Title: Antibody discovery for developing vaccines and therapies against infectious diseases: from high-throughput methodologies to the AI revolution

By Giuseppe A. Sautto, PhD, MBA

Assistant Professor of Molecular Medicine | Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Candidate for a faculty position in Virology and Vectors of Infectious Diseases in the Department of Biological Sciences

Abstract

The characterization and dissection of the antibody (Ab) response following influenza vaccination is fundamental to deploy next-generation vaccine strategies that can overcome the virus variability.

Vaccination with next-generation vaccines confers a broad protective Ab response against multiple influenza strains in influenza naïve as well as in preimmune pre-clinical animal models. Dissection of the immune response at the monoclonal antibody (mAb) level and following next-generation vaccines revealed the elicitation of peculiar Ab populations capable of neutralizing multiple influenza strains within a subtype.

To assess B cell immunity to the main influenza virus surface glycoprotein, hemagglutinin (HA), blood was sampled longitudinally before and after influenza vaccination of individuals belonging to different age groups for 4 consecutive influenza seasons (spanning 2013-2017). Binding and hemagglutination-inhibiting (HAI) polyclonal Ab titers were determined against a large panel of historical, recent and next-generation vaccine HA and virus strains, respectively. Single-cell antibody sequencing was performed and following sequence analysis, mAbs of interest were cloned, recombinantly expressed and evaluated for their breadth of binding and functional activity.

Several individuals showed outstanding breadth, displaying protective titers against many strains, both at the polyclonal and mAb level. Importantly the mAb protective activity was confirmed in vivo following their prophylactic and therapeutic administration upon challenge with H1N1, H3N2, H5N1 or influenza B strains. Finally, these mAbs recognized and showed HAI activity also against COBRA HA and viruses, respectively. This large dataset of Ab binding and functional activity was leveraged to build an AI model for predicting the HA binding and HAI activity of Abs using only the Ab sequence information.

These results suggest that next-generation influenza vaccines may be capable of recalling and eliciting Abs endowed with a cross-reactive and cross-neutralizing activity that will contribute to confer a broad immune response to circulating influenza virus variants, including pre-pandemic and pandemic strains. These results also demonstrate the potential of AI foundation models to enable more efficient prioritization of Ab candidates and open the door for the use of prediction models for de novo Ab in silico design.

Short Bio

Dr. Sautto obtained his Bachelor’s degree in Medical Biotechnology at the University of Milan (Italy) in 2006. He then received a Master’s Degree in Molecular and Cellular Medical Biotechnology in 2008, and a PhD in Molecular Medicine in 2012 at the Vita-Salute San Raffaele University of Milan.He gave also lectures on Microbiology and Virology to undergraduate and graduate students as adjunct professor. He joined as a visiting scientist the International Novartis BioCamp in Basel (Switzerland) in 2012, the Institut de Biologie Structurale in Grenoble (France) in 2013, the Institute of Virology of the Technical University of Munich (Germany) in 2014. In 2016 he moved to the US at the Center for Vaccines and Immunology of the University of Georgia, where he expanded is area of investigation to the development and characterization of next-generation vaccines. During this period at the University of Georgia, he also completed the MBA program of the Terry College of Business. Through the training funds he was awarded, he also had the opportunity to join as a visiting scientist the Vanderbilt University Medical Center and the University of Texas at Austin. His main expertise is focused on B cell immunology, antibody discovery and characterization, especially for infectious diseases-associated pathogens, including hypervariable viruses such as influenza virus, SARS-CoV-2, respiratory syncytial virus (RSV), human metapneumovirus (HMPV) and hepatitis C virus (HCV). This expertise is demonstrated by numerous awards and more than 70 peer-reviewed publications (Scopus H-index: 23). He is also editor and reviewer of several international scientific journals focused on virology and immunology.

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