A Phase 1/2a, randomized study of a Tfh-targeting genetic vaccine adjuvant designed to induce broad, durable immune responses

PROJECT SUMMARY/ABSTRACT This U01-supported clinical trial will test a unique T follicular helper (Tfh)-targeting vaccine approach, "s3", that we predict will generate exceptionally broad and long-lived antigen-specific antibody responses, characteristics likely to result in resilient vaccines that maintain protection over long periods. The "s3" adjuvant moiety is an anti- CD3 antibody fragment (scFv) that safely induces a potent Tfh and B-cell response to an immunogen to which it is fused. The combined immunogen simultaneously targets immunogen-specific B cells and local Tfh cells, thus accelerating and expanding B-cell development. Using the RBD immunogen in a low dose Ad35 vector, we showed in macaques that s3 safely stimulates high NAb titers that are stable for >10 months. The major deficiencies of current SARS-COV-2 and other vaccines (such as influenza) are limited durability and breadth of protection, even with booster vaccination. Over the course of 6 months, serum antibodies in COVID- naïve vaccine recipients decline by one order of magnitude. Booster vaccination confers greater durability but notable declines in serum NAb titers occur by 4-6 months. Limited mucosal IgA responses is another major deficit that may underlie failure of current vaccine options to prevent acquisition at the site of virus entry. Finally, the breadth of responses is limited, even with bivalent vaccines. These vaccine deficiencies have been linked repeatedly to inadequate T-cell help. Thus, new approaches that provide abundant T-cell help, such as the proposed s3 approach, are needed to deliver more effective SARS-CoV-2 as well as pancoronavirus, influenza, and other vaccines. We will test the safety and immunogenicity of the s3 adjuvant using Ad35 as the vector and the SARS-CoV-2 BA.5 receptor-binding domain (RBD) as the immunogen. We will compare a vaccine with s3 (CoTend-s3B) against one lacking s3 (CoTend-B). The vaccines will be given as a "booster" vaccine on the background of prior SARS-CoV-2 spike mRNA vaccination. This approach will allow us to evaluate the ability of CoTend-s3B to (i) boost pre-existing antibodies and (ii) recruit new naïve B cells with new specificity for BA.5 RBD. Aim 1. Test safety of s3-adjuvanted/Tfh-targeted (CoTend-s3B) and unadjuvanted (CoTend-B) SARS- CoV-2 RBD vaccines. The primary safety readouts are local and systemic reactions, grade 3+ adverse events (AEs), serious adverse events, AEs of special interest (including thrombotic events), and anti-PF4 antibodies. Aim 2. Evaluate intensity, breadth, and durability of adaptive immune responses to CoTend-s3B compared to CoTend-B in blood and saliva. We hypothesize that Tfh responses to CoTend-s3B will support NAb responses of sufficient breadth and potency for long-lived protection against SARS-CoV-2 variants. Aim 3. Examine the mechanisms of s3 adjuvant activity in germinal centers. Tfh targeting via s3 is predicted to generate robust germinal-center reactions that democratize recruitment of naïve B cells and spur development of long-lived plasma cells.