478 Translation of a therapeutic neoantigen vaccine workflow to SARS-CoV-2 vaccine development

• Published in: Journal for immunotherapy of cancer 2020-11, Vol.8 (Suppl 3), p.A293-A295
• Main Authors: Smith, Christof, Entwistle, Sarah, Willis, Caryn, Vensko, Steven, Beck, Wolfgang, Garness, Jason, Sambade, Maria, Routh, Eric, Olsen, Kelly, Carpenter, Brandon, Gentry, Kaylee, Fadri, Maria, Fini, Misha, Washington, Amber, Kodysh, Julia, O’Donnell, Timothy, Haber, Carsten, Heiss, Kirsten, Stadler, Volker, Garrison, Erik, Grant, Oliver, Woods, Robert, Heise, Mark, Vincent, Benjamin, Rubinsteyn, Alexander
• Format: Article
• Language: English
• Subjects: Amino acids; Cancer research; COVID-19; Immunotherapy; Ligands; Localization; Lymphocytes; Medical research; Peptides; Population; Proteins; Severe acute respiratory syndrome coronavirus 2; Vaccines
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2020-SITC2020.0478

BackgroundThere is an urgent need for a vaccine with efficacy against SARS-CoV-2. We hypothesize that peptide vaccines containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation would drive both humoral and cellular immunity with high specificity, potentially avoiding undesired effects such as antibody-dependent enhancement (ADE) (figure 1). Leveraging methods initially developed for prediction of tumor-specific antigen targets, we combine computational prediction of T cell epitopes, recently published B cell epitope mapping studies, and epitope accessibility to select candidate peptide vaccines for SARS-CoV-2 (figure 2).MethodsSARS-CoV-2 HLA-I and HLA-II ligands were predicted using multiple MHC binding prediction software. T cell vaccine candidates were further refined by predicted immunogenicity, viral source protein abundance, sequence conservation, coverage of high frequency HLA alleles, and co-localization of CD4+/CD8+ T cell epitopes. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, filtering to select regions with surface accessibility, high sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. Using murine compatible T/B cell epitopes, vaccine studies were performed with downstream ELISA/ELISpot to monitor immunogenicity.ResultsWe observed distribution of HLA-I (n = 2486) and -II (n = 3138) ligands evenly across the SARS-CoV-2 proteome, with significant overlap between predicted human and murine ligands (figure 3). Applying a multivariable immunogenicity model trained from IEDB viral tetramer data (AUC 0.7 and 0.9 for HLA-I and -II, respectively), alongside filters for entropy and protein expression resulted in 292 CD8+ and 616 CD4+ epitopes (figure 4). From an initial pool of 58 B cell epitope candidates, three epitope regions were identified (figure 5). Combining B cell and T cell analyses, alongside manufacturability heuristic, we propose a set of SARS-CoV-2 vaccine peptides for use in subsequent murine studies and clinical trials (figure 6). Preliminary murine studies demonstrate evidence of T and B cell activation (figure 7).Abstract 478 Figure 1Summary of combination CD4+/CD8+ T cell and B cell SARS-CoV-2 peptide vaccine. Humoral immunity (blue dashed box) is targeted through B cell and HLA-II epitopes, aimed at viral neutralization while avoiding non-neutralizing and AD