Development of an AI-driven platform for the discovery of conserved conformational epitopes (CoCoTopes) and their use in antibody discovery and vaccination

Antibody based therapies and vaccines are central to combating viral infections, yet rapidly mutating pathogens such as SARS CoV 2, Influenza, RSV, and HIV continually undermine conventional immunotherapeutic approaches. Frequent antigenic mutations facilitate viral escape, rendering monoclonal antibody therapies and traditional vaccines less effective over time. To overcome these challenges, we propose a transformative, AI-driven platform that harnesses conserved, three-dimensional epitopes on viral surface proteins—termed “CoCoTopes”. By focusing on these immutable regions, our strategy aims to develop resilient, next-generation therapeutics capable of withstanding viral evolution.

Our innovative approach integrates state-of-the-art artificial intelligence with advanced computational protein design and engineering. Central to our strategy is the development of CoCoTopesGPT, an AI based large-language model that will learn the evolution of viral sequences from databases such as GISAID, NCBI, and UniProt. By generating multiple sequences, CoCoTopesGPT, will precisely identify conserved, functional epitopes that are ideal targets for neutralizing antibodies.

Next, building on these insights, we will leverage cutting-edge AI tools—including RFdiffusion, ProteinMPNN, ESM2, and AF3/Boltz-1—to design mini-protein scaffolds that accurately recapitulate the native three-dimensional structure of these conserved epitopes. Finally, our engineered mini-proteins will serve a dual function. First, they will be used as precise baits to isolate and identify broadly neutralizing antibodies from donor samples. Second, these mini-proteins will serve as advanced immunogens in vaccine strategies, eliciting robust and durable immune responses.

The project is structured around five key tasks:

1. CoCoTopesGPT – AI-Driven Epitope Discovery Pipeline: Develop an AI-enhanced pipeline to identify conserved, solvent-accessible epitopes on viral proteins.

2. AI-Enabled Scaffold Engineering: Integrate the identified CoCoTopes into mini-protein scaffolds, generating a diverse library of variants that mimic native epitope presentation.

3. Expression, Purification, and Validation: Translate computational designs into functional mini-proteins and rigorously validate them through a suite of biochemical and structural assays.

4. Antibody Discovery: Employ validated mini-proteins as baits to isolate and characterize broadly neutralizing human antibodies from donor plasma or PBMCs.

5. Vaccine Evaluation: Assess the immunogenicity of our mini-protein immunogens in animal models, comparing their performance with conventional vaccines to confirm their potential for durable protection.

By seamlessly integrating AI-driven protein design into a streamlined experimental pipeline, our platform will dramatically accelerate the discovery of resilient antibody therapies and next-generation vaccines. Its versatile design also allows rapid adaptation to other disease areas—such as oncology and autoimmune disorders—providing a powerful, scalable strategy to address emerging global health challenges. Ultimately, our innovative approach will enhance pandemic preparedness, reduce healthcare burdens, and drive sustainable economic growth.