What is your role in the LWNVIVAT project?
We lead WP1, focused on the computational design of a vaccine to protect against WNV. Our primary goal is to identify and stabilize conserved viral epitopes while minimizing cross-reactivity with other flaviviruses. We use advanced bioinformatic tools to achieve this.
We collaborate closely with project coordinator Jorge Carrillo (IrsiCaixa). This ensures alignment across all project stages. We also coordinate with WP2, led by Carlo Carolis (CRG), for protein production and antigenicity. Additionally, we work with WP4 and WP5, led by Julia García Prado (IrsiCaixa) and Jorge Carrillo, respectively, to test vaccine candidates’ immunogenicity. These efforts integrate computational design with experimental validation and immune response testing.
What is the primary goal of your research?
Our group specializes in structural bioinformatics, focusing on protein property prediction, specifically for vaccine design. We develop tools to analyze proteins, contributing to the goal of creating a structurally stabilized WNV vaccine. This vaccine aims to promote long-lasting immune responses and avoid cross-reactive immune responses with other flaviviruses.
What tools do you use to predict which proteins or genes trigger the strongest response against WNV?
Instead of identifying new proteins, we focus on predicting T-cell epitopes across the entire proteome, identifying potential immunogenic regions. For antibody recognition sites, we concentrate on the E protein, crucial for viral entry.
We use a range of publicly available tools, some developed in-house at BSC’s Electronic and Atomic Protein Modeling group, and others externally sourced. These include:
- NOAH: A structural-based MHC-I binding affinity predictor.
- NetCleave: A neural network predictor for C-terminal antigen processing.
- PredIG: A T-cell epitope immunogenicity predictor.
- Brewpitopes: A B-cell epitope prediction refinement pipeline.
What factors do you consider when determining whether a protein is immunogenic?
To assess immunogenicity, we evaluate a protein’s ability to induce neutralizing antibodies and T-cell responses. We also consider the conservation of epitopes across WNV strains and their structural stability. Evolutionary analysis helps us avoid regions that might cause cross-reactivity with other flaviviruses.
Can you explain what cross-reactivity is?
Cross-reactivity happens when an immune response triggered by one pathogen (e.g., WNV) also interacts with related pathogens (e.g., dengue or Zika). This occurs due to shared antigenic regions, potentially leading to unintended immune effects, such as ADE (antibody-dependent enhancement), where non-neutralizing antibodies enhance viral entry into host cells.
What are the latest results you have achieved?
We identified B-cell epitopes on the WNV E protein that have high neutralization potential, are conserved across WNV variants, and have minimal cross-reactivity with other flaviviruses.
We also designed stabilized recombinant E proteins as immunogens. Using AI techniques, we modeled these proteins and screened them for mutations that stabilize key conformations, enhance epitope exposure, and eliminate cross-reactivity regions. These optimized designs are now ready for experimental validation.
What are the next steps in your research?
We’re currently focusing on two areas:
- Creating smaller, epitope-enriched domains as independent immunogens, potentially reducing cross-reactivity.
- Predicting and selecting immunogenic T-cell epitopes for a T-cell-based vaccine that addresses global HLA gene diversity. This step is vital for effective antigen presentation and strong cellular immune responses across diverse global populations.
