memory CD4 T lymphocyte ; memory CD4 T cell ; manufacturing process ; scale up ; innovation ; innovate ; innovative ; vaccine candidate ; protective efficacy ; risk minimization ; Regimen ; T cell response ; arm ; Middle East Respiratory Syndrome Coronavirus ; MERS corona virus ; MERS coronavirus ; MERS virus ; MERS-CoV ; Middle East Respiratory Syndrome Corona Virus ; Middle East Respiratory Syndrome Virus ; Middle East Respiratory Syndrome-CoV ; Middle Eastern Respiratory Syndrome Corona virus ; Middle Eastern Respiratory Syndrome Coronavirus ; Middle Eastern Respiratory Syndrome Virus ; Middle Eastern Respiratory Syndrome-CoV ; Antibody Response ; high risk population ; high risk group ; experimental study ; experiment ; experimental research ; Adaptive Immune System ; acquired immune system ; Immunize ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; 2019-nCoV ; 2019 novel corona virus ; 2019 novel coronavirus ; COVID-19 virus ; COVID19 virus ; CoV-2 ; CoV2 ; SARS corona virus 2 ; SARS-CoV-2 ; SARS-CoV2 ; SARS-associated corona virus 2 ; SARS-associated coronavirus 2 ; SARS-coronavirus-2 ; SARS-related corona virus 2 ; SARS-related coronavirus 2 ; SARSCoV2 ; 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-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 related corona virus 2 ; Wuhan coronavirus ; coronavirus disease 2019 virus ; hCoV19 ; nCoV2 ; COVID-19 vaccine ; 2019-nCoV vaccine ; COVID19 vaccine ; SARS-CoV-2 vaccine ; SARS-CoV2 vaccine ; SARS-coronavirus-2 vaccine ; Severe Acute Respiratory Syndrome CoV 2 vaccine ; Severe acute respiratory syndrome coronavirus 2 vaccine ; corona virus disease 2019 vaccine ; coronavirus disease 2019 vaccine ; 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 for novel coronavirus ; COVID-19 vaccination ; COVID19 vaccination ; SARS-CoV-2 vaccination ; Severe acute respiratory syndrome coronavirus 2 vaccination ; coronavirus disease 2019 vaccination ; 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 ; antibody test ; antibody based test ;