PROposing Action to ConTrol and Impede betacoronaVirus Emergencies

Introduction

The COVID-19 pandemic caught the world unprepared. Vaccines and monoclonal antibodies (mAbs), developed in record time, mitigated the health and economic damages. However, our reaction has always been one step behind the virus evolution, and emerging variants repeatedly escaped our interventions.

Challenges with Variants

The omicron variant escaped humoral immunity generated by most vaccines and mAbs by mutating immunodominant epitopes. The extremely potent mAb developed by our laboratory also lost potency against omicron.

Proposed Solution

Here we propose to develop vaccines and monoclonals neutralizing existing and future variants of SARS-CoV-2 and other coronaviruses by targeting immunologically subdominant regions which are less susceptible to antigenic variation.

Methodology

1. Isolation of mAbs: We will isolate mAbs from individuals who had infection and multiple vaccinations, whose repertoire is enriched in B cells encoding broadly neutralizing antibodies, to build a map of the broadly shared epitopes.
2. Structural Prediction: Structural prediction and clustering of the immune repertoire through deep neural networks will be used to improve the breadth of coverage of the mAbs.
3. In-silico Design: The Monte Carlo-based sequence design of Rosetta and free energy perturbation calculations will be used to in-silico “design protein-binding proteins” and identify newly designed immunogens which can be loaded on nanoparticles and used as vaccines.

Expected Outcomes

This approach will provide broadly protective mAbs and vaccines proactively designed to neutralize all variants of SARS-CoV-2 and new coronaviruses that are very likely to jump from animals to humans in the future.

Broader Implications

If successful, the approach to map subdominant epitopes and use of genomic and structural information to design mAbs and vaccines targeting subdominant, broadly conserved epitopes will pave the way to approach other pathogens with high antigenic variability such as:

• Influenza
• HIV viruses
• Plasmodium spp.
• Antibiotic-resistant bacteria

This will strongly increase European competitiveness in fighting infections.