Prion Antibody Discovery Using LIBRA-seq

Funding period: 2023-2025
Lead: Ben Bailey-Elkin
Total GRDI funding: $531,400

Prion diseases are untreatable and fatal neurodegenerative diseases that include Creutzfeldt-Jakob disease in humans and chronic wasting disease, which is spreading rapidly in deer and other cervids. Prion diseases are caused by misfolding of the body’s own prion protein into an insoluble, infectious form that can be readily transmitted to susceptible hosts. As infectious prions lack a genetic component, infectivity and strain types are encoded in the three-dimensional shape of the protein. Detection and surveillance methods therefor rely extensively on the use of specific antibodies to detect and distinguish between prion variants. Such reagents are critical for disease surveillance; particularly for the detection of newly emergent strains, and novel zoonotic diseases that could pose a risk to public health. Additionally, antibodies that block prion protein misfolding are promising therapeutic candidates.

Antibody discovery is a time-intensive and laborious process. New genomic technologies to characterize the immune response and accelerate the selection antigen-specific biomolecules are rapidly transforming the field of antibody research and discovery. We will harness one of the latest genomic innovations, LIBRA-seq (Linking B-cell Receptor to Antigen Specificity through Sequencing), which leverages single-cell sequencing methods to streamline antibody discovery. In this method, single B-cells can be screened and sorted for their ability to recognize panels of infectious and recombinant prion antigens whilst simultaneously indexing them using libraries of DNA barcodes. Each antibody producing B-cell can then be individually interrogated using “next-generation” sequencing technology and bioinformatics to link B-cell receptor sequences to antigen affinity. The result is a streamlined and highly adaptable pipeline to identify promising antibody sequences for characterization and validation, while exploiting the inherent diversity present within a natural repertoire of antibody-producing B-cells. This project will not only allow us to identify antibodies with specificity to infectious and emerging prion strains for diagnosis, surveillance, and therapies, but will also serve to establish this technology at the NML. LIBRA-seq is a promising strategy for the rapid development of vaccines and therapeutics for infectious diseases and has proven success in characterizing the immune response to SARS-CoV-2.

This multiomics approach to harness the power of next generation sequencing for analysing antibody repertoires with unprecedented resolution will be a valuable tool in the timely deployment of medical countermeasures to infectious diseases.