Phase I Amount
$1,000,000
Tendel's CoTend-s3B SARS-CoV-2 booster vaccine targets T follicular helper (Tfh) cells to generate extraordinarily broad and long-lived antibody responses, which are required for resilient vaccines that maintain protection over long periods. The vaccine candidate incorporates the "s3" targeting moiety, which induces a potent T follicular helper (Tfh) cell response. This novel, first-in-class adjuvant is fused to the receptor binding domain (RBD) from the Omicron variant of SARS-CoV-2 (BA.4/BA.5). The combined molecule simultaneously targets RBD-specific B cells and T cells, and especially local Tfh cells, thus accelerating and expanding B-cell development. Preclinical non-human primate (NHP) studies have demonstrated extraordinarily high neutralizing antibody titers that were stable for >10 months when delivered via a low dose of adenovirus type 35 (Ad35) delivery vector. In contrast, neutralizing antibody responses to control vaccine lacking the s3 moiety (i.e., CoTend-B containing immunogen alone), were diminished to below the level of protection within 6 months, similar to results seen in humans with FDA-approved mRNA vaccines. In cooperation with academic partners Steve Deeks (UCSF) and Kara Chew (UCLA), Tendel completed favorable pre-IND interactions for this s3-adjuvanted vaccine and designed a first-in-human trial. In this R44 application we propose several tasks that will provide the needed investigational products and toxicology data, as well as additional supportive mechanistic data, to support comparative phase-1 testing of CoTend-B and CoTend-s3B as booster vaccines beginning in early 2024. We will complete GMP-grade production of both vaccines in amounts sufficient for both GLP safety studies and the planned phase-1 trial. We will test the technical feasibility of adventitious-agent testing by next-generation sequencing (NGS). Finally, we will use the vialed vaccine to complete GLP safety studies in macaques while simultaneously gathering high-dimensional repertoire data to demonstrate superior B-cell recruitment by the s3 adjuvant platform. The deliverables of this work are fully characterized, GMP-grade vaccine stocks (CoTend-B and CoTend-s3B) and corresponding safety data that will permit a successful IND application and commencement of clinical trials. Aim 1. Produce vialed CoTend-B and CoTend-s3B vaccine products according to GMP. Aim 2. Complete release testing, including adventitious-agent testing by an NGS approach. Aim 3. Perform GLP toxicology and immunogenicity testing of the vialed product. The work proposed in this R44 application will enable necessary steps towards the first test in humans of a new approach to promoting development of antigen-specific B cells. If successful, de-risking of the s3 platform will provide a transformative new tool that can enable and drive human B-cell development along paths that are infrequently reached by current vaccines.
Public Health Relevance Statement: Narrative Deliverables of this proposal will provide the needed investigational products and toxicology data, as well as additional supportive mechanistic data, to support comparative phase-1 testing of a SARS-Cov-2 vaccine candidate that incorporates a novel genetic adjuvant designed to induce antiviral neutralizing antibodies of superior magnitude, breadth, and durability.
Project Terms: Acceleration; Adenoviridae; Adenoviruses; immunogen; Antigens; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; California; Clinical Trials; Feedback; Genome; Goals; Helper-Inducer T-Lymphocyte; Helper Cells; Helper T-Cells; Helper T-Lymphocytes; Helper-Inducer T-Cells; Inducer Cells; Inducer T-Lymphocytes; Human; Modern Man; Immunoglobulin Fragments; Antibody Fragments; Laboratories; Libraries; Macaca; Macaque; Persons; United States National Institutes of Health; NIH; National Institutes of Health; Production; Running; Safety; Serial Passage; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Testing; Toxicology; Transfection; Vaccines; Virus; Work; CD3; CD3 Complex; CD3 molecule; OKT3 antigen; T3 Antigens; T3 Complex; T3 molecule; CD3 Antigens; Chimera Protein; Fusion Protein; Chimeric Proteins; Vial; Vial device; Clinical; Phase; non-human primate; nonhuman primate; Funding; Letters; Genetic; tool; programs; Complex; Techniques; Antibody titer measurement; antibody titering; neutralizing antibody; Viral; particle; receptor binding; receptor bound; novel; response; Monoclonal Antibody HuM291; Anti-CD3 Antibody; HuM291; MoAb HuM291; genome sequencing; Dose; B-Cell Development; Data; Qualifying; Adjuvant; Development; developmental; safety study; pre-clinical; preclinical; deep sequencing; vector; cost; immunogenicity; virus detection; viral detection; designing; design; new approaches; novel approaches; novel strategy; novel strategies; resilient; resilience; manufacturing process; booster dose; booster shot; booster vaccine; new vaccines; next generation vaccines; novel vaccines; comparative; plasmid DNA; FDA approved; regenerative; vaccine candidate; safety testing; NGS Method; NGS system; next gen sequencing; nextgen sequencing; next generation sequencing; phase 1 trial; phase I trial; trial design; Antibody Response; high dimensionality; recruit; RNA-based vaccine; mRNA vaccine; mRNA-based vaccine; RNA vaccine; phase 1 evaluation; phase I evaluation; phase I testing; phase 1 testing; first in man; first-in-human; 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; coronavirus disease-19 vaccine; nCoV vaccine; nCoV-19 vaccine; nCoV19 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 vaccine; COVID-19 booster; COVID-19 vaccine booster; SARS-CoV-2 booster; SARS-CoV-2 vaccine booster; booster against COVID-19; booster against SARS-CoV-2; delivery vehicle; delivery vector; Good Manufacturing Process; Good manufacturing practice; manufacture; manufacturing run; production run; SARS-CoV-2 B.1.1.529; B.1.1.529; Omicron variant; SARS-CoV-2 omicron; SARS-CoV-2 omicron variant; omicron variant of COVID-19; omicron variant of SARS-CoV-2; severe acute respiratory syndrome coronavirus 2 B.1.1.529
