Computational Identification of Antigen-Binding Antibody Fragments

Abstract Determining which parts of the Ab are essential for Ag recognition and binding is crucial for understanding B cell–mediated immunity. Identification of fragments of Abs that maintain specificity to the Ag will also allow for the development of improved Ab-based therapy and diagnostics. In this article, we show that structural analysis of Ab–Ag complexes reveals which fragments of the Ab may bind the Ag on their own. In particular, it is possible to predict whether a given CDR is likely to bind the Ag as a peptide by analyzing the energetic contribution of each CDR to Ag binding and by assessing to what extent the interaction between that CDR and the Ag depends on other CDRs. To demonstrate this, we analyzed five Ab–Ag complexes and predicted for each of them which of the CDRs may bind the Ag on its own as a peptide. We then show that these predictions are in agreement with our experimental analysis and with previously published experimental results. These findings promote our understanding of the modular nature of Ab–Ag interactions and lay the foundation for the rational design of active CDR-derived peptides.</jats:p

Computational fingerprinting of immune-mediated pressure on SARS-CoV-2 viral evolution reveals preliminary evidence for immune-evasion

Abstract The global emergence of SARS-CoV-2 variants and Omicron in particular, has highlighted the risk of novel variants that will evade adaptive immune responses following vaccination and natural infection. Determining which viral mutations escape T-cells and antibodies is crucial for designing therapeutics and vaccines and assessing the implications of newly emerging variants. We developed an automated immunoinformatic pipeline that considers both data on viral sequences and experimentally identified T-cell and antibody responses, to identify specific viral mutations that may be associated with immune escape. We used an unsupervised clustering method to cluster a set of 108 non-redundant anti-SARS-CoV-2 spike protein antibodies with solved 3D structures from the PDB database, and identified 9 unique antibody clusters. We computed the predicted changes in binding energies (ΔΔG) for each antibody and each specific mutation within its contact footprint. Using these ΔΔG scores, we computed an antibody escape score for each mutation. We also predicted the change in binding between predicted and experimentally verified T-cell epitopes and their presenting MHC molecules. We ranked frequent spike protein mutations based on their predicted effect on immune evasion, as well as individual SARS-CoV-2 variants, with a specific focus on VOCs. Our novel immune escape scores identified several key mutations in the Omicron variant, which were not present in previous VOCs, and may be used to identify key mutations that are likely associated with immune escape, which may appear in novel variants of concern. Supported by an NIH grant (75N93021C00016)</jats:p

Obesity is associated with an altered baseline and post-vaccination influenza antibody repertoire

AbstractAs highlighted by the ongoing COVID-19 pandemic, vaccination is critical for infectious disease prevention and control. Obesity is associated with increased morbidity and mortality from respiratory virus infections. While obese individuals respond to influenza vaccination, what is considered a seroprotective response may not fully protect the global obese population. In a cohort vaccinated with the 2010-2011 trivalent inactivated influenza vaccine, baseline immune history and vaccination responses were found to significantly differ in obese individuals compared to healthy controls, especially towards the 2009 pandemic strain of A/H1N1 influenza virus. Young, obese individuals displayed responses skewed towards linear peptides versus conformational antigens, suggesting aberrant obese immune response. Overall, these data have vital implications for the next generation of influenza vaccines, and towards the current SARS-CoV-2 vaccination campaign.One Sentence SummaryObese individuals have altered baseline and post-vaccination influenza antibody repertoires.</jats:sec