GMP production and GLP safety of bidirectionally targeted SARS-CoV-2 booster vaccine

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.