ORIZZONTI in Medicina e Biologia: The evolution of adaptive responses to respiratory pathogens in the context of repeated exposures and vaccinations

The Sant’Anna School resumes the "Orizzonti in Medicina e Biologia" series with a seminar titled “The evolution of adaptive responses to respiratory pathogens in the context of repeated exposures and vaccinations”, featuring Alessandro Sette, Professor of Immunology, La Jolla Institute for Immunology. 

The event will take place on April 14, 2026 (Aula Magna). 
Read the abstract and learn more about the speaker. 

Abstract 

To characterize the long-term effects of repeated COVID-19 vaccinations on adaptive immunity we conducted a three-year longitudinal study examining T cell and antibody responses in 68 vaccinated individuals without reported symptomatic infections. While antibody titers incrementally increased and stabilized with each booster, T cell responses rapidly plateaued, maintaining remarkable stability across CD4+ and CD8+ subsets. Approximately 30% of participants showed T cell reactivity to non-Spike antigens, consistent with asymptomatic infections. Single-cell RNA sequencing revealed no evidence of exhaustion or functional impairment. Individuals with evidence of asymptomatic infection had increased frequencies of Th17-like and regulatory CD4+ T cells, and GZMKhi/IFNR-like CD8+ T cell subsets. We recently expanded our analysis to vaccinated individuals experiencing symptomatic SARS-2 breakthrough infections. Parallel studies have investigated the antigen specificity and response phenotypes in the context of vaccination and infection, to a different respiratory pathogen, namely the bacterium Bordetella pertussis. The second part of the lecture will highlight differences and similarity between the two microbial respiratory pathogens. 

Bio 

Professor Alessandro Sette has devoted more than 40 years to understanding the basic mechanisms of antigen recognition and immune responses, measuring and predicting immune activity, and developing disease intervention strategies against cancer, infectious diseases, autoimmune diseases, and allergies. A recent focus of his work, of particular relevance to the present application, has been the definition of conserved T cell epitope regions (CTERs) across different viral families of potential pandemic concern, as a tool for pandemic preparedness and for the development of vaccines eliciting broadly cross-reactive T cell responses. Throughout his career, Professor Sette has been continuously involved in hundreds of T cell epitope identification studies spanning cancer, autoimmunity, allergy, and infectious diseases, applying this knowledge to understand immunity and immunopathology in specific disease systems. His group’s work on flaviviruses, and on DENV in particular, has resulted in 50 publications detailing T cell responses in the context of natural infection and vaccination. Beyond the most recent SARS-CoV-2 studies mentioned below, his research in infectious diseases has addressed a wide range of pathogens, including bacteria (Mycobacteria, Bordetella), chronic viral infections (HHV, HIV, HBV, HCV), and acute viral infections of pandemic relevance (poxviruses, arenaviruses, and others). His early work, from the mid-1980s to the mid-1990s, demonstrated that the primary biological function of MHC molecules is to bind epitopes. Building on these findings, he further developed the concept that different MHC molecules have distinct binding specificities that can be leveraged to predict epitopes. His group has defined motifs for over one hundred class I and class II MHC variants expressed in humans and several other species. Since 2003, Professor Sette has served as PI of the Immune Epitope Database and Analysis Resource, a freely accessible platform for the scientific community that hosts immune reactivity data and bioinformatics tools to predict and evaluate immune responses. Subsequent research characterized how MHC variants can be grouped according to broad functional specificities (MHC supertypes), greatly facilitating epitope classification and the understanding of epitope–MHC interactions. During the COVID-19 pandemic, his laboratory focused on SARS-CoV-2 adaptive immunity. His group was among the first to define successful adaptive responses to SARS-CoV-2 by studying mild convalescent cases and characterizing the durability of immune memory following natural infection and vaccination. They reported the presence of pre-existing immune memory in unexposed individuals and demonstrated its influence on vaccination outcomes. Furthermore, his team showed that T cell responses are largely preserved in their recognition of SARS-CoV-2 variants, including Omicron and Delta, and compared different vaccine platforms in terms of their ability to induce memory responses in both T cells and B cells.